ABCMdb

ABCG2 p.Val12Met

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PMID: 12479221 [PubMed] Imai Y et al: "C421A polymorphism in the human breast cancer resistance protein gene is associated with low expression of Q141K protein and low-level drug resistance."

No. Sentence Comment

5 BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (⌬315-6)] were identified. Login to comment
60 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were designated PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6 cells, respectively. Login to comment
83 G34A mutation that substitutes Met for Val-12 was found in MCF-7 cells. Login to comment
92 Western blotting of mutant BCRP-transfected PA317 cells demonstrated markedly low expression of Q141K BCRP in PA/Q141K cells compared with other BCRP-transfected cells. Login to comment
93 PA/WT, PA/V12M, and PA/⌬315-6 cells showed similar BCRP expression (Fig. 3A). Login to comment
96 In contrast, Northern blotting demonstrated similar levels of BCRP mRNA in PA/WT, PA/V12M, PA/ Q141K, and PA/⌬315-6 cells (Fig. 3B). Login to comment
104 Table 1 BCRP cDNA variants identified in this study Variant Amino acid change Cell line G34A Val-12 to Met MCF-7a C421A Gln-141 to Lys MDA-MB-231a A549a HCT-116a Deletion of 944-949 Deletion of Ala-315 and Thr-316 MCF-7 A549 HT-29 SK-OV-3 a Heterozygous allele. Login to comment
116 PA/WT and PA/V12M cells showed similar levels of resistance to the anticancer drugs (Table 2; Fig. 4A). Login to comment
125 In contrast, only a marginal shift occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells (Fig. 5). Login to comment
126 Increases of mean fluorescence channel number in PA/ WT, PA/V12M, and PA/⌬315-6 cells were 1.5-, 1.6-, and 1.5-fold in the presence of topotecan, respectively. Login to comment
137 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
145 Table 2 IC50 a (ng/ml) of BCRP-transfected PA317 cells PA317 PA/WT PA/V12M PA/Q141K PA/⌬315-6 SN-38 2.5 98 98 30 55 Mitoxantrone 0.060 0.58 0.63 0.25 0.42 Topotecan 17 Ͼ200 Ͼ200 100 190 a IC50s (drug dose causing 50% inhibition of cell growth) were determined from cell growth curves in each experiment. Login to comment
148 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
149 A, sensitivity to SN-38 (A-1), mitoxantrone (A-2), and topotecan (A-3) of PA317, PA/WT, PA/V12M, and PA/Q141K cells. Login to comment
151 F, PA317; E, PA/WT; ‚, PA/V12M; Ⅺ, PA/Q141K; ᭛, PA/⌬315-6. Login to comment
165 By Western blotting, BCRP expression in PA/Q141K cells was markedly lower than that in the other BCRP transfectants. Login to comment
166 Another transfection experiment of mutant BCRP cDNAs in KB-3-1 human epidermoid carcinoma cells also revealed markedly lower expression of Q141K BCRP compared with wild-type and V12M BCRP (data not shown). Login to comment
186 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
188 In parental PA317 cells, a fluorescence peak shift to the right after the incubation with topotecan indicates cellular uptake of topotecan, whereas only marginal shifts occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells. Login to comment
4 BCRP cDNA was isolated from 11 cancer cell lines and three variant cDNAs [G34A substituting Met for Val-12 (V12M), C421A substituting Lys for Gln-141 (Q141K), and 944-949 deletion lacking Ala-315 and Thr-316 (⌬315-6)] were identified. Login to comment
59 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were designated PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6 cells, respectively. Login to comment
82 G34A mutation that substitutes Met for Val-12 was found in MCF-7 cells. Login to comment
95 In contrast, Northern blotting demonstrated similar levels of BCRP mRNA in PA/WT, PA/V12M, PA/ Q141K, and PA/⌬315-6 cells (Fig. 3B). Login to comment
103 Table 1 BCRP cDNA variants identified in this study Variant Amino acid change Cell line G34A Val-12 to Met MCF-7a C421A Gln-141 to Lys MDA-MB-231a A549a HCT-116a Deletion of 944-949 Deletion of Ala-315 and Thr-316 MCF-7 A549 HT-29 SK-OV-3 a Heterozygous allele. Login to comment
115 PA/WT and PA/V12M cells showed similar levels of resistance to the anticancer drugs (Table 2; Fig. 4A). Login to comment
124 In contrast, only a marginal shift occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells (Fig. 5). Login to comment
136 PA317 cells transfected with wild-type, G34A, C421A, and 944-949-deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
144 Table 2 IC50 a (ng/ml) of BCRP-transfected PA317 cells PA317 PA/WT PA/V12M PA/Q141K PA/⌬315-6 SN-38 2.5 98 98 30 55 Mitoxantrone 0.060 0.58 0.63 0.25 0.42 Topotecan 17 Ͼ200 Ͼ200 100 190 a IC50s (drug dose causing 50% inhibition of cell growth) were determined from cell growth curves in each experiment. Login to comment
147 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
150 F, PA317; E, PA/WT; ‚, PA/V12M; Ⅺ, PA/Q141K; ᭛, PA/⌬315-6. Login to comment
185 PA317 cells transfected with wild-type, G34A, C421A, and 944-949- deleted BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K, and PA/⌬315-6, respectively. Login to comment
187 In parental PA317 cells, a fluorescence peak shift to the right after the incubation with topotecan indicates cellular uptake of topotecan, whereas only marginal shifts occurred in PA/WT, PA/V12M, and PA/⌬315-6 cells. Login to comment

PMID: 12544509 [PubMed] Zamber CP et al: "Natural allelic variants of breast cancer resistance protein (BCRP) and their relationship to BCRP expression in human intestine."

No. Sentence Comment

4 Of the missense mutations, exon 2 SNP (G34A) resulted in a V12M change; exon 5 SNP (C421A) resulted in a Q141K substitution; exon 6 SNP (A616C) resulted in an I206L amino acid substitution; and exon 15 SNP (A1768T) resulted in a N590Y change in the BCRP protein. Login to comment
92 Exon 2 A 34G.A transition results in a Val12 Met change (Fig. 1). Login to comment
119 Table 1 Frequencies of BCRP alleles in different ethnic groups Position in gene AC084732Ã Position in mRNA XM_032424Ã Sequence Region Caucasians African-Americans Japanese (n ¼ 20) Chinese (n ¼ 20) SE Asians (not Chinese or Japanese) (n ¼ 20) Pacific Islanders (n ¼ 14) À18398 À29 gctct(A/G)ttaag Exon 1 0.02 (1.5%)a 0 (0%)e ND ND ND ND 34 34 tccca(G/A)tgtca Exon 2 (V12M) 0.02 (4.7%)b 0.04 (8.3%)f 0.15 (30%) 0.20 (40%) 0.45 (70%) 0.64 (85.7%) 114 114 ttaag(T/C)tttca Exon 2 0.01 (1.2%)b 0 (0%)f 0 (0%) 0 (0%) 0 (0%) 0 (0%) 239 tttta (A/G)tttac Intron 2 0.03 (5.9%)c 0.05 (9.5%)g 0.15 (30%) 0.20 (40%) 0.45 (70%) 0.64 (85.7%) 8184 369 ggtta(C/T)gtggt Exon 4 0 (0%)a 0.07 (13.3%)e ND ND ND ND 8825 421 actta(C/A)agttc Exon 5 (Q141K) 0.14 (25.9%)d 0 (8%)f 0.35 (50%) 0.35 (60%) 0.15 (20%) 0.14 (28.6%) 18186 attat(A/G)atatt Intron 5 0 (0%)c 0 (8%)g 0 (0%) 0.05 (10%) 0 (0%) 0 (0%) 18286 616 cttcc(A/C)tcttg Exon 6 (I206L) 0 (0%)a 0 (8%)e 0 (0%) 0 (0%) 0 (0%) 0 (0%) 45073 1768 gacaa(A/T)acttc Exon 15 (N590Y) 0.01 (1.5%)a 0 (8%)e ND ND ND ND Position in gene AC084732Ã Position in mRNA XM_032424Ã Sequence Region Mexican-Indians (n ¼ 10) Mexicans (n ¼ 20) Hispanic Livers (n ¼ 10) Middle Eastern (n ¼ 40) Ashkenazi Jewish (n ¼ 20) Africans North of Sahara (n ¼ 14) À18398 À29 gctct(A/G)ttaag Exon 1 ND ND ND ND ND ND 34 34 tccca(G/A)tgtca Exon 2 (V12M) 0.90 (100%) 0.10 (20%) 0.40 (60%) 0.05 (10%) 0.10 (20%) 0.14 (14.3%) 114 114 ttaag(T/C)tttca Exon 2 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 239 tttta(A/G)tttac Intron 2 0.90 (100%) 0.10 (20%) 0.40 (60%) 0.05 (10%) 0.10 (20%) 0.14 (14.3%) 8184 369 ggtta(C/T)gtggt Exon 4 ND ND ND ND ND ND 8825 421 actta(C/A)agttc Exon 5 (Q141K) 0.10 (20%) 0.05 (10%) 0.10 (20%) 0.13 (25%) 0.05 (10%) 0 (0%) 18186 attat(A/G)atatt Intron 5 0 (0%) 0.10 (20%) 0 (0%) 0 (0%) 0.05 (10%) 0.07 (14.3%) 18286 616 cttcc(A/C)tcttg Exon 6 (I206L) 0 (0%) 0 (0%) 0.10 (20%) 0 (0%) 0 (0%) 0 (0%) 45073 1768 gacaa(A/T)acttc Exon 15 (N590Y) ND ND ND ND ND ND Data reported as: allele frequency (% individuals with at least one variant allele). Login to comment
125 Unauthorized reproduction of this article is prohibited. G34A V12M Exon 2 C71T1 A24V Exon 2 623C1 F208S Exon 6 A616C I206L Exon 6 C496G1 Q166E Exon 5 C421A Q141K Exon 5 A1444G2 R482G Exon 12 G1445C3 R482T Exon 12 A1768T N590Y Exon 15 Walker A motif: amino acids 80-89 Walker B motif: amino acids 206-210 SNPs found in human samples in this study Reported in ABCP1 Drug selected variants, MXR2 and BCRP3 MXR BCRP Fig. 1 BCRP protein topology and the positions of the identified SNPs resulting in missense mutations. Login to comment
173 The Val12 Met and the Gln141 Lys were the most frequent allelic variants. Login to comment
174 The Val12 Met was linked to an intron 2 A239G SNP in all populations. Login to comment
175 Marked population variation in the frequency of the BCRP Val12 Met SNP was found from as high as 100% in the Mexican-Indian population with at least one variant allele to as low as 4.7% in the Caucasian population. Login to comment

PMID: 12642696 [PubMed] Honjo Y et al: "Single-nucleotide polymorphism (SNP) analysis in the ABC half-transporter ABCG2 (MXR/BCRP/ABCP1)."

No. Sentence Comment

6 Nonsynonymous SNPs at nucleotide 238 (V12M; exon 2) and nucleotide 625 (Q141K; exon 5) showed a greater frequency of heterozygosity (22.2% and 10%) than the SNP at 2062 (D620N; exon 16). Login to comment
104 Amplification in the MCF-7 SINGLE-NUCLEOTIDE POLYMORPHISM (SNP) ANALYSIS IN THE ABC HALF-TRANSPORTER ABCG2 (MXR/BCRP/ABCP1) www.landesbioscience.com Cancer Biology & Therapy 699 Table 2 PRIMERS USED IN SEQUENCING 90 DNA SAMPLES Forward Primer (5`-> 3`) Reverse Primer (5`-> 3`) Exon 1 TGCCCACTCAAAAGGTTC CCAACCCACACTTAACACAC Exon 2 TGTCACCTAGTGTTTGCAATC GCCAGTTTCTTGGAAATAGCC Exon 3 AATCCTGCTTTGGTCTCC TCTCCCATTCTTTTTCCTC Exon 4 AGCATGTGTTGGAGGGAAAA ATCAGCCAAAGCACTTACCC Exon 5 GCAGGCTTTGCAGACATCTA TGCTGATCATGATGCTTTCA Exon 6 TCTTACAGGACTGGCACACG CCCCAAGAATATCTGGGACA Exon 7 TCAGGCTGAACTAGAGCAAACA CAAACAGCACTCCTGCAGAC Exon 8 CATGGGAAGAAGAGAGAAAG GTTGACTGGTATCAGAAGAC Exon 9 ACTCCTGACCTCGTAATCC GAAGCAGATGATAACAGAACC Exon 10 TCTAATTGAAACTCTTCCCC AGTTCGAAGCCAGTCTAGC Exon 11 TGAGTTGACTGCGGTGATTT GTAATCCTCCGGATCCCATC Exon 12 GTCTAGCCCTGAGGATGTGG TGCAAAATGGACAGGTGTTT Exon 13 CAGACACAACATTGGAGAC TAAGGGCAAAGAGGAAAG Exon 14 CTGCATGAAATTACTCAAGC CCATCCTCTCATTTACTTCC Exon 15 AAACTGTTTACCTTGCCC GCACCTCACTTCAATCTC Exon 16 GAGTAACATTTGACGGATG CTCTACTCTACCCACAGTTC Table 3 RESULTS OF SNP ANALYSIS OF 16 EXONS ENCODING ABCG2* Wild-type Frequency Frequency Frequency Amino Acid Exon Nucleotide+ allele SNP Wt/Wt Wt/Var Var/Var aa# 1 91 C T 98.9% 1.1% Noncoding 175 A G 97.8% 2.2% Noncoding 2 238 G A 76.7% 22.2% 1.1% 12 Val to Met 5 625 C A 88.9% 10% 1.1% 141 Gln to Lys 9 1302 G A 97.8% 2.2% 366 Glu to Glu 12 1629 A G 98.9% 1.1% 475 Leu to Leu 16 2062 G A 98.9% 1.1% 620 Asp to Asn 2597 C A 98.9% 1.1% Noncoding Intronic Variants 2 +36** A G 76.7% 22.2% 1.1% 6 -16 A G 88.9% 8.9% 2.2% 7 -20 T A 98.9% 1.1% +18 A G 93.3% 5.6% 1.1% 11 +20 A G 63.3% 27.8% 8.9% 12 +49 G T 75.6% 22.2% 2.2% 14 -21 C T 67.8% 28.9% 3.3% *Identified SNPs are recorded in the table with all 16 exons sequenced in 90 DNA samples. Login to comment

PMID: 12694888 [PubMed] Backstrom G et al: "Genetic variation in the ATP-binding cassette transporter gene ABCG2 (BCRP) in a Swedish population."

No. Sentence Comment

62 Because To determine allele frequencies for the sequence varia- of the highly repetitive sequences surrounding exon 10, Table 2 Sequence variation in the human ABCG2 gene identified in the present study Sequence variant Nucleotide sequence (59 to 39) Affected Effect Identity to a ID DHPLC dbSNP b c Reference sequence Alteration pools g.-19572-19569 actcaCTCAcaaag actca caaag 15 59 Flanking deletion ss 4480605 ]] ]]]]d delCTCA g.-19202G.C gtactGatcag gtactCatcag 5 CpG island SNP rs 2231134 ] ] g.-18845T.C tgagcTcgtcc tgagcCcgtcc 8 59 UTR SNP rs 2231135 ] ] g.-18604delA cggcaAggagg cggca ggagg 1 59 UTR deletion ss 4480606 ] ]d g.34G.A tcccaGtgtca tcccaAtgtca 2 Missense SNP rs 2231137 ] ] Val12Met g.8007G.A ttggaGggaaa ttggaAggaaa 3 Intronic SNP ss 4480607 ] ]d g.8825C.A acttaCagttc acttaAagttc 4 Missense SNP rs 2231142 ] ] Gln141Lys d g.44997G.A ttcttAaaatt ttcttGaaatt 9 Intronic SNP rs 2231164 ] ] a Sequence variant ID in accordance with the nomenclature for sequence variation described at http://www.dmd.nl/mutnomen.html. Login to comment
80 The SNPs g.-19202G.C and g.34G.A (Val12Met) the CCAAT-box, a G/C single nucleotide polymorphism were less common, with frequencies of 0.05 and 0.02, (SNP), g.-19202G.C, was observed. Login to comment

PMID: 14576842 [PubMed] Doyle LA et al: "Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2)."

No. Sentence Comment

127 Allelic variation as a result of SNPs results in alterations of the BCRP protein at amino acids 12 (V12M), 141 (Q141K), 206 (I206L), and 590 (N590Y), with the most frequent polymorphisms being the exon 2 SNP (G34A) and the exon 5 SNP (C421A), which produce changes in amino acids 12 and 141 (Honjo et al., 2002; Imai et al., 2002a; Zamber et al., 2003). Login to comment

PMID: 14750175 [PubMed] Mizuarai S et al: "Single nucleotide polymorphisms result in impaired membrane localization and reduced atpase activity in multidrug transporter ABCG2."

No. Sentence Comment

2 In this study, we analyzed the effects of polymorphisms in ABCG2, V12M and Q141K on transporter function. Login to comment
3 When polarized LLC-PK1 cells were transfected with variant ABCG2, drug-resistance to topoisomerase I inhibitor of cells expressing V12M or Q141K was less than 1/10 that of wild-type ABCG2 transfected cells, and was accompanied by increased drug accumulation and decreased drug efflux in the variant ABCG2-expressing cells. Login to comment
5 Confocal microscopic analysis revealed that apical plasma membrane localization of V12M was disturbed, while the localization of wild-type transporters occurred specifically in the apical plasma membrane of polarized LLC-PK1 cells. Login to comment
15 Homozygous CC patients expressed lower P-gp in the intestine compared to TT patients, resulting in increased digoxin plasma concentration after orally administered digoxin.21 Another report showed that a naturally occurring mutation of R433S in MRP1 caused increased organic anion transport and decreased doxorubicin resistance.22 Several groups have reported naturally occurring ABCG2 SNPs in various ethnic populations, including Caucasian, Asian and African.23-27 In those reports, polymorphisms at V12M and Q141K occurred at high frequency in most of the ethnic populations. Login to comment
21 The previously reported polymorphisms,V12M and Q141K, had high frequencies of 10.3% and 9.0%, respectively. Login to comment
22 Drug resistance to the ABCG2 substrate, indolocarbazole topoisomerase I inhibitor, was reduced more than 10-fold in polarized cells that expressed variant ABCG2 with either V12M or Q141K compared Abbreviations: ABC, ATP-binding cassette; ABCP1, placenta-specific ABC transporter; BCRP, breast cancer-resistant protein; GFP, green fluorescent protein; in; HRP, horse radish peroxidase; MDR, multidrug resistance protein; MRP, multidrug resistance-associated prote; MXR, mitoxantrone resistance protein; P-gp, P-glycoprotein; PVDF, polyvinylidene difluoride; Sf9 cells, Spodoptera frugiperda ovarian cells; SNPs, single nucleotide polymorphisms. Login to comment
28 We concluded that the functional impairment of these 2 variants were due to disturbance of apical plasma membrane localization for V12M and reduced ATPase activity for Q141K, indicating ABCG2 gene SNPs may greatly influence resistance to ABCG2 substrate. Login to comment
43 Establishment of LLC-PK1 cells expressing wild-type and mutant ABCG2 Wild-type ABCG2 and mutated ABCG2 genes (G34A for V12M and C421A for Q141K), the point mutations of which were introduced by PCR mutagenesis, were cloned into HindIII and XhoI sites of pcDNA3.1(ϩ) (Invitrogen). Login to comment
61 Drug efflux assay LLC-PK1 cells were incubated with the indicated concentration of indolocarbazole compound for 120 min under energy-depleted TABLE I - SINGLE NUCLEOTIDE POLYMORPHISMS IN ABCG21 SNP Effect Region Domain Frequency in 30 cell lines Frequency in 150 clinical samples Hetero Home Hetero Homo Allele (%) G34A V12M Exon2 N-terminal 5 (16.7%) 0 27 (18.0%) 2 (1.3%) 10.3 Aϩ10G Intron3 ND ND 21 (14.0%) 4 (2.7%) 9.7 C369T Wobble Exon4 ABC 0 0 1 (0.67%) 0 0.3 C376T Q126Term Exon4 ABC 0 1 (3.3%) 0 0 0.0 C421A Q141K Exon5 ABC 5 (16.7%) 1 (3.3%) 22 (15.3%) 2 (1.3%) 9.0 C458T T153M Exon5 ABC 1 (3.3%) 0 0 0 0.0 C474T Wobble Exon5 ABC 0 0 1 (0.67%) 0 0.3 Aϩ20G Intron11 ND ND 34 (22.7%) 10 (6.7%) 18.0 A1444G R482G Exon12 TM3 0 0 0 0 0.0 G1445C R482T Exon12 TM3 0 0 0 0 0.0 C-21T Intron13 ND ND 32 (21.3%) 4 (2.7%) 13.3 A1768T N590Y Exon15 EC3 0 0 1 (0.67%) 0 0.3 G2237T Exon16 3ЈUTR 1 (3.3%) 0 0 0 0.0 G2393T Exon16 3ЈUTR 1 (3.3%) 0 0 0 0.0 The positions of the polymorphisms correspond to that of the ABCG2 cDNA (GenBank accession number AB051855) with the first base of the ATG start codon set to 1. Login to comment
89 Samples of 7 ␮g RNA extracted from HeLa, control C4, WT, V12M and Q141K cells (lanes 1, 2, 3, 4 and 5 respectively) were subjected to Northern hybridization and the blots were probed with a cDNA fragment of ABCG2. Login to comment
92 Vector transformant C4 (a) and stable clones expressing wild-type (b), V12M (c) and Q141K (d) were stained with monoclonal antibody BXP-34. Login to comment
102 Two polymorphisms, V12M and Q141K, had high frequency rates of 10.3% and 9.0%, respectively, in the 150 Caucasian subjects. Login to comment
103 V12M was located at the N-terminal intracellular region and Q141K at the ATP-binding cassette region. Login to comment
108 LLC-PK1 cells expressing WT, V12M and Q141K were incubated with opti-MEM with 50 ␮M (A) or 0.5 ␮M (B) of radiolabeled topoisomerase inhibitor for 180 min. Login to comment
119 TABLE II - RESISTANT PROFILE (IC50) OF ABCG2 TO ANTI-CANCER COMPOUNDS Anti-cancer compound IC50 (␮M)1 Control C4 Wild type V12M Q141K TopoI inhibitor2 0.12 Ͼ50 (420) 0.94 (7.8) 5.9 (49) Mitoxantrone 0.0015 0.029 (19) 0.00093 (0.62) 0.0053 (3.5) Topotecan 0.098 2.1 (22) 0.16 (1.7) 0.48 (4.9) Doxorubicin 0.010 0.039 (3.9) 0.0073 (0.73) 0.014 (1.4) Vincristine 0.0034 0.0053 (1.6) 0.0021 (0.62) 0.0058 (1.7) Camptothecin 0.0087 0.021 (2.4) 0.012 (1.4) 0.027 (3.1) 1 Relative resistances to control cells are described in parentheses.-2 TopoI inhibitor, Indolocarbazole topoisomerase I inhibitor. Login to comment
120 Resistance profile of variant ABCG2 transporters to anticancer compounds Among the polymorphisms detected, V12M and Q141K had a high frequency of amino acid substitutions. Login to comment
123 Northern blotting and immunocytochemical analysis with a monoclonal antibody revealed that approximately equal levels of ABCG2 were expressed in V12M and Q141K clones compared to the expression in the wild-type (WT) clone (Fig. 1). Login to comment
125 Wild-type cells conferred greater than 420-fold higher resistance to an indolocarbazole I topoisomerase inhibitor compared to that of control C4 cells as previously reported.10 In contrast, IC50 values of variant ABCG2 clones, V12M and Q141K, were less than 1/10 that of WT cells. Login to comment
127 The IC50 values of WT cells to mitoxantrone and topotecan increased 19- and 22-fold, respectively, over C4 cells, whereas in the variant V12M and Q141K cells, IC50 values to mitoxantrone and topotecan decreased as observed with the indolocarbazole compound. Login to comment
130 Accumulation and efflux assay of topoisomerase I inhibitor in ABCG2 variant-expressing cells Increased sensitivities of V12M and Q141K cells are thought to arise from changes in the intracellular drug concentration of topoisomerase I inhibitor. Login to comment
134 However, significantly higher indolocarbazole topoisomerase I inhibitor accumulation was observed in both V12M and Q141K cells compared to that in WT cells (2.7and 1.8-fold higher, respectively). Login to comment
135 A drug accumulation assay performed at a low dose (0.5 ␮M) of the compound confirmed that compound accumulations increased in variant cell lines (3.1and 2.8-fold increase for V12M and Q141K, respectively). Login to comment
141 Compared to WT cells, Vmax of V12M and Q141K cells decreased 2.5-and 1.8-fold, respectively, indicating that the increased drug accumulation and consequent reduction in drug resistance were due to the decreased efflux velocity. Login to comment
145 Vmax values of V12M and Q141K decreased 2.2- and 1.7-fold, respectively, which agrees well with the results of drug efflux assays using cell lines. Login to comment
146 Subcellular localization of wild-type and variant ABCG2 Experimental data described above indicate that the V12M polymorphism impaired function of the transporter, leading to increased drug accumulation and subsequent decreased drug resistance to anticancer compounds. Login to comment
152 In the V12M clone, however, ABCG2 staining was not specifically localized to the apical membrane and showed sparse staining in all basolateral, apical and cytosolic stains (Fig. 3c). Login to comment
154 These data indicate that the polymorphism at V12M impairs the specific apical membrane localization of this transporter. Login to comment
163 (A) Control C4 cells; (B) and E, WT cells; (C,F), V12M cells; (D,G), Q141K cells. Login to comment
164 Impairment of ABCG2 localization in V12M also was confirmed by double staining of cells with ABCG2 and F-actin (Fig. 3E-G). Login to comment
168 In V12M cells, specific apical localization was disturbed, and the staining of cytosolic and other membrane regions was observed (Fig. 3F). Login to comment
169 To further confirm disturbed membrane localization of ABCG2 in V12M stable cell lines, cells co-stained with E-cadherin (localized to the lateral-membrane) also were analyzed with confocal microscopy. Login to comment
170 The expected pattern of apical staining with anti-ABCG2 antibody was observed in wild-type and Q141K variant expressing cell lines, whereas dispersed staining was confirmed in V12M cells (data not shown). Login to comment
171 Presence of substrate did not restore the localization of V12M variant (data not shown). Login to comment
178 In the case of V12M, no significant difference in ATPase activity was observed. Login to comment
182 We concluded that Q141K and V12M polymorphisms did not restore drug stimulation, which was observed in R482 mutant. Login to comment
185 Unexpectedly, the Km value of Q141K also increased 1.4-fold compared to that of WT (0.64 mM; WT, 0.64 mM; V12M, 0.91 mM; Q141K). Login to comment
186 In the V12M membrane, the ATPase activity increased in almost same manner as in the WT membrane. Login to comment
187 No significant difference in either Vmax or Km between WT and V12M membranes was found, indicating that V12M does not affect any changes in ATPase activity. Login to comment
188 DISCUSSION In our study, we confirmed the locations and frequencies of SNPs in ABCG2 using 30 cancer cell lines and 150 Caucasian clinical samples, and then characterized the functional effects of the major SNPs, V12M and Q141K (Fig. 5). Login to comment
192 Membrane fractions isolated from Sf9 cells expressing wild-type, V12M and Q141K ABCG2 transporters were subjected to Western blotting with BXP-21 monoclonal antibody. Login to comment
203 the impaired function of ABCG2, membrane localization of transporter for V12M and ATPase activity for Q141K. Login to comment
204 The polymorphism at V12M impaired apical membrane localization of ABCG2 in polarized LLC-PK1 cells. Login to comment
208 Our observation of the deficiency of apical membrane localization of V12M implies that the N-terminal intracellular region may be critical for apical membrane localization of ABCG2 protein. Login to comment
209 It would be interesting to study the effect of V12M on vectorial transport because the transporters are expressed in polarized LLC-PK1 cells. Login to comment
221 Since V12M affected apical membrane localization of ABCG2, the variant V12M could have a more significant effect on polarized LLC-PK1 FIGURE 4 - CONTINUED. Login to comment
224 Three identified variants, which affect transporter function, were designated as V12M (1), Q126Term (2) and Q141K (3). Login to comment

PMID: 14754410 [PubMed] Han B et al: "Multidrug resistance in cancer chemotherapy and xenobiotic protection mediated by the half ATP-binding cassette transporter ABCG2."

No. Sentence Comment

108 Nonsynonymous SNPs at nucleotide 238 (Val12 Met; exon 2) and nucleotide 625 (Gln141 Lys; exon 5) showed a greater frequency of heterozygosity (22.2% and 10%, respectively) than the SNP at 2062 (Asp620 Asn; exon 16). Login to comment
113 Two non-synonymous SNPs, Val12 Met and Gln141 Lys, were also identified, which are consistent with the study by Honjo et al. [25]. Login to comment

PMID: 15160935 [PubMed] Plasschaert SL et al: "Breast cancer resistance protein (BCRP) in acute leukemia."

No. Sentence Comment

80 Another polymorphism was the G34A, which causes the substitution of valine for methionine at amino acid position 12. Login to comment

PMID: 15165903 [PubMed] Sarkadi B et al: "ABCG2 -- a transporter for all seasons."

No. Sentence Comment

127 These SNPs yield ABCG2 variants containing V12M and Q141K. Login to comment

PMID: 15475413 [PubMed] Kobayashi D et al: "Functional assessment of ABCG2 (BCRP) gene polymorphisms to protein expression in human placenta."

No. Sentence Comment

3 In placentas, G34A (Val12 Met) and C421A (Gln141 Lys) were frequently observed (18-36%), but C376T, which creates a stop codon (Gln126 stop codon), was found with an allelic frequency of 1%. Login to comment
110 Of these, five SNPs resulted in the following amino acid substitutions: G34A (Val12Met), C376T (Gln126stop), C421A (Gln141Lys), G1322A (Ser441Asn), and T1465C (Phe489Leu). Login to comment
112 C376T, which is associated with an amino acid substitution from Gln to a stop codon at codon 126 (Gln126stop), was detected in only two placental samples (1.0%) as TABLE 1 Genetic polymorphism in the BCRP gene in Japanese placentas (n ϭ 100) Location Positiona Reference Alleleb Variant Allele Amino Acid Substitution Genotype Frequency of Variant Allele R/R R/V V/V 5Ј-Flanking region -20445 gtctCctcc gtctTctcc 98 2 0 0.010 -20296 agctAttaa agctGttaa 80 18 2 0.110 -19781 aaaaAttat aaaaGttat 99 1 0 -19572_-19569 ctcaCTCAcaaa ctca--caaa 60 33 7 0.235 Exon 2 34 cccaGtgtc cccaAtgtc Val12Met 70 24 6 0.180 Intron 2 203 ϩ 16 tttaAttta tttaGttta 70 24 6 0.180 Intron 3 263 ϩ 10 tataAgaga tataGgaga 85 14 1 0.080 263 ϩ 72 ttttGtgtg ttttTGtgtg 99 1 0 0.005 Exon 4 376 ggtaCaagt ggtaTaagt Gln126stop 98 2 0 0.010 Exon 5 421 cttaCagtt cttaAagtt Gln141Lys 42 45 13 0.355 Intron 5 532-16 ttatAatat ttatGatat 99 1 0 0.005 Exon 9 1098 aggaGatca aggaAatca Synonymous 98 2 0 0.010 Intron 10 1277 ϩ 95 atagTgtaa atagAgtaa 97 3 0 0.015 Exon 11 1322 agcaGtgtt agcaAtgtt Ser441Asn 99 1 0 0.005 Intron 11 1367 ϩ 20 ttctAggaa ttctGggaa 71 25 4 0.165 Exon 12 1465 tataTttac tataCttac Phe489Leu 99 1 0 0.005 Intron 12 1492 ϩ 49 ctatGggtg ctatCggtg 44 45 11 0.335 Exon 13 1515 atgcCttct atgc-ttct Phe506Ser 99 1 0 0.005 Phe507Leu Val508Leu Met509stop Intron 13 1648-42 tgaaAttac tgaaTttac 99 1 0 0.005 1648-21 gactCttag gactTttag 71 25 4 0.165 Intron 14 1738-46 tcttAaaat tcttGaaat 24 52 24 0.500 3Ј-UTR 2332 cttcAgtct cttcTAgtct 86 14 0 0.070 2364 tgccAttat tgccCttat 99 1 0 0.005 2512 agaaCttac agaaTttac 99 1 0 0.005 R, reference allele; V, variant allele. Login to comment
148 SNP Amino Acid Change Population Genotypes Frequency of Variant Allele R/R R/V V/V G34A Val12Met Japanese (n ϭ 120) 81 37 2 0.17 (0.12-0.22) Caucasian (n ϭ 150) 139 11 0 0.04 (0.02-0.06) African American (n ϭ 150) 132 17 1 0.06 (0.04-0.09) C376T Gln126stop Japanese (n ϭ 120) 118 2 0 0.01 (0.00-0.02) Caucasian (n ϭ 150) 150 0 0 0.00 African American (n ϭ 150) 150 0 0 0.00 C421A Gln141Lys Japanese (n ϭ 120) 61 45 14 0.30 (0.25-0.36) Caucasian (n ϭ 150) 121 25 4 0.11 (0.08-0.15) African American (n ϭ 150) 144 5 1 0.02 (0.01-0.04) R, reference allele; V, variant allele. Login to comment
169 Among the nonsynonymous polymorphisms, G34A (Val12Met) and C421A (Gln141Lys) appeared commonly in Japanese subjects, and allelic frequencies of these polymorphisms were in keeping with those of a previous report (Imai et al., 2002). Login to comment

PMID: 15553238 [PubMed] Kondo C et al: "Functional analysis of SNPs variants of BCRP/ABCG2."

No. Sentence Comment

3 The cellular localization was identified using the wild type and seven different SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP) after transfection of their cDNAs in plasmid vector to LLC-PK1 cells. Login to comment
8 Furthermore, the transport activity of E1S, DHEAS, MTX, and PAH normalized by the expression level of BCRP protein was almost the same for the wild type, V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP. Login to comment
26 On analyzing the specimens from the 100 Japanese volunteers, 7 kinds of SNPs were identified for the BCRP gene: G34A (V12M), C376T (Q376Stop), C421A (Q141K), G1098A (E366E), G1322A (S441N), T1465C (F489L), and C1515- (AFFVM505-509ASSL Stop). Login to comment
27 The allele frequencies of these SNPs are 18, 1, 36, 1, 0.5, 0.5, and 0.5%, respectively. In the 84 cell lines, 7 kinds of SNPs were identified and their frequency for G34A (V12M), C376T (Q126Stop), C421A (Q141K), G445C (A149P), G488A (R163K), C805T (P269S), and G1098A (E366E) are 22, 3, 29, 1, 0.6, 0.6 and 2%, respectively. Login to comment
29 We constructed expression systems for the wild type and SNPs variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, S441N BCRP) and examined whether these SNPs variants of BCRP alter its localization, expression level, and transport activity. Login to comment
42 Using site-directed mutagenesis, SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S and S441N BCRP) were constructed on pcDNA3.1 vector (SNPs type BCRP/pcDNA3.1). Login to comment
43 V12M BCRP was amplified with 5Ј- GTCGAAGTTTTTATCCCAATGTCACAAGGAAA- CACCAATGGC-3Ј and `-GCCATTGGTGTTTCCTTGT- GACATTGGGATAAAAACTTCGAC-3Ј. Login to comment
52 For SNPs type BCRPs, viruses were prepared in the same way, resulting in the production of pAd-SNPs BCRP (pAd-V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP). Login to comment
110 Except for two SNP variants of BCRP (Q141K and S441N BCRP), the ATP-dependent uptakes per mg membrane protein of SNP variants (V12M, A149P, R163K, Q166E, P269S BCRP) were similar to that of the wild-type BCRP (Fig. 3a). Login to comment
114 As shown in Fig. 3b, the transport activity of other SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP) was almost identical to that of the wild-type BCRP. Login to comment
115 As far as V12M and Q141K BCRP were concerned, these have a high allele frequency in Japanese and we determined the kinetic parameters for the transport of [3 H]E1S. Login to comment
116 As shown in Fig. 4, the ATP-dependent uptake of [3 H]E1S was saturable, and the Km values were 11.6 ± 4.79, 9.07 ± 1.52, and 14.0 ± 7.27 ␮M, and the Vmax values were 13.3 ± 3.3, 13.5 ± 1.29, and 4.57 ± 1.58 nmol min-1 mg-1 protein, for the wild type, V12M, and Q141K BCRP, respectively. In addition to [3 H]E1S, the transport of other BCRP substrates was examined. Login to comment
120 Figure 5a shows the ATP-dependent uptake of DHEAS, PAH, and MTX per mg membrane protein for the wild-type and SNPs BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP). Login to comment
155 Concerning the cellular localization of SNPs variants of BCrP, Mizuarai et al. reported the intracellular localization of V12M BCRP in stably transfected LLC-PK1 cells very recently (23). Login to comment
156 The finding by Mizuarai et al. (23) was in marked contrast to the present finding that V12M BCRP is expressed on the apical membrane of transiently transfected LLC-PK1 cells (Fig. 1). Login to comment
158 It is possible that the cellular localization of V12M BCRP is affected by the culture conditions of LLC-PK1 cells. Login to comment
162 For these compounds, our results indicated that the transport activity per BCRP molecule for 6 kinds of SNP variants (V12M, A149P, R163K, Q166E, P269S, and also Q141K BCRP) is almost the same as that of the wild type BCRP (Figs. Login to comment
173 Saturation of [3 H]E1S transport was determined for the wild-type, V12M, and Q141K BCRP. Login to comment
180 Furthermore, the Km values for E1S were similar between the wild type, V12M and Q141K BCRP (Fig. 4). Login to comment

PMID: 15598215 [PubMed] Wang H et al: "Linkage disequilibrium and haplotype architecture for two ABC transporter genes (ABCC1 and ABCG2) in Chinese population: implications for pharmacogenomic association studies."

No. Sentence Comment

57 SNP Nucleotide sequence Minor allele dbSNP ID effect position (major/minor) frequency (%) ABCC1 1 5`FR/-1862 gacccG/Aggcca 44.4 2 5`FR/-1830 atcctA/Gtctac 1.9 3 5`FR/-1680 gaggaG/Aaaaag 1.9 4 5`FR/-471 cggatA/Gctgtc 7.4 5 E2/218 caaaaC/Tcaaaa 3.7 Thr73Ile 6 I2/-26 gttgtG/Aggggg 1.9 rs8187842 7 I3/-66 ctgggT/Cgacaa 37.0 rs4148337 8 I7/+54 ccactC/Actgtg 9.3 rs903880 9 I7/+64 ggcctC/Gaatcc 48.1 rs246232 10 E8/816 cagccG/Agtgaa 1.9 wobble 11 E8/825 aaggtT/Cgtgta 38.9 rs246221 wobble 12 E9/1062 gtgaaT/Cgacac 35.2 rs35587 wobble 13 I9/+8 aggggA/Gcgctg 37.0 rs35588 14 I12/-37 cactcA/Ggggca 20.4 rs35604 15 E13/1684 tggccT/Ctgtgc 20.4 rs35605 wobble 16 I13/+105 ccggtC/Tgggct 20.4 rs35606 17 I14/+105 ccagcC/Tgcttg 1.9 18 I15/+627 gctgtA/Gtttta 25.8 rs35628 19 I15/+669 aatctG/Ttagaa 7.4* rs4148353 20 I15/-967 ctttcT/Ggctgt 37.0 rs152029 21 E16/2007 atcccC/Tgaagg 3.7 rs2301666 wobble 22 E17/2168 tctccG/Aagaaa 5.6 rs4148356 Arg723Gln 23 I18/-30 gcactG/Cacgtg 16.7 rs2074087 24 I22/+62 aattaT/Ctccct 27.8 rs3887893 25 I22/-43 gtcagC/Ttccct 3.7 26 E27/3915 gaggaC/Tctgga 1.9 wobble 27 E28/4002 aagtcG/Atccct 11.1 rs2239330 wobble 28 I28/-35 tcagcA/Gtgaca 27.8 rs212087 29 I30/+30 gcacaG/Atggcc 29.6 rs212088 30 3`UTR/+801 accccC/Gactcc 33.3 rs129081 noncoding 31 3`UTR/+866 tactgT/Atccca 14.8 rs212090 noncoding 32 3`FR/+1513 gttctT/Ctaagg 27.8 ABCG2 1 5`UTR/-407 cgcagC/Tgcctc 1.9 2 5`UTR/-376 ggggaG/Acgctc 1.9 3 E2/34 tcccaG/Atgtca 20.4 rs2231137 Val12Met 4 I2/+36 ttttaA/Gtttac 25.9 rs4148152 5 I3/+10 gtataA/Ggagag 20.4 rs2231138 6 E5/421 acttaC/Agttct 22.2 rs2231142 Gln141Lys 7 E7/805 acgggC/Tctgct 3.7 Pro269Ser 8 I9/-126 agccaT/Gtgagt 7.4 9 I11/+20 gttctA/Gggaac 31.5 rs2231153 10 I12/+49 cctatG/Tggtga 16.7 rs2231156 11 I13/+40 tgtttT/Ctttcc 24.1 rs2231157 12 I13/-21 tgactC/Tttagt 29.6 rs2231162 13 I14/-46 ttcttG/Aaaatt 48.1 rs2725267 SNPs in specific regions, i.e. 5`flanking region (5`FR), 5`untranslated region (5`UTR), intron (I), exon (E), 3`UTR, and 3`FR, are presented as region/+(-): for 5`FR and 5`UTR, n nucleotides upstream (-) from the translation initiation site; for 3`UTR and 3`FR, n nt downstream (+) from the third base of stop codon; for coding regions, n corresponds to positions of their cDNA with the first base of start codon set to 1; and for introns, n nt upstream (-) from 3` site or downstream (+) from 5` site of introns. Login to comment

PMID: 15618737 [PubMed] Itoda M et al: "Eight novel single nucleotide polymorphisms in ABCG2/BCRP in Japanese cancer patients administered irinotacan."

No. Sentence Comment

46 Information on ABCG2WBCRP single nucleotide polymorphisms (SNPs) has been published.8-10) Five naturally occurring nonsynonymous SNPs have been reported in Japanese and Caucasians: V12M, Q126Stop, Q141K, I206L, and N590Y.8-10) SNP Q126Stop was found in 3 out of 124 healthy Japanese subjects.9) Since it may be possible that ABCG2WBCRP polymorphisms are associated with the eŠectiveness and adverse eŠects of irinotecan, ABCG2WBCRP exons and their ‰anking regions were sequenced to identify Japanese speciˆc SNPs. Login to comment
126 Masaya ITODA, et al.SNP18 (216) Novel ABCG2 SNPs SNP19 (217) tion of ABCG2WBCRP haplotypes in conjunction with other frequently found SNPs, including non-synonymous ones (34GÀA (V12M, SNP frequency 19z) and 421CÀA (Q141K, SNP frequency 33z)) in the Japanese population. Login to comment
128 MPJ6äAG2012 was closely associated with the known SNP, IVS1-99GÀA (rs1584481, ssj0001922), but not with the SNPs, 34GÀA (V12M) and 421CÀA (Q141K). Login to comment

PMID: 15657365 [PubMed] Ifergan I et al: "Cytoplasmic confinement of breast cancer resistance protein (BCRP/ABCG2) as a novel mechanism of adaptation to short-term folate deprivation."

No. Sentence Comment

236 It was found that an N-terminal BCRP mutation (Val12Met) disrupted the apical plasma membrane localization of BCRP in polarized LLC-PK1 cells. Login to comment

PMID: 15743976 [PubMed] Vethanayagam RR et al: "Functional analysis of the human variants of breast cancer resistance protein: I206L, N590Y, and D620N."

No. Sentence Comment

20 Two variants, V12M and Q141K, occurred at particularly high allele frequencies in Chinese and Japanese populations (30-60%) and at relatively lower allele frequencies in white people and African-Americans (5-26%) (Zamber et al., 2003). Login to comment
207 Imai et al. (2002) demonstrated that Q141K was expressed at a lower level in transfected murine fibroblast PA317 cells and conferred lower levels of drug resistance compared with wild-type BCRP, whereas V12M exhibited an expression level and drug resistance profiles very similar to those of wild-type protein (Imai et al., 2002). Login to comment
208 Another study (Mizuarai et al., 2004) showed that V12M and Q141K were expressed in the polarized LLC-PK1 porcine kidney cells at levels comparable to that of wild-type protein; however, both V12M and Q141K conferred significantly lower drug resistance than wild-type protein, accompanied with increased drug accumulation and decreased drug efflux. Login to comment
209 Further analysis of the mechanism of transport dysfunction revealed that the apical membrane localization of V12M was disrupted, whereas the expression and apical membrane localization of Q141K were not affected; however, the ATPase activity of Q141K was decreased. Login to comment
210 A recent study illustrated that V12M was expressed in HEK cells at levels similar to that of wild-type BCRP, whereas the Q141K level was significantly decreased compared with wild-type protein; however, the transport activity normalized by the BCRP expression was almost the same for V12M, Q141K and wild-type BCRP (Kondo et al., 2004). Login to comment

PMID: 15838659 [PubMed] Morisaki K et al: "Single nucleotide polymorphisms modify the transporter activity of ABCG2."

No. Sentence Comment

0 ORIGINAL ARTICLE Kuniaki Morisaki Æ Robert W. Robey Csilla O¨ zvegy-Laczka Æ Yasumasa Honjo Orsolya Polgar Æ Kenneth Steadman Bala´ zs Sarkadi Æ Susan E. Bates Single nucleotide polymorphisms modify the transporter activity of ABCG2 Received: 21 July 2004 / Accepted: 1 October 2004 / Published online: 19 April 2005 Ó Springer-Verlag 2005 Abstract Single nucleotide polymorphism (SNP) analyses of the ABCG2 gene have revealed three nonsynonymous SNPs resulting in the amino acid changes at V12M, Q141K and D620N. Login to comment
4 Values for V12M and D620N ABCG2 were comparable to those for wild-type R482 ABCG2. Login to comment
6 Basal ATPase activity in cells transfected with Q141K ABCG2 was 1.8-fold lower than in cells transfected with wild-type ABCG2, but was comparable among cells expressing wild-type, V12M or D620N ABCG2. Login to comment
7 Confocal studies of ABCG2 localization revealed higher intracellular staining in the Q141K transfectants than in cells transfected with wild-type or V12M ABCG2. Login to comment
8 Decreased transport of Hoechst 33342 was observed in Sf9 cells expressing V12M ABCG2; however, this was not true in HEK-293 cells expressing V12M ABCG2. Login to comment
30 We previously sequenced the ABCG2 gene in 90 genomic DNA samples representing a global genetic diversity and identified three nonsynonymous SNPs -34G fi A, substituting a valine for methionine (V12M); 421C fi A, substituting a glutamine for lysine (Q141K); and 1858C fi A, substituting an aspartic acid for asparagine (D620N)-in the coding region of ABCG2 [18]. Login to comment
33 In a study of SNPs in ABCG2 in the general Japanese population, the V12M and Q141K SNPs were observed at higher allelic frequencies (17.2% and 26.6%, respectively) [19]. Login to comment
34 Similarly, in other studies, the V12M and Q141K SNPs have also been found to be the most frequent polymorphisms in various ethnic and racial groups including Caucasian, Asian, and Swedish populations [3, 48]. Login to comment
37 containing full-length ABCG2 encoding wild-type (R482), mutant (R482T, R482G), or SNP variants (V12M, Q141K, or D620N) of ABCG2. Login to comment
97 Additionally, we generated an ABCG2 transfectant with the first 11 amino acids deleted and the V12M SNP (1_33del34G fi A, 1_11delV12M) in order to examine whether the substituted methionine at amino acid 12 can serve as the first codon for a functional ABCG2. Login to comment
98 Clones were initially screened using the anti-ABCG2 antibody 5D3 and, from the positive clones obtained, 12 clones transfected with V12M, Q141K, D620N, or 1_11delV12M were selected for further study: V12M-12, -13 and -14; Q141K-5, -8, -13 and -16; D620N-2, -3 and -23; and 1_11delV12M-2 and -8. Login to comment
101 Although Northern blot analysis demonstrated higher expression of ABCG2 mRNA in wild-type (482R) ABCG2-transfected clones than in V12M-13 and Q141K-8 clones, immunoblot analysis showed generally comparable (within two- to threefold) ABCG2 protein expression in 482R, V12M-13, and Q141K-8 transfectants. Login to comment
103 Differential resistance among cells transfected with wild-type, V12M and Q141K ABCG2 To determine whether the SNPs affected the transport activity of ABCG2, 4-day cytotoxicity assays were performed with the ABCG2 substrates mitoxantrone, topotecan, SN-38, and diflomotecan (BN80915) on ABCG2-transfected HEK-293 cells expressing comparable amounts of ABCG2. Login to comment
105 Comparable surface expression of ABCG2 in the 482R-2, Q141K-5, Q141K-8 and V12M-13 clones was confirmed using the 5D3 antibody, as shown in Fig. 2a. Login to comment
106 This is in contrast to the immunoblot data that showed somewhat higher levels of ABCG2 in the V12M-13 clone. Login to comment
108 a Northern blot analysis of ABCG2 expression in representative HEK-293 cells transfected with wild-type, V12M, Q141K, or D620N ABCG2. Login to comment
116 The V12M-13 and 482R-2 clones were comparably resistant to mitoxantrone, topotecan, SN-38 and diflomotecan, whereas the Q141K-5 and -8 clones had IC50 values that were 3-fold to 5-fold lower for mitoxantrone and topotecan, 2-fold to 3.4-fold lower for SN-38, and 1.2-fold to 2.3-fold lower for diflomotecan. Login to comment
121 b Cytotoxicity assays were performed with mitoxantrone, topotecan, SN-38, or diflomotecan on HEK-293 cells transfected with empty vector (filled circles), or the 482R-2 (open circles), V12M-13 (filled triangles), Q141K-5 (open squares), and Q141K-8 (hatched squares) clones from a. Login to comment
122 Representative results are shown clones each of ABCG2-transfected cells expressing R482, R482T, R482G, V12M, Q141K or D620N ABCG2. Login to comment
133 Efflux and expression values for cells transfected with V12M and D620N ABCG2 fell close to the line, while values for cells transfected with Q141K ABCG2 fell predominantly below the line. Login to comment
135 Among the transfectants, Q141K variants showed significantly lower values compared to the transfectants with wild-type ABCG2 and the other SNP variants, V12M and D620N (P=0.0048, 0.0005, and 0.0126, respectively), suggesting that Q141K ABCG2 transports mitoxantrone less efficiently than wild-type ABCG2. Login to comment
136 Although V12M and D620N variants showed somewhat higher efficiency of mitoxantrone transport than 482R, no statistically significant difference was found. Login to comment
140 We next examined the ATPase activity of V12M, Q141K, and D620N variants using this system. Login to comment
148 At 1 lM Clone Mitoxantrone Topotecan SN-38 Diflomotecan IC50 RR IC50 RR IC50 RR IC50 RR pcDNA3-10 0.6±0.3 - 8.7±1.2 - 1.2±0.7 - 0.3±0.2 - 482R-2 34±5.4 57 275±150 32 123±68 103 1.4±0.6 5 V12M-13 44±15 73 250±71 29 100±1 83 1±0.1 3 Q141K-5 7.4±1.8 12 55±7 6 36±11 30 0.6±0.07 2 Q141K-8 10.8±5.3 18 90±14 10 66±11 55 0.9±0.1 3 Table 1 Relative resistance (RR) of ABCG2-transfected cells to ABCG2 substrates. Login to comment
157 Effect of SNPs on cellular localization of ABCG2 To determine if the SNPs affected membrane localization of ABCG2, we performed immunofluorescence studies on HEK-293 cells stably transfected with wild-type, V12M or Q141K ABCG2. Login to comment
159 Similarly, cells expressing V12M ABCG2 also had ABCG2 localized primarily to the cell surface (Fig. 6b). Login to comment
163 To examine whether the nonsynonymous SNPs in ABCG2 affect the transport of this compound, Hoechst 33342 dye transport was measured in intact Sf9 cells expressing wild-type, V12M, Q141K, or D620N ABCG2, as well as the nonfunctional mutant, R482G/K86M. Login to comment
165 In contrast, Hoechst 33342 transport was significantly lower in cells expressing V12M ABCG2 following normalization to the higher ABCG2 expression in these cells, suggesting less efficient Hoechst 33342 transport by V12M ABCG2 (Fig. 7b). Login to comment
168 To evaluate the possibility that Hoechst 33342 transport was impaired in human cells expressing V12M ABCG2, we performed Hoechst accumulation studies with HEK-293 cells transfected with the wild-type or SNP variants of ABCG2. Login to comment
172 Representative histograms for 482R-9, 482G-1, V12M-13, D620N-2, Q141K-5, and 1_11delV12M-8 are shown substrate-free medium for 60 min continuing with or without FTC. Login to comment
174 No significant difference in FTC-inhibitable Hoechst efflux was observed between cells expressing wild-type (R482), V12M or Q141K ABCG2 (Fig. 7c, right column). Login to comment
175 Cytotoxicity assays with Hoechst 33342 confirmed marked resistance conferred by ABCG2, with an IC50 for the 482R-2 clone of 16.3±15.8 lM and for the V12M-13 clone of 56.7±5.8 lM. Login to comment
176 Since the IC50 for empty vector-transfected cells was 26.3±15.8 n M, this translates to a relative resistance of 621 for 482R-2 and 2155 for V12M-13. Login to comment
177 These data are not consistent with impaired transport of Hoechst 33342 by V12M ABCG2 and are in contrast to the results obtained with intact Sf9 insect cells. Login to comment
178 Discussion We and others have recently identified several polymorphisms in ABCG2, including three nonsynonymous SNPs resulting in amino acid substitution in the coding region of ABCG2: V12M, Q141K, D620N [4, 19, 20, 50]. Login to comment
189 Values from the experiment in a were obtained for ABCG2-transfected HEK-293 clones expressing varying levels of 482R, R482G, R482T, V12M, Q141K, and D620N ABCG2 and a box plot was generated. Login to comment
204 Four-day cytotoxicity assays demonstrated that, among HEK-293 cells transfected with wild-type, V12M, or Q141K ABCG2, those expressing Q141K ABCG2 had IC50 values for mitoxantrone, topotecan, SN-38 and diflomotecan that were as much as fivefold lower than those for cells expressing comparable levels Fig. 5 ATPase activity in Sf9 insect cells infected with ABCG2-bearing baculovirus. Login to comment
205 a Immunoblot detection of human wild-type, D620N, Q141K and V12M ABCG2 expressed in Sf9 insect cells. Login to comment
206 Membranes of Sf9 cells (1.5 lg total protein from V12M/Sf9, Q141K/Sf9 and D620N/Sf9, 1.0 lg from wild-type ABCG2/Sf9, and 1.2 lg from b-galactosidase/Sf9) dissolved in disaggregation buffer were subjected to electrophoresis on 7.5% Laemmli-type gels and blotted onto PVDF membranes, followed by immunodetection with the BXP-21 antibody. b ATPase activity measured in membranes of Sf9 cells expressing the wild-type, V12M, Q141K, and D620N variants of human ABCG2. Login to comment
210 HEK-293 cells transfected with wild-type (482R-2) (a), V12M (V12M-13) (b), or Q141K (Q141K-8) (c) ABCG2 were fixed, permeabilized, and then incubated with the mouse monoclonal anti-ABCG2 antibody, BXP-21. Login to comment
211 After washing, cells were incubated with Alexa Fluor 488-labeled secondary antibody and subjected to confocal laser scanning microscopy of wild-type or V12M ABCG2. Login to comment
212 When surface ABCG2 expression was used to normalize the FTC-inhibitable mitoxantrone efflux, we found that HEK-293 cells expressing Q141K ABCG2 transported mitoxantrone less efficiently than cells expressing wild-type, V12M or D620N ABCG2. Login to comment
214 However, in contrast to the results of Mizuarai et al., we did not observe enhanced sensitivity to ABCG2 substrate drugs in cells transfected with V12M ABCG2. Login to comment
217 Indeed, we noted impaired Hoechst 33342 transport in Sf9 cells expressing V12M ABCG2. Login to comment
218 This was in contrast to cytotoxicity assays with transfected human cells that displayed comparable resistance to Hoechst 33342 in cells expressing wild-type or V12M ABCG2. Login to comment
219 It is of note that Imai et al., using a human expression system, did not find increased sensitivity to mitoxantrone in PC3 cells transfected with V12M ABCG2 compared to cells transfected with wild-type [20]. Login to comment
220 These contrasting results suggest that the glycosylation status of the protein may be significant for the V12M SNP. Login to comment
243 In contrast to results in non-mammalian systems, no impairment of the V12M variant was observed in the HEK-293 transfectants. Login to comment

PMID: 15882131 [PubMed] Lepper ER et al: "Mechanisms of resistance to anticancer drugs: the role of the polymorphic ABC transporters ABCB1 and ABCG2."

No. Sentence Comment

134 An additional potentially functional polymorphism has been identified in the ABCG2 gene at nucleotide position 34, resulting in a Val12Met amino acid change. Login to comment
157 Position in gene* Nucleotide‡ Region Wild-type allele Variant allele Amino acid Change -19572 to -19569 5`-Flanking region CTCA - CTCA deletion -19202 5` UTR G C -18845 5` UTR T C -18604 5` UTR A - Deletion -18482 -113 Exon 1 C T Non-coding -18398 -29 Exon 1 A G Non-coding 34 34 Exon 2 G A 12 Val to Met 71 71 Exon 2 C T 24 Ala to Val 114 114 Exon 2 T C 38 Synonymous 239 Intron 2 A G 7268 Intron 2 T C 7420 Intron 3 - T Insertion 8007 Intron 3 G A 8184 369 Exon 4 C T 123 Synonymous 8191 376 Exon 4 C T 126 Gln to Term 8825 421 Exon 5 C A 141 Gln to Lys 8862 458 Exon 5 C T 153 Thr to Met 8878 474 Exon 5 C T 158 Synonymous 8900 496 Exon 5 C G 166 Gln to Glu 18186 Intron 5 A G 18286 616 Exon 6 A C 206 Ile to Leu 18293 623 Exon 6 T C 208 Phe to Ser 21530 Intron 6 C T 21718 Intron 6 A G 21903 Intron 7 A G 24618 Intron 7 T A 26297 1098 Exon 9 G A 366 Synonymous 38389 1291 Exon 11 T C 431 Phe to Leu 38485 Intron 11 A G 40111 Intron 11 G A 40303 1425 Exon 12 A G 475 Synonymous 40322 1444 Exon 12 A G 482 Arg to Gly 40323 1445 Exon 12 G C 482 Arg to Thr 40343 1465 Exon 12 T C 489 Phe to Leu 40419 Intron 12 G T 42314 Intron 13 T G 44997 Intron 14 A G 45022 Intron 14 C T 45073 1768 Exon 15 A T 590 Asn to Tyr 47355 1858 Exon 16 G A 620 Asp to Asn 47734 2237 Exon 16 G T Non-coding 47890 2393 Exon 16 G T Non-coding 47891 2394 Exon 16 C A Non-coding ABC: ATP-binding cassette; UTR: Untranslated region. Login to comment
174 Outside of cell Cell membrane C terminus ATP-binding site N terminus Inside of cellGln141Lys Walker A Walker B Signature motif Arg482Thr Val12Met Table 5. Login to comment

PMID: 16108826 [PubMed] Sugimoto Y et al: "Breast cancer resistance protein: molecular target for anticancer drug resistance and pharmacokinetics/pharmacodynamics."

No. Sentence Comment

165 From these analyses, we identified three BCRP coding SNP, G34A (V12M), C376T (Q126Stop) and C421A (Q141K), and a splicing variant, ∆315-6, that lacked nucleotides 944-949 (deletion of A315 and T316) (Fig. Login to comment
176 V12M-BCRP-transfected and ∆315-6-BCRP-transfected PA317 cells showed similar and somewhat lower BCRP protein expression and drug resistance levels compared with wild-type BCRP-transfected cells. Among the normal subjects in our analysis, 67 were wild type, 48 were heterozygous and nine were homozygous for the C421A allele. Login to comment
216 PA317 cells transfected with wild-type, G34A, C421A and ∆944-949 BCRP cDNAs were termed PA/WT, PA/V12M, PA/Q141K and PA/∆315-6, respectively. Login to comment

PMID: 16116030 [PubMed] Meissner K et al: "The ATP-binding cassette transporter ABCG2 (BCRP), a marker for side population stem cells, is expressed in human heart."

No. Sentence Comment

126 Among the four identified naturally occurring single nucleotide polymorphisms, 34G.A (V12M) and 421C.A (Q141K) were most common in diverse populations of different ethnic origin in North America (Zamber et al. 2003). Login to comment
127 Among the four identified naturally occurring single nucleotide polymorphisms, 34G.A (V12M) and 421C.A (Q141K) were most common in diverse populations of different ethnic origin in North America (Zamber et al. 2003). Login to comment

PMID: 16146333 [PubMed] Mao Q et al: "Role of the breast cancer resistance protein (ABCG2) in drug transport."

No. Sentence Comment

160 A variety of naturally occurring variants of BCRP have been identified in DNA samples of ethnically diverse origins.95-98 Notably, the alterations of BCRP protein at position 12 (V12M) and 141 (Q141K) occur frequently in Asia populations (~30%-60%) and relatively low frequencies in Caucasians and African-Americans (~5%-10%). Login to comment
161 For example, in a Japanese population studied, 39% to 50% are heterozygous and 7% are homozygous for the variant Q141K.95,96 In a Chinese population, 60% are heterozygous for Q141K.95 Several other variants such as I206L, N590Y, and D620N are much less frequent with allele frequencies of ~1%.95,97 For instance, N590Y is present in ~1.5% of Caucasians.95 I206L is found only in Hispanic populations so far.95 D620N is detected in 1.1% of all DNA samples examined with unknown genetic origin.97 In addition, a polymorphism in exon 4 that results in a substitution of stop codon for Gln at position 126 has also been identified.96 Amino acid changes at position 482 that were found in some drug-selected resistant cell lines have so far not been identified in normal populations or in DNA samples from cancer patients.49 In vitro functional characterization of the variants V12M and Q141K produced contradicting results. Login to comment
162 One study reported that Q141K was expressed at lower levels in transfected cells and therefore conferred lower drug resistance compared with the wild-type protein.96 The variant V12M displayed expression levels and drug-resistance properties similar to the wild-type protein.96 Another study reported that V12M and Q141K were expressed at levels comparable to the wild-type protein; however, both V12M and Q141K conferred significantly lower levels of drug resistance relative to the wild-type protein as compared with increased drug accumulation and decreased drug efflux.98 Further analysis of the mechanism of the transport dysfunction revealed that the apical membrane localization of V12M was disrupted and that ATPase activity of Q141K was decreased.98 A recent clinical study by Sparreboom et al73 has shown that the Q141K polymorphism is associated with significant changes of pharmacokinetic properties of diflomotecan, a substrate of BCRP. Login to comment

PMID: 16158227 [PubMed] Krishnamurthy P et al: "The ABC transporter Abcg2/Bcrp: role in hypoxia mediated survival."

No. Sentence Comment

127 The SNPs in Bcrp that produce non-synonymous changes (i.e., amino acid substitutions) are at amino acids 12 (V12M), 141 (Q141K), 206 (I206L), and 590 (N590Y). Login to comment
128 The most frequent polymorphisms being the exon 2 SNP (G34A/ V12M) and the exon 5 SNP (C421A/Q141K), which produce changes in amino acids 12 and 141 (Imai et al. 2002; Mizuarai et al. 2004). Login to comment

PMID: 16160819 [PubMed] Ishikawa T et al: "Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design."

No. Sentence Comment

87 Non-synonymous SNPs are located at nucleotides 238 (exon 2) and 625, resulting in amino acid substitutions: V12M and Q141K. Login to comment
89 The V12M polymorphism in exon 2 (c.34G>A) affects the N-terminal intracellular region of the protein. Login to comment
91 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90% of only 5 individuals tested), but only 1.7% in a Swedish population (B¨ackstr¨om et al. 2003). Login to comment
93 Thus, there is a large difference in the allele frequency of the V12M polymorphism among different ethnic groups (Table 2). Login to comment
109 Imai et al. (2002) reported that the Q141K variant of ABCG2, stably expressed in PA317 cells, had a markedly lower expression level than the wild-type ABCG2 or the V12M variant. Login to comment
111 On the other hand, Mizuarai et al. (2004) expressed ABCG2 in polarized LLC-PK1 cells, and by using confocal microscopy demonstrated that the wild-type and the Q141K variant of ABCG2 mainly showed apical staining, while the V12M variant showed intracellular localization. Login to comment
112 However, Kondo et al. (2004) demonstrated that both V12M and Q141K variants were localized at the apical membrane in LLC-PK1 cells. Login to comment
113 These contradictory expression and localization data for ABCG2 variants indicate that differences in transfection conditions (transient or stable expression), the copy number of cDNA incorporated in genomic DNA or other cellular determinants may variably Table 2 Frequencies of ABCG2 alleles in different ethnic groups Position Ethnic group Variant allele Allele Reference Amino acid cDNA N Hetero Homo Frequency (%) V12M c.34G>A Japanese 29 9 1 19.0 Imai et al. (2002) Japanese 10 - - 15.0 Zamber et al. (2003) Japanese 220 61 8 17.5 Kobayashi et al. (2005) Chinese 10 - - 20.0 Zamber et al. (2003) Southeast Asians 10 - - 45.0 Zamber et al. (2003) Pacific Islanders 7 - - 64.0 Zamber et al. (2003) Swedish 60 2 0 1.7 B¨ackstr¨om et al. (2003) Dutch 100 11 1 6.5 Bosch et al. (2005) Caucasian 86 - - 2.0 Zamber et al. (2003) Caucasian 150 27 2 10.3 Mizuarai et al. (2004) Caucasian 150 11 0 3.7 Kobayashi et al. (2005) Ashkenazi Jewish 10 - - 10.0 Zamber et al. (2003) Middle Eastern 20 - - 5.0 Zamber et al. (2003) Africans North of Sahara 7 - - 14.0 Zamber et al. (2003) African American 150 17 1 6.3 Kobayashi et al. (2005) Mexicans 10 - - 10.0 Zamber et al. (2003) Hispanic Livers 5 - - 40.0 Zamber et al. (2003) Mexican Indians 5 - - 90.0 Zamber et al. (2003) Q126Stop c.376C>T Japanese 124 3 0 1.2 Imai et al. (2002) Japanese 60 2 0 1.7 Itoda et al. (2003) Japanese 220 4 0 0.9 Kobayashi et al. (2005) Caucasian 150 0 0 0.0 Mizuarai et al. (2004) Caucasian 150 0 0 0.0 Kobayashi et al. (2005) African American 150 0 0 0.0 Kobayashi et al. (2005) Q141K c.421C>A Japanese 124 48 9 26.6 Imai et al. (2002) Japanese 10 - - 35.0 Zamber et al. (2003) Japanese 220 90 27 32.7 Kobayashi et al. (2005) Chinese 95 43 11 34.2 de Jong et al. (2004) Chinese 10 - - 35.0 Zamber et al. (2003) Southeast Asians 10 - - 15.0 Zamber et al. (2003) Pacific Islanders 7 - - 14.0 Zamber et al. (2003) Swedish 60 10 1 10.0 B¨ackstr¨om et al. (2003) Dutch 100 20 2 12.0 Bosch et al. (2005) Caucasian 85 - - 14.0 Zamber et al. (2003) Caucasian 172 33 3 11.3 de Jong et al. (2004) Caucasian 150 22 2 8.7 Mizuarai et al. (2004) Caucasian 150 25 4 11.0 Kobayashi et al. (2005) Ashkenazi Jewish 10 - - 5.0 Zamber et al. (2003) Middle Eastern 20 - - 13.0 Zamber et al. (2003) Africans North of Sahara 7 - - 0.0 Zamber et al. (2003) African, Sub-Saharan 938 14 1 0.9 de Jong et al. (2004) African American 24 - - 0.0 Zamber et al. (2003) African American 150 5 1 2.3 Kobayashi et al. (2005) African American 94 8 1 5.3 de Jong et al. (2004) Mexicans 10 - - 5.0 Zamber et al. (2003) Hispanic Livers 5 - - 10.0 Zamber et al. (2003) Mexican Indians 5 - - 10.0 Zamber et al. (2003) R160Q c.479G>A Dutch 100 1 0 0.5 Bosch et al. (2005) I206L c.616A>C Japanese 10 - - 0.0 Zamber et al. (2003) Chinese 10 - - 0.0 Zamber et al. (2003) Southeast Asians 10 - - 0.0 Zamber et al. (2003) Pacific Islanders 7 - - 0.0 Zamber et al. (2003) Caucasian 65 - - 0.0 Zamber et al. (2003) Table 2 Continued Position Ethnic group Variant allele Allele Reference Amino acid cDNA N Hetero Homo Frequency (%) Ashkenazi Jewish 10 - - 0.0 Zamber et al. (2003) Middle Eastern 20 - - 0.0 Zamber et al. (2003) Africans North of Sahara 7 - - 0.0 Zamber et al. (2003) African American 15 - - 0.0 Zamber et al. (2003) Mexicans 10 - - 0.0 Zamber et al. (2003) Hispanic Livers 5 - - 10.0 Zamber et al. (2003) Mexican Indians 5 - - 0.0 Zamber et al. (2003) F431L c.1291T>C Japanese 60 1 0 0.8 Itoda et al. (2003) S441N c.1322G>A Japanese 100 1 0 0.5 Kobayashi et al. (2005) F489L c.1465T>C Japanese 60 1 0 0.8 Itoda et al. (2003) Japanese 100 1 0 0.5 Kobayashi et al. (2005) R575Stop c.1723C>T Dutch 100 1 0 0.5 Bosch et al. (2005) N590Y c.1768A>T Caucasian 65 - - 1.0 Zamber et al. (2003) Caucasian 150 1 0 0.3 Mizuarai et al. (2004) African Americans 15 - - 0.0 Zamber et al. (2003) D620N c.1858G>A Dutch 100 1 0 0.5 Bosch et al. (2005) affect the cellular processing and sorting of these proteins. Login to comment
114 Detailed studies are needed to clarify the mechanism of a reduced protein expression for Q141K and the altered cellular localization of V12M and Q141K variants. Login to comment
118 For this purpose, we have created variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G, and R482T) by site-directed mutagenesis. Login to comment
130 After the normalization of expression levels, the V12M and T153M variants showed increased levels of MTX transport activity, whereas the I206L, N590Y, and D620N variants had lower transport activities. Login to comment

PMID: 16169662 [PubMed] Huang Y et al: "Membrane transporters and channels in chemoresistance and -sensitivity of tumor cells."

No. Sentence Comment

79 Two additional SNPs, i.e. V12M and Q141K, also affect substrate specificity and transport capacity of ABCG2 [26]. Login to comment

PMID: 16259577 [PubMed] Sakurai A et al: "Genetic polymorphisms of ATP-binding cassette transporters ABCB1 and ABCG2: therapeutic implications."

No. Sentence Comment

210 In different ethnic groups, seven naturally-occurring non-synonymous SNPs have been reported: V12M, Q126Stop, Q141K, I206L, F431L, S441N, F489L, N590Y and D620N. Login to comment
211 Among the above variations, two alterations (c.34G > A [V12M], c.421C > A [Q141K]) affecting the protein structure have been reported to be polymorphic in several populations. Login to comment
215 Non-synonymous SNPs are located at nucleotides 238 (exon 2) and 625 (exon 5), resulting in the amino acid substitutions V12M and Q141K. Login to comment
217 The V12M polymorphism in exon 2 (c.34G > A) affects the N-terminal intracellular region of the protein. Login to comment
219 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90%, but only 10 individuals were tested), but only 2% in a Swedish population [130,132]. Login to comment
220 Upon the combination of several population studies, a consistent and significant (p < 0.0001) difference can be observed between the overall allele frequencies of V12M in Caucasian/African-American and Japanese populations (Table 4). Login to comment
225 Location Position Allele Amino acid Allele frequency in Caucasian populations Allele frequency in Japanese populatins Allele frequency in African populations n % n % n % Exon 2 34 G A 12 Val 12 Met 546 94.4 5.6 259 82.4 17.6 181 93.7 6.3 Exon 4 376 C T 126 Gln 126 stop 300 100 0 404 98.9 1.1 150 100 0 Exon 5 421 C A 141 Gln 141 Lys 717 89.0 11.0 354 69.4 30.6 1213 98.6 1.4 Exon 5 479 G A 160 Arg 160 Gln 100 99.5 0.5 ND ND ND ND ND ND Exon 11 1291 T C 431 Phe 431 Leu ND ND ND 60 99.2 0.8 ND ND ND Exon 11 1322 G A 441 Ser 441 Asn ND ND ND 100 99.5 0.5 ND ND ND Exon 12 1465 T C 489 Phe 489 Leu ND ND ND 160 99.4 0.6 ND ND ND Exon 14 1723 C T 575 Arg 575 stop 100 99.5 0.5 ND ND ND ND ND ND Exon 15 1768 A T 590 Asn 590 Tyr 215 99.5 0.5 ND ND ND 15 100 0 Exon 16 1858 T A 620 Asp 620 Asp 100 99.5 0.5 ND ND ND ND ND ND Data are from [129-135,137]. Login to comment
228 Similar to V12M, substantial and significant (p < 0.0001) allele frequency differences can be observed among the three major ethnic groups tested, potentially reflecting different population admixtures and unequal effects of environmental selection factors. Login to comment
242 Imai et al. [129] reported that the Q141K variant of ABCG2 stably expressed in PA317 cells had a markedly lower expression level than the wild-type ABCG2 or the V12M variant. Login to comment
244 On the other hand, Mizuarai et al. [135] expressed ABCG2 in polarised LLC-PK1 cells, and by using confocal microscopy demonstrated that the wild-type and the Q141K variant of ABCG2 showed mainly apical staining, and the V12M variant showed intracellular localisation. Login to comment
245 However, Kondo et al. [138] demonstrated that both V12M and Q141K variants were localised at the apical membrane in LLC-PK1 cells. Login to comment
250 COOH H2N N590Y V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L F489L D620N R482G R482T S441N F571I EXTRACELLULAR INTRACELLULAR R160Q R575stop ATP-binding site (transient or stable expression), the copy number of cDNA incorporated in genomic DNA or other cellular determinants may variably affect the cellular processing and sorting of these proteins. Login to comment
251 Detailed studies are needed to clarify the mechanism of a reduced protein expression for Q141K and the altered cellular localisation of V12M and Q141K variants. Login to comment
255 For this purpose, variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G and R482T) were created by site-directed mutagenesis (Figure 3). Login to comment
267 The V12M and T153M variants showed increased levels of MTX transport activity, whereas the I206L, N590Y and D620N variants had lower transport activities. Login to comment
318 W T G 51C D 620N R 482G R 482T N 590Y E334stop I206L Q 166E T153M Q 141K Q 126stop V12M ATP-dependentMTXtransport (nmol/min/mgprotein) 2.0 1.5 1.0 0.5 0.0 5. Login to comment

PMID: 16303243 [PubMed] Yanase K et al: "Functional SNPs of the breast cancer resistance protein-therapeutic effects and inhibitor development."

No. Sentence Comment

1 We have previously identified three polymorphisms within the BCRP gene, G34A (substituting Met for Val-12), C376T (substituting a stop codon for Gln-126) and C421A (substituting Lys for Gln-141). Login to comment
42 C421A (Q141K) BCRP SNP We have previously identified three variant BCRP cDNAs, containing the substitutions G34A (V12M), C421A (Q141K) and a 944-949 deletion lacking Ala-315 and Thr-316 (D315-6) [23]. Login to comment
45 In addition, both G34A BCRP-transfected PA317 (PA/ V12M) cells and 944-949-deleted BCRP-transfected PA317 (PA/D315-6) cells showed either similar or marginally lower protein expression and drug resistance levels compared to PA/WT cells (Fig. 1 and Table 1). Login to comment
74 However, in our Table 1 Drug sensitivities of BCRP-transfected PA317 cells Cells IC50 (ng/ml) SN-38 Topotecan MXR PA317 2.5 0.060 17 PA/WT 98 0.58 O200 PA/V12M 98 0.63 O200 PA/Q141K 30 0.25 100 PA/D315-6 55 0.42 190 Cells were cultured for 5 days in the absence or presence of increasing concentrations of the indicated anticancer agents. Login to comment
92 Therefore, we first Table 3 SNPs within the BCRP gene Variation Region Effect Domain A-1379G 50 -flanking (promoter) - D-654-651 50 -flanking (promoter) - G-286C 50 -flanking (promoter) - T-476C Exon 1 (50 - UTR) - D-235A Exon 1 (50 - UTR) - A-113G Exon 1 (50 - UTR) - A-29G Exon 1 (50 - UTR) - G34A Exon 2 V12M N-terminal T114C Exon 2 No change N-terminal G151T Exon 2 G51C N-terminal C369T Exon 4 No change NBD C376T Exon 4 Q126stop NBD C421A Exon 5 Q141K NBD C458T Exon 5 T153M NBD C474T Exon 5 No change NBD C496G Exon 5 Q166E NBD A564G Exon 6 No change NBD A616C Exon 6 I206L NBD T623C Exon 6 F208S NBD T742C Exon 7 S248P Linker G1000T Exon 9 E334stop Linker G1098A Exon 9 No change Linker T1291C Exon 11 F431L TMD A1425G Exon 12 No change TMD T1465C Exon 12 F489L TMD A1768T Exon 15 N590Y TMD G1858A Exon 16 D620N TMD G2237T Exon 16 (30 - UTR) - G2393T Exon 16 (30 - UTR) - Abbreviations: UTR, untranslated region; NBD, nucleotide-binding domain; TMD, transmembrane domain. Login to comment

PMID: 16337740 [PubMed] Cervenak J et al: "The role of the human ABCG2 multidrug transporter and its variants in cancer therapy and toxicology."

No. Sentence Comment

109 To date, altogether eight non-synonymous (V12M, Q141K, I206L, F431L, S441N, F489L, N590Y, D620N), five synonymous (silent) (c.114TOC, c.369COT, c.474COT, c.1098GOA, c.1425AOG) missense mutations, one nonsense (Q126X), and one frameshift (c.1515delC) mutations were identified in the coding region of ABCG2 in healthy individuals or in patients [43-46,49,63-65]. Login to comment
110 Among the above variations, affecting the protein structure, two alterations [c.34GOA (V12M), c.421CO A (Q141K)] have been reported to be polymorphic in several populations. Login to comment
114 The V12M polymorphism in exon 2 (c.34GOA) affects the N-terminal intracellular region of the protein. Login to comment
116 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90%, but only 10 individuals were tested), while only 2% in a Swedish population [43,49]. Login to comment
117 Upon the combination of several population studies, a consistent and significant (P!0.0001) difference can be observed between the overall allele frequencies of V12M in Caucasian/African American and Japanese populations (Table 1). Login to comment
122 Similarly to V12M, substantial and significant (P!0.0001) allele frequency differences can be observed between the three major ethnic groups tested, potentially reflecting different population admixture and unequal effects of environmental selection factors. Login to comment
123 On the basis of definitive molecular haplotype analyses (PCR-RFLP) for the three major variants [c.34GOA (V12M), c.376COT (Q126X), c.421COA (Q141K)] in a Japanese population, four haplotypes were identified G-C-C (V-Q-Q), G-C-A (V-Q-K), A-CC (M-Q-Q), and G-T-C (V-X-Q). Login to comment
127 The above results collectively suggest that the V12M, Q126X, and Q141K variants are likely to occur on separate chromosomes. Login to comment
130 Mainly the two major non-synonymous polymorphisms, V12M and Q141K, were investigated. Login to comment
132 Imai et al. [64] and Morisaki et al. [66] in stable mammalian expression systems found that in PA317 or HEK-293 cells the expressed Q141K ABCG2 protein had a lower expression level than the wild-type ABCG2, or the V12M variant. Login to comment
133 Morisaki et al. demonstrated that both the V12M and Q141K ABCG2 could reach the plasma membrane in the HEK-293 cells, while a significant portion of Table 1 Summary of population genetics data on naturally occurring sequence variations, affecting the coding region of the human ABCG2 gene Position in the ABCG2 genea Position in the ABCG2 cDNAb Amino acid substitution Population n C/K C/C AF (%G 95%CI) Ref. Login to comment
134 g.34GOA (exon 2) c.34GOA V12M Caucasian 150 27 2 10.3G3.5 [47] Caucasian 150 11 0 3.7G2.2 [46] Caucasian 86 n.a n.a 2.0Gn.a [49] Swedish 60 2 0 1.7G2.3 [43] Total Caucasian 360 40 2 6.1G1.8 Japanese 220 61 8 17.5G3.6 [46] Japanese 29 9 1 19.0G10.3 [64] Total Japanese 249 70 9 17.7G3.4 African-American 150 17 1 6.3G2.8 [46] g.8191COT (exon 4) c.376COT Q126X Caucasian 150 0 0 0.0 [46] Caucasian 150 0 0 0.0 [47] Total Caucasian 300 0 0 0.0 Japanese 220 4 0 0.9G0.9 [46] Japanese 124 3 0 1.2G1.4 [64] Japanese 60 2 0 1.7G2.3 [45] Total Japanese 404 9 0 1.1G0.7 African-American 150 0 0 0.0 [46] g.8825CO A (exon 5) c.421COA Q141K Caucasian 172 33 3 11.3G3.4 [63] Caucasian 150 25 4 11.0G3.6 [46] Caucasian 150 22 2 8.7G3.2 [47] Caucasian 85 n.a n.a 14.0Gn.a [49] Swedish 60 10 1 10.0G5.5 [43] Total Caucasian 532 90 10 10.3G1.9 Japanese 220 90 27 32.7G4.5 [46] Japanese 124 48 9 26.6G5.6 [64] Chinese 95 43 11 34.2G6.9 [63] Total Asian 439 181 47 31.3G3.1 African, Sub-Saharan 938 14 1 0.9G0.4 [63] African-American 150 5 1 2.3G1.7 [46] African-American 94 8 1 5.3G3.3 [63] Total Africanc 1182 27 3 1.4G0.5 g.40645AO T (exon 12) c.1465TOC F489L Japanese 100 1 0 0.5G1.0 [46] Japanese 60 1 0 0.8G1.7 [45] Total Japanese 160 2 0 0.6G0.9 g.45367AO T (exon 15) c.1768AOT N590Y Caucasian 150 1 0 0.3G0.7 [47] Caucasian 65 1 0 0.8G1.5 [49] Total Caucasian 215 2 0 0.5G0.7 Only those cDNA SNPs were listed that were detected in at least two independent studies. Login to comment
146 Mizuarai et al. expressed ABCG2 in polarized LLC-PKI cells, and by using confocal microscopy demonstrated that the wtABCG2 and Q141K showed mainly apical staining, while the V12M variant showed intracellular localization [47]. Login to comment
147 In a recent study, similarly LLC-PKI cells where used to express the V12M and Q141K variants and additionally five other polymorphisms (A149P, R163K, Q166E, P269S and S441N [55]). Login to comment
148 Interestingly, they found that all polymorphisms, including V12M and Q141K, had an apical localization, and only the S441N variant showed intracellular staining. Login to comment
151 Clearly, more detailed studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the altered cellular localization found for the V12M and Q141K variants under certain conditions. Login to comment
153 When the functions of the ABCG2 variants were examined in cytotoxicity assays, a 10-fold decrease in drug resistance, as compared to the wild-type ABCG2, was reported by Mizuarai et al., when the V12M or Q141K-transfected LLC-PKI cells were challenged by mitoxantrone, topotecan, or an indolocarbazole topoisomerase I inhibitor [47]. Login to comment
162 Two studies compared the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes [47,66]. Login to comment
164 On the other hand, the V12M (and D620N) ABCG2 showed a similar ATPase activity as the wild-type protein. Login to comment

PMID: 16399366 [PubMed] Ishikawa T et al: "High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: new strategies in pharmacogenomics."

No. Sentence Comment

115 For this purpose, variant forms (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, E334stop, N590Y, D620N, R482G, and R482T) have been created by site‐ directed mutagenesis with the QuikChange site‐directed mutagensis kit (Stratagene, La Jolla, CA). Login to comment
235 Imai et al. (2002) identified three allelic variants in the ABCG2 gene, of which two were nonsynonymous SNPs (V12M and Q141K) and the third was a splice variant with deletion of nucleotides 944-949 that lacks Ala‐315 and Thr‐316 (Á315‐6). Login to comment

PMID: 16402910 [PubMed] Krishnamurthy P et al: "Role of ABCG2/BCRP in biology and medicine."

No. Sentence Comment

186 Interestingly, some human variants of ABCG2 (ABCG2-V12M) have impaired membrane localization (98). Login to comment
296 The two SNPs most frequently identified were in exon 2 (G34A, resulting in a V12M change) and exon 5 (C421A, resulting in a Q141K substitution). Login to comment

PMID: 16454695 [PubMed] Tian Q et al: "Topotecan is a substrate for multidrug resistance associated protein 4."

No. Sentence Comment

47 However, resistance levels of TPT are inconsistent in different BCRP overexpressing cell lines [51-59], probably due to the existence of three mutant variants of BCRP resulting in the amino acid changes at V12M, Q141K and D620N [63-67]. Login to comment

PMID: 16608919 [PubMed] Tamura A et al: "Functional validation of the genetic polymorphisms of human ATP-binding cassette (ABC) transporter ABCG2: identification of alleles that are defective in porphyrin transport."

No. Sentence Comment

2 In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
82 GC indicates the percentage of guanine and cytosine contents in the PCR primer set. Tm shows the melting temperature (Tm) for each PCR primer set. Variant and Primers Primer Sequence (5Ј 3 3Ј) Primer Length GC Tm bases % °C V12M 33 39 55 Forward CGAAGTTTTTATCCCAATGTCACAAGGAAACAC Reverse GTGTTTCCTTGTGACATTGGGATAAAAACTTCG G51C 42 35 59 Forward ATCGAGTAAAACTGAAGAGTTGCTTTCTACCTTGTAGAAAAC Reverse GTTTTCGACAAGGTAGAAAGCAACTCTTCAGTTTTACTCGAT Q126stop 40 40 62 Forward GTAATTCAGGTTACGTGGTATAAGATGATGTTGTGATGGG Reverse CCCATCACAACATCATCTTATACCACGTAACCTGAATTAC Q141K 35 42 55 Forward CGGTGAGAGAAAACTTAAAGTTCTCAGCAGCTCTT Reverse AAGAGCTGCTGAGAACTTTAAGTTTTCTCTCACCG T153M 42 40 60 Forward CGGCTTGCAACAACTATGATGAATCATGAAAAAAACGAACGG Reverse CCGTTCGTTTTTTTCATGATTCATCATAGTTGTTGCAAGCCG Q166E 35 42 55 Forward GGATTAACAGGGTCATTGAAGAGTTAGGTCTGGAT Reverse ATCCAGACCTAACTCTTCAATGACCCTGTTAATCC I206L 36 44 59 Forward CTTATCACTGATCCTTCCCTCTTGTTCTTGGATGAG Reverse CTCATCCAAGAACAAGAGGGAAGGATCAGTGATAAG F208S 35 45 55 Forward TGATCCTTCCATCTTGTCCTTGGATGAGCCTACAA Reverse TTGTAGGCTCATCCAAGGACAAGATGGAAGGATCA S248P 35 40 55 Forward TTCATCAGCCTCGATATCCCATCTTCAAGTTGTTT Reverse AAACAACTTGAAGATGGGATATCGAGGCTGATGAA E334stop 35 31 55 Forward TCATAGAAAAATTAGCGTAGATTTATGTCAACTCC Reverse GGAGTTGACATAAATCTACGCTAATTTTTCTATGA F431L 28 60 62 Forward AGCTGGGGTTCTCCTCTTCCTGACGACC Reverse GGTCGTCAGGAAGAGGAGAACCCCAGCT S441N 34 47 59 Forward AACCAGTGTTTCAGCAATGTTTCAGCCGTGGAAC Reverse GTTCCACGGCTGAAACATTGCTGAAACACTGGTT F489L 46 34 62 Forward GAGGATGTTACCAAGTATTATACTTACCTGTATAGTGTACTTCATG Reverse CATGAAGTACACTATACAGGTAAGTATAATACTTGGTAACATCCTC F571I 36 47 61 Forward GTCATGGCTTCAGTACATCAGCATTCCACGATATGG Reverse CCATATCGTGGAATGCTGATGTACTGAAGCCATGAC N590Y 42 38 62 Forward CATAATGAATTTTTGGGACAATACTTCTGCCCAGGACTCAAT Reverse ATTGAGTCCTGGGCAGAAGTATTGTCCCAAAAATTCATTATG D620N 32 56 62 Forward GGTAAAGCAGGGCATCAATCTCTCACCCTGGG Reverse CCCAGGGTGAGAGATTGATGCCCTGCTTTACC veloped by using Western Lighting Chemiluminescent Reagent Plus (PerkinElmer Life and Analytical Sciences, Boston, MA) and detected by Lumino Imaging Analyzer FAS-1000 (Toyobo Engineering, Osaka, Japan). Login to comment
144 For this purpose, based on the currently available data on SNPs and acquired mutations, we generated variant forms (i.e., V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis. Login to comment
214 In the present study, based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
219 The frequencies of the Q126stop, S441N, and F489L alleles are relatively low (less than 2%) compared with those of the V12M and Q141K alleles. Login to comment
224 Potential Risk Amino Acid Transport Allele Frequency cDNA Position Located on Exon Allele Data Sourcea Hemato MTX Wild-Type Allele % V12M ϩϩ ϩϩ 2.0-90.0 34 2 G A 1, 2, 4, 5, 7, 8 ૽૽ Q126stop - - 0.0-1.7 376 4 C T 1, 3, 5, 7 Q141K ϩϩ ϩϩ 0.0-35.5 421 5 C A 1, 2, 4, 5, 6, 7, 8 T153M ϩϩ ϩϩ 3.3 458 5 C T 5 R160Q N.D. N.D. 0.5 479 5 G A 8 Q166E ϩϩ ϩϩ N.D. 496 5 C G NCBI dbSNP rs1061017 I206L ϩϩ ϩϩ 10.0 616 6 A C 2 ૽૽ F208S - - N.D. 623 6 T C NCBI dbSNP rs1061018 ૽૽ S248P - - N.D. 742 7 T C NCBI dbSNP rs3116448 ૽૽ E334stop - - N.D. 1000 9 G T NCBI dbSNP rs3201997 F431L ϩϩ - 0.8 1291 11 T C 3 ૽૽ S441N - - 0.5 1322 11 G A 7 ૽ F489L ϩ - 0.5-0.8 1465 12 T C 3, 7 F571L ϩϩ ϩϩ 0.5 1711 14 T A NCBI dbSNP rs9282571 (૽૽) R575stop N.D. N.D. 0.5 1723 14 C T 8 N590Y ϩϩ ϩϩ 0.0-1.0 1768 15 A T 2, 5 D620N ϩϩ ϩϩ 0.5 1858 16 G A 8 Hemato, hematoporphyrin; NCBI, National Center for Biotechnology Information; N.D., not determined; ૽, risk of porphyria; (૽), potential risk is assumed as the lack of transport activity being as a result of a truncated protein. Login to comment

PMID: 16702730 [PubMed] Maekawa K et al: "Genetic variation and haplotype structure of the ABC transporter gene ABCG2 in a Japanese population."

No. Sentence Comment

17 In vitro studies have also indicated that a number of anticancer drugs are good substrates for ABCG2: e.g. topotecan, an irinotecan metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38), and its glucuronide conjugate, SN-38G.810) Indeed, inhibition of the murine ABCG2 homologue, Bcrp 1, increases the bioavailability of topotecan when orally administered to mdr1aW1b- decient mice.11) In a clinical study, coadministration of topotecan with GF120918, a dual inhibitor for ABCG2 and P-glycoprotein, was shown to markedly increase the bioavailability and systemic exposure of topotecan.12) The cloning of ABCG2 from drug-selected cell lines revealed that acquired amino acid substitutions at residue 482 (Arg482Gly and Arg482Thr) of ABCG2 resulted in marked alterations in substrate recognition and transport ability.13) Thereafter, naturally occurring genetic variations in ABCG2 have been extensively examined in various ethnic populations1421) because they were expected to explain interindividual dierences in oral bioavailability and clearance of ABCG2 substrate drugs.22) Two nonsynonymous polymorphisms, 34GÀA (Val12Met) and 421CÀA (Gln141Lys), were detected at relatively high frequencies in most ethnic groups including Caucasians, Asians, and Africans.1416,1821,23) Both polymorphisms were reported to be associated with reduced protein expression in vitro andWor the increased sensitivity of the expressed cells toward several anticancer drugs although conicting data were also reported.16,2426) The expression of ABCG2 protein in placenta was signicantly lower in homozygotes with the 421A alleles than in those with the 421C alleles, while 34GÀA (Val12Met) did not aect ABCG2 protein expression.23) However, in intestinal samples, no association was found between the ABCG2 protein levels and the 421CÀA (Gln141Lys) genotype.18) A pharmacokinetic study showed that 421A (Gln141Lys) was unlikely to inuence the in vivo disposition of irinotecan in European Caucasian cancer patients.27) On the other hand, diomotecan pharmacokinetics were signicantly aected by the 421A genotype.28) To explain these inconsistencies, the elucidation of the haplotype structure of ABCG2 would be helpful; however, only limited information is available for the linkage disequilibrium (LD) prole and haplotype structure of this gene.20,21) Also, to facilitate future pharmacogenetic studies on ABCG2 genetic variations, haplotype analysis using its high-density SNPs found in a large number of samples is warranted. Login to comment
70 The observed allele frequencies were all in Hardy-Weinberg equilibrium (pÀ0.05) except for 34GÀA (Val12Met) and IVS2 {36AÀG (p0.028 for both variations). Login to comment
80 However, marked ethnic dierences in the allele frequencies were observed with |1203ä |1200delCTCA, 34GÀA (Val12Met), 421CÀA (Gln141Lys), and some intronic variations. Login to comment
85 115Haplotype Structure in Human ABCG2 (from |1836 to |1175 bp upstream of the translational start site) of the basal promoter,30) and was suggested to inuence irinotecan pharmacokinetics.31) The frequencies of two well-known nonsynonymous SNPs, 34GÀA (Val12Met) and 421CÀA (Gln141Lys), were 0.192 and 0.319 in our study, which were comparable to those in Chinese (0.204 and 0.2220.350, respectively).20,27) However, the frequencies were much higher than those in Caucasians (0.020.065 and 0.080.15), African-Americans (00.09 and 00.05), and a Swedish population (0.02 and 0.1).18,19,21,23,27) Of other relatively rare nonsynonymous SNPs, 376CÀT (Gln126X), 1291TÀC (Phe431Leu), 1322GÀA (Ser441Asn), 1465TÀC (Phe489Leu), and 1515delC (Phe506SerfsX4) were already detected in a Japanese population by Itoda et al.17) andWor Kobayashi et al.,23) but not found in other ethnic groups. Login to comment
98 As previously reported in various ethnic groups,14,18) perfect LD (r2 1.0) was observed between 34GÀA (Val12Met) and IVS2{ 36AÀG. Login to comment
130 In Block 1, seven haplotype groups (*1 to *7) were inferred, and the groups of *2 to *7 harbored non-synonymous SNPs, 421CÀA (Gln141Lys) (*2), 34GÀA (Val12Met) (*3), 376CÀT (Gln126X) (*4), 38CÀT (Ser13Leu) (*5), 479GÀA (Arg160Gln) (*6), and 1060GÀA (Gly354Arg) (*7). Login to comment
134 The haplotype-tagging SNPs (htSNPs) that were able to resolve the 8 common haplotypes were the following 7 variations: IVS199GÀA, 34GÀA (Val12Met), IVS293TÀC, 376CÀT (Gln126X), 421CÀA (Gln141Lys), IVS6217AÀG, and IVS6204CÀT. Login to comment
154 Mizuarai et al. showed that 34GÀA (Val12Met) was associated with reduced drug resistance in polarized LLC-PK1 cells, which might be caused by its impaired apical membrane localization.25) In contrast, several groups did not nd any signicant eects of Val12Met on the protein expression levels as well as drug resistance using stable and transient mammalian expression systems.16,24,26) According to Imai et al. and Kondo et al.,16,24) the Gln141Lys substitution resulted in decreased protein expression and reduced drug resistance. Login to comment
162 Except for Val12Met, Gln126X, and Gln141Lys, the allele frequencies of eight nonsynonymous SNPs were less than 0.01, and these low frequency variations do not largely contribute to the overall heterozygosity of ABCG2; however, they might have clinical importance. Login to comment
188 In a Swedish population, |1203ä |1200delCTCA was reported to be linked with 34GÀA (Val12Met), the representative SNP in the Block1 *3 group.19) Due to the high (0.54) and low (0.02) allele frequencies of |1203ä|1200delCTCA and 34GÀA (Val12Met), respectively, the Block |1 *1bBlock 1 *3 combination is not predominant in the Swedish population. Login to comment
189 Zhou et al. suggested that |1203ä |1200delCTCA might inuence pharmacokinetic parameters of irinotecan.31) On the other hand, the functional signicance of 34GÀA (Val12Met) is not fully elucidated as described above.16,2426) In this context, the major combination in Japanese, Block |1 *1bBlock 1 *3a, should be carefully considered in pharmacogenetic studies in Japanese. Login to comment

PMID: 16766035 [PubMed] Cascorbi I et al: "Role of pharmacogenetics of ATP-binding cassette transporters in the pharmacokinetics of drugs."

No. Sentence Comment

901 Both identified 34G>A (V12M) and 421C>A (Q141K). Login to comment
914 0.235 Exon 2 c. 34 G>A V12M 0.17 0.04a 0.06b IVS 2+16 A>G ? Login to comment
929 Moreover, decreased transport rates were found in Sf9 insect cells, transfected with the V12M variant (Morisaki et al., 2005). Login to comment
934 Interestingly, V12M was associated with elevated activity compared to the wild-type, whereas ABCG2 with premature stop-codon lacked any activity as expected (Ishikawa et al., 2005). Login to comment

PMID: 16784736 [PubMed] Zhang W et al: "Role of BCRP 421C>A polymorphism on rosuvastatin pharmacokinetics in healthy Chinese males."

No. Sentence Comment

109 In addition, the G34A (V12M) mutation causes disturbance of membrane localization and happens relatively high in Asians. Login to comment

PMID: 16791115 [PubMed] Anderson PL et al: "Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study."

No. Sentence Comment

165 For example, intracellular ZDV-phosphate concentrations (mono-, di-, tri-) were dependent on the cellular expression of MRP4,23,24 and the pharmacological activity of ZDV and 3TC was dependent on the expression of BCRP.25 Two relatively common functional polymorphisms have been identified in the BCRP gene, one a G-to-A change at nucleotide 34 in exon 2 (Val to Met at codon 12) and a C-to-A change at nucleotide 421 in exon 5 (Glu to Lys at codon 141).26 However, we did not observe relationships between these polymorphisms and ZDV-triphosphate or 3TC-triphosphate concentrations. Login to comment

PMID: 16842198 [PubMed] Perez-Tomas R et al: "Multidrug resistance: retrospect and prospects in anti-cancer drug treatment."

No. Sentence Comment

219 The results showed three BCRP-coding SNPs [G34A (V12M), C376T (Q126stop) and C421A (Q141K)] (Fig. 6). Login to comment
220 The V12M and the Q141K SNPs greatly Fig. (6). Login to comment
227 V12M- and 315-6-BCRP transfected cells showed similar and somewhat lower BCRP protein and drug resistance levels than did wild-type BCRP-transfected cells [137, 138]. Login to comment

PMID: 16863427 [PubMed] Xia CQ et al: "Breast cancer resistance protein in pharmacokinetics and drug-drug interactions."

No. Sentence Comment

170 The G34A variant in exon 2, resulting in a Val12Met amino acid change, has been associated with a low BCRP protein expression and an altered efflux function in cancer cells [73-74]. Login to comment

PMID: 16877258 [PubMed] Wakabayashi K et al: "Human ABC transporter ABCG2 in xenobiotic protection and redox biology."

No. Sentence Comment

176 Based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in Sf9 insect cells. Login to comment

PMID: 17015488 [PubMed] Sarkadi B et al: "Human multidrug resistance ABCB and ABCG transporters: participation in a chemoimmunity defense system."

No. Sentence Comment

997 In healthy individuals or patients, altogether eight nonsynonymous (V12M, Q141K, I206L, F431L, S441N, F489L, N590Y, D620N), five synonymous (silent) (c. Login to comment
1006 From these numerous reported alterations, two protein variants, V12M, and Q141K, were found in relatively high frequencies, with significant differences in allele frequencies in different areas of the world (Fig. 11). Login to comment
1007 The V12M polymorphism affects the NH2-terminal intracellular region of the protein. Login to comment
1009 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90%), while only 2% in a Swedish population (18, 418), and also with a significant difference in allele frequencies in Caucasian and Japanese populations. Login to comment
1016 (251), by using stable mammalian expression systems, found that in PA317 or HEK-293 cells the expressed Q141K ABCG2 protein had a lower expression level than the wild-type ABCG2, or the V12M variant. Login to comment
1018 (251) demonstrated that both the V12M and Q141K ABCG2 could reach the plasma membrane in the HEK-293 cells, while a significant portion of Q141K remained intracellular. Login to comment
1023 (247) expressed ABCG2 in polarized LLC-PK1 cells, and by using confocal microscopy, the authors observed that the wild-type ABCG2 and Q141K showed mainly apical staining, while the V12M variant 1210 SARKADI, HOMOLYA, SZAKA´ CS, AND VA´ RADI Physiol Rev • VOL 86 • OCTOBER 2006 • www.prv.org showed mostly intracellular localization. Login to comment
1025 (188) also used LLC-PK1 cells to express the V12M and Q141K variants and found that all polymorphisms, including V12M and Q141K, had an apical localization. Login to comment
1028 (247), when the V12M or Q141K-transfected LLC-PK1 cells were challenged by mitoxantrone, topotecan, or an indolocarbazole topoisomerase I inhibitor. Login to comment
1033 Two studies compared the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes (247, 251). Login to comment
1035 On the other hand, the V12M ABCG2 showed a similar ATPase activity as the wild-type protein. Login to comment
1038 Clearly, more detailed studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the altered cellular localization found for the V12M and Q141K variants under certain conditions. Login to comment

PMID: 17027309 [PubMed] Li YF et al: "Towards understanding the mechanism of action of the multidrug resistance-linked half-ABC transporter ABCG2: a molecular modeling study."

No. Sentence Comment

174 Subsequently, a symmetric dimer Y.-F Li et al. / Journal of Molecular Graphics and Modelling 25 (2007) 837-851844 Table 4 Locations of mutations as predicted by the ABCG2 model and functional correlation Mutation Position in ABCG2 Phenotype Reference V12M N-terminal Membrane localization, SNP, and somewhat lower expression and lower resistance [22] S25Pa N-terminal Low drug resistance for the cell line due to lower expression at cell surface [42] T82Aa NBD, Walker A Low drug resistance for the cell line due to lower expression at cell surface [42] K86M NBD, Walker A No expression at cell surface, retained in the Golgi [43] K86I NBD, Walker A No expressed at cell surface [43] Q141K NBD SNP with lower protein expression and low drug resistance [22,23] T237V NBD Fully functional b I239K,R NBD Loss of expression may be due to structural disruption b R309G Linkerc Low drug resistance [42] D315-6 Linker Deletion mutant for A315 and T316. Login to comment

PMID: 17159598 [PubMed] Deeken JF et al: "Toward individualized treatment: prediction of anticancer drug disposition and toxicity with pharmacogenetics."

No. Sentence Comment

326 These SNPs occur at mRNA positions 34 (V12M; exon 2), 421 (Q141K, exon 16), 616 (I206L, exon 6) and 1768 (N590Y, exon 15). Login to comment
328 The SNPs of V12M, I206L and N590Y have not to date been found to confer an alteration in protein expression or function. Login to comment
331 Table 12 Ethnic frequencies (%) of allelic variants in ABCG2 gene Allelic variant Caucasians African-Americans Asians Hispanics Africans Middle Easterns V12M 2 4 20-45 40 5 Q141K 11-14 2.3-5.0 15-35 10 1.0 13 I206L 0 0 0 10 0 N590Y 1 Sources: [150-153]. Login to comment

PMID: 17228519 [PubMed] Tamura A et al: "Genetic polymorphisms of human ABC transporter ABCG2: development of the standard method for functional validation of SNPs by using the Flp recombinase system."

No. Sentence Comment

48 Standard method for functional validation of ABCG2 SNPs Journal of Experimental Therapeutics and Oncology Vol. 6 2006 3 Plasma Membrane inside outside S S S homodimer A B CH2N COOH V12M Q141K F208S S248P F431L S441N F489L R482G R482T Acquired mutation Figure 1. Login to comment
67 PCR primers and conditions for site-directed mutagenesis to create variants of ABCG2 Variant Forward/Reverse Primer sequence (5` →→ 3`) Primer length % GC Tm (ºC) (F/R) primers (bases) V12M F CGAAGTTTTTATCCCAATGTCACAAGGAAACAC 33 39 55 R GTGTTTCCTTGTGACATTGGGATAAAAACTTCG Q141K F CGGTGAGAGAAAACTTAAAGTTCTCAGCAGCTCTT 35 42 55 R AAGAGCTGCTGAGAACTTTAAGTTTTCTCTCACCG F208S F TGATCCTTCCATCTTGTCCTTGGATGAGCCTACAA 35 45 55 R TTGTAGGCTCATCCAAGGACAAGATGGAAGGATCA S248P F TTCATCAGCCTCGATATCCCATCTTCAAGTTGTTT 35 40 55 R AAACAACTTGAAGATGGGATATCGAGGCTGATGAA F431L F AGCTGGGGTTCTCCTCTTCCTGACGACC 28 60 62 R GGTCGTCAGGAAGAGGAGAACCCCAGCT S441N F AACCAGTGTTTCAGCAATGTTTCAGCCGTGGAAC 34 47 59 R GTTCCACGGCTGAAACATTGCTGAAACACTGGTT F489L F GAGGATGTTACCAAGTATTATACTTACCTGTATAGTGTACTTCATG 46 34 62 R CATGAAGTACACTATACAGGTAAGTATAATACTTGGTAACATCCTC Sites of mutagenesis are indicated by underbars. Login to comment
104 Standard method for functional validation of ABCG2 SNPs Journal of Experimental Therapeutics and Oncology Vol. 6 2006 0 1 2 RelativemRNAlevel Mock WT V12M Q141K mRNA A ABCG2 GAPDH Mock WT F208S S248P F431L S441N F489L ABCG2 GAPDH 0 1 2 RelativemRNAlevel mRNA B GAPDH ABCG2 Mock WT F208S S248P F431L S441N F489L Protein 0 1 2 Relativeproteinlevel * * * C DProtein GAPDH ABCG2 0 1 2 Relativeproteinlevel * * Mock WT V12M Q141K Figure 3. mRNA and protein expression levels of ABCG2 WT and variants expressed in Flp-In-293 cells. Login to comment
114 Characterization of V12M, Q141K, F208S, S248P, F431L, S441N, and F489L variants expressed in Flp-In-293 cells The mRNA levels of ABCG2 and GAPDH were measured by quantitative PCR, and the ratios of ABCG2 variants vs. GAPDH were plotted. Login to comment
119 Figure 3 demonstrates mRNA and protein levels of ABCG2 WT and V12M, Q141K, F208S, S248P, F431L, S441N, and F489L variants expressed in Flp-In-293 cells. Login to comment
121 The Q141K variant of ABCG2 stably expressed in Flp-In-293 cells had a lower expression level than did the wild-type ABCG2 or the V12M variant (Fig. 3C). Login to comment
124 The other variants, i.e., V12M, Q141K, S248P, F431L, and F489L, were expressed in plasma membrane as was ABCG2 WT. Login to comment
132 Figure 4 summarizes the characteristics of those Tamura et al. 8 Journal of Experimental Therapeutics and Oncology Vol. 6 2006 Class Class Class Class WT V12M Q141K F431L S248P F489L F208S S441N R482G R482T Protein expression + + + + + + - - + + SN-38 resistance + + + + + / - - - - + + MX resistance + + + + / - - - - - + + Doxorubicin resistance - - - - - - - - + + Daunorubicin resistance - - - - - - - - + + Figure 4. Login to comment
138 WT, V12M, and Q141K form one group where protein expression and resistance to SN-38 and mitoxantrone are positive, but contribution to doxorubicin- and daurorubicin-resistance are negative. Login to comment
142 Finally, the acquired mutants R482G and R482T form another group, which is characteristic Standard method for functional validation of ABCG2 SNPs Journal of Experimental Therapeutics and Oncology Vol. 6 2006 9 Table 3 Remarks mRNA Protein Author Ref Host cell Vector Expression SNP expression expression Imai et al. (15) PA317 pHaL-IRES-DHFR bicistronic Stable V12M Similar to WT Similar to WT - - retrovirus vector plasmid - Q141K Similar to WT Lower than WT Mizuarai et al. (18) LLC-PK1 pcDNA3.1(+) Stable V12M Similar to WT N.D. - - - - Q141K Similar to WT N.D. Morisaki et al. (25) HEK293 pcDNA3.1 Stable V12M Vary among clones Vary among clones - - - - Q141K Vary among clones Vary among clones - - - - D620N Vary among clones Vary among clones Kondo et al. (26) LLC-PK1/ pcDNA3.1/ Stable/ V12M N.D. Similar to WT - HEK293 Adenovirus Transient Q141K N.D. 30 - 40% of WT - - - - A149P N.D. Similar to WT - - - - R163K N.D. Similar to WT - - - - Q166E N.D. Similar to WT - - - - P269S N.D. Similar to WT - - - - S441N N.D. Lower than WT Vethanayagam (27) HEK293 pcDNA3.1/myc-His(-) Stable I206L N.D. Vary among clones et al. - - - - N590Y N.D. Vary among clones - - - - D620N N.D. Vary among clones N.D.: No data Table 2. Login to comment
143 Resistance profile (IC50 ) of ABCG2 Compounds IC50 (nM) Mock WT V12M Q141K F208S S248P F431L S441N F489L SN-38 1.0 ± 0.2 49.9 ± 6.0 51.1 ± 13.8 17.7 ± 0.9 0.7 ± 0.0 3.6 ± 0.4 12.1 ± 1.5 0.8 ± 0.0 3.9 ± 0.4 (49.9)* (51.1)* (17.7)* (0.7) (3.6) (12.1)* (0.8) (3.9) Mitoxantorone 7.0 ± 1.1 108.0 ± 4.9 94.0 ± 18.6 46.7 ± 12.7 5.1 ± 1.0 13.4 ± 1.3 15.2 ± 1.4 5.7 ± 0.8 12.1 ± 6.2 (15.4)* (13.4)* (6.7)* (0.7) (1.9) (2.2)* (0.8) (1.7) Doxorubicin 38.8 ± 3.8 105.2 ± 24.9 123.6 ± 35.3 156.8 ± 27.5 19.9 ± 8.7 23.7 ± 6.7 43.5 ± 6.1 39.4 ± 4.1 47.6 ± 3.1 (2.7) (3.2) (4.0) (0.5) (0.6) (1.1) (1.0) (1.2) Daounorubicin 13.0 ± 0.6 32.3 ± 6.5 58.2 ± 5.0 57.7 ± 4.1 14.1 ± 2.3 22.1 ± 4.2 15.9 ± 1.2 13.3 ± 1.1 23.6 ± 1.6 (2.5) (4.5) (4.4) (1.1) (1.7) (1.2) (1.0) (1.8) Etoposide 117.1 ± 16.0 210.2 ± 18.4 297.3 ± 58.5 233.9 ± 54.2 122.9 ± 17.6 137.7 ± 14.8 139.1 ± 12.3 154.3 ± 8.5 186.9 ± 10.1 (1.8) (2.5) (2.0) (1.0) (1.2) (1.2) (1.3) (1.6) Vincristine 1.8 ± 0.2 4.3 ± 0.3 7.1 ± 1.4 5.6 ± 1.6 0.6 ± 0.0 4.3 ± 0.9 1.8 ± 0.3 0.9 ± 0.1 3.0 ± 0.7 (2.4) (3.0) (3.1) (0.3) (2.4) (1.0) (0.5) (1.7) The drug resistance profiles of ABCG2 WT and variants were obtained by incubating Flp-In-293/ABCG2 WT, V12M, Q141K, F208S, S248P, F431L, S441N, or F489L cells in the presence of SN-38, mitoxantrone, doxorubicin, daunorubicin, etoposide, or vincristine at different concentrations as described in Materials and Methods. Login to comment

PMID: 17237154 [PubMed] Lee SS et al: "Identification and functional assessment of BCRP polymorphisms in a Korean population."

No. Sentence Comment

3 BCRP V12M, Q141K, P269S, and Q126Stop were detected at frequencies of 23, 28, 0.2, and 1.9%, respectively. These four coding variants were also screened in Chinese and Vietnamese subjects; the allelic frequencies among the three populations were compared; and predictions were made as to the potential frequency of each variant. Login to comment
23 According to the current literature, the most frequent BCRP polymorphisms detected among different ethnic groups are 34GϾA, which codes for V12M, and 421CϾA, which codes for Q141K (Zamber et al., 2003). Login to comment
25 The BCRP V12M SNP has been reported as having similar activity to the wild type in terms of dehydroepiandro- This study was supported by the Ministry of Science and Technology (National Research Laboratory Program) and Korea Health 21 R&D Project, Ministry of Health and Welfare, Korea (03-PJ10-PG13-GD01-0002). Login to comment
31 However, Mizuarai et al. (2004) have shown disrupted membrane localization of the V12M variant, which results in decreased transport activity. Login to comment
34 The functional capability of the P269S variant to take up [3 H]estrone-3-sulfate (ES) and [3 H]MTX has been reported as being comparable with that of the wild-type protein TABLE 1 Primer sequences used for the amplification of the BCRP gene fragment and the annealing temperatures used in the PCR Name Region Primer Sequence (5Ј33Ј) Size PCR Condition base pair Tm; °C BCRP1P Promoter F: AACCCAGCTAGGTCAGACGA 557 60.0 R: TTTGAGTGGGCACAGCAC BCRP2P Promoter F: TTCCTAGGGTAGATGCAGCAG 509 60.0 R: CAGGGACAAGCCAAACACTC BCRP3P Promoter F: GTAGAGGCAGGGTTTCACCA 559 60.0 R: AAGTGATTGCGCATGTTCAG BCRP4P Promoter F: CGTGCCTGGCCTCTATGTAT 572 60.0 R: CTGACGCAGGCAGATCACT BCRP5P Promoter F: GCCACCACACCCAGTGTAAT 518 64.7 R: TGCAAAGTAAAAACAAATCAAAACC BCRP1E Exon 1 F: AGCTCGTCCCCTGGATGT 516 54.0 R: CCACCAACCTTTCCAGACAC BCRP2E Exon 2 F: CTGCTCATTGCCACACATTT 400 54.0 R: GCCAAAACCTGTGAGGTTCA BCRP3E Exon 3 F: GTCTCAAACTCCTGGCCTCA 403 54.0 R: GCGTTGCAAATGCTCAATAA BCRP4E Exon 4 F: TGGATTCAAAGTAGCCATGAGA 402 54.0 R: ATTCTCCCTGCCTTTTCACA BCRP5E Exon 5 F: GGTTCATCATTAGCTAGAACTTTACC 403 54.0 R: TGGAAAGCAACCATTTTTGA BCRP6E Exon 6 F: TCTTACAGGACTGGCACACG 426 54.0 R: CCTTCCCTACATTCTTACCTGCT BCRP7E Exon 7 F: TCAGGCTGAACTAGAGCAAACA 387 60.0 R: AGCACCAAATGGAACAAACA BCRP8E Exon 8 F: CATGGGAAGAAGAGAGAAAGAAA 412 60.0 R: CAAAAACACCAACAGCACTCA BCRP9E Exon 9 F: GGTGTTAGGGAAGCATCCAA 413 54.0 R: TGAAGCAGATGATAACAGAACCA BCRP10E Exon 10 F: GCCAAGCCATTGAGTGTTTA 386 60.0 R: TGGGCAACAGAGCATGAC BCRP11E Exon 11 F: CCACAACAATCCAAGACTGTG 423 60.0 R: GTAATCCTCCGGATCCCATC BCRP12E Exon 12 F: GGTCTAGCCCTGAGGATGTG 403 64.7 R: GAGTGCAAAATGGACAGGTG BCRP13E Exon 13 F: AGGGTGGTTGGAGAGTGGAT 412 60.0 R: AGCAGAGCCCCATTTACAGA BCRP14E Exon 14 F: TGAGTGTCTTGAGTAAGTGGAGAGA 420 54.0 R: GACTCCCCAGCCTTGTGTTA BCRP15E Exon 15 F: TCTTGATTGCCAGGGAAAAT 404 60.0 R: CGCGCACAACTCACTTTATG BCRP16E Exon 16 F: TGACGGATGCTAGGAATGAA 430 64.7 R: CCCATGGTTACTGTCTGAGGA TABLE 2 Primer sequences used for the pyrosequencing-based genotyping of functional BCRP variants SNPa Variant Primer Sequence (5Ј33Ј) Size PCR Condition base pair Tm; °C 34GϾA V12M 5Ј-Biotin-CTCTCCAGATGTCTTCCAGTAATG-3Ј 278 54.0 5Ј-GCCAAAACCTGTGAGGTTCA-3Ј For sequencing: 5Ј-AGTGTTCCTTTGTGGTTAC-3Ј 8191CϾT Q126Stop 5Ј-Biotin-ACTATCAGCCAAAGCACTTACCC-3Ј 174 54.5 5Ј-GTCTTAGCTGCAAGGAAAGATCCA-3Ј For sequencing: 5Ј-AATGTAATTCAGGTTACGTG-3Ј 8825CϾA Q141K 5Ј-Biotin-GTTGCAAGCCGAAGAGCTG-3Ј 69 54.0 5Ј-TGATGTTGTGATGGGCACTC-3Ј For sequencing: 5Ј-GACGGTGAGAGAAAACTT-3Ј 21850CϾT P269S 5Ј-Biotin-TAGCACCAAATGGAACAAACAC-3Ј 236 54.0 5Ј- TGTTTGATAGCCTCACCTTATTGG-3Ј For sequencing: 5Ј-GAAGACTTATGTTCCACG-3Ј a Position is indicated with respect to the start codon (ATG) of the BCRP gene; the A in the ATG triplet is designated as ϩ1, and the next base toward the 5Ј-end is designated as -1. Login to comment
37 Functional information on P269S is sparse, as compared with the amount of information that has been collected for other coding variants, such as V12M, Q141K, and the null allele Q126Stop. Login to comment
39 Therefore, we performed a functional study of the P269S variant among the four variants identified in the study (V12M, Q141K, P269S, and Q126Stop). Login to comment
65 All the subjects were screened for BCRP V12M, Q126Stop, Q141K, and P269S. Login to comment
105 SNP and Positionb Position Relative to Transcription Start Site Location Effect N Allelic Frequency % 1 -20296AϾG -1379 Promoter 92 13 2 -19855CϾT -938 Promoter 92 0.5 3 -19605AϾG -688 Promoter 92 0.5 4 -19031CϾT -114 Promoter 92 1.6 5 -18631CϾT ϩ286 5ЈUTR 92 2.2 6 34GϾA Exon 2 V12M 275 23 7 238AϾG Intron 2 92 25 8 7430AϾG Intron 3 92 9.8 9 8191CϾT Exon 4 Q126Stop 375 1.9 10 8825CϾA Exon 5 Q141K 275 28 11 21850CϾT Exon 7 P269S 674 0.2 12 26297GϾA Exon 9 92 1.1 13 38485AϾG Intron 11 92 24 14 40086insA Intron 12 92 0.5 15 40110GϾT Intron 12 92 22 16 42288CϾT Intron 13 92 67.4 17 42313TϾG Intron 13 92 2.2 18 44072CϾT Intron 13 92 23.4 19 44997AϾG Intron 14 92 49.5 20 45235CϾT Intron 15 92 20.1 a The reference sequence used has GenBank accession no. Login to comment
149 The four coding SNP were 34GϾA coding for V12M, 8191CϾT coding for Q126Stop, 8825CϾA coding for Q141K, and 21850CϾT coding for P269S. Login to comment
150 For more extensive evaluation of the allelic frequencies of the four BCRP variants found in the Korean population, the remaining 183 subjects were screened by pyrosequencing for the presence of V12M, Q126Stop, Q141K, and P269S. Login to comment
152 V12M and Q141K were found in 23 and 28% of Koreans, respectively. Login to comment
176 The haplotype analysis suggests that none of the Q141K-containing haplotypes are linked to the V12M variant. Login to comment
177 To support this strong linkage, the V12M and Q141K variations were assigned to the same haplotype block among two discrete haplotype blocks of the BCRP gene (Fig. 1B). Login to comment
200 From the screening of four nonsynonymous variants in other ethnic groups, the allelic frequencies of V12M, Q126Stop, Q141K, and P269S were obtained (Table 4). Login to comment
201 The frequency of V12M was 10 to 13% higher in Chinese and Vietnamese subjects than in Koreans, whereas Q141K showed no significant differences among the three Asian ethnic groups. Login to comment
219 Among the BCRP coding variants, V12M and Q14lK were the most common in Koreans, with allelic frequencies of 23 and 28%, respectively. These variants are also found frequently in other ethnic groups, such as Caucasians, Japanese, and Chinese (Zamber et al., 2003; Kobayashi et al., 2005). Login to comment
221 The allelic frequency of V12M in Koreans (23%) is much lower than that reported for Southeast Asians (45%), Pacific Islander (64%), Mexican-Indian (90%), and Hispanic (40%) subjects (Zamber et al., 2003). Login to comment
230 Haplotypes 4, 8, and 11 indicate that a single promoter SNP (20296AϾG) and the 238AϾG change accompany the V12M nonsynonymous change in Koreans (Table 3). Login to comment
234 Our results on BCRP haplotypes in the Korean population TABLE 4 Haplotype distribution of BCRP gene in Koreans PNS 69202- G>A 43 A>G 832 G>A 0347 G>A 5288 A>C 58483 G>A 01104 T>G 88224 T>C 27044 T>C 79944 G>A 53254 T>C ycneuqerF )%( egnahcAA K141QM21V 4.621 2 9.91 3 8.7 4 6.7 5 4.7 6 9.5 7 7.4 8 9.2 9 5.2 01 8.1 11 7.1 21 4.1 31 1.1 Haplotype 41 1.1 TABLE 5 Expected allelic frequencies of BCRP V12M, Q126Stop, Q141K, and P269S variants in different Asian populations Population No. Login to comment
235 of Subjects Allelic Frequency (95% CI) V12M Q126Stop Q141K P269S % % % % Korean 275-674a 23 (19.6-26.6) 1.9 (0.9-2.9) 28 (23.8-31.2) 0.2 (0-0.4) Chinese 191 33b (28.5-37.9) 0.5 (0-1.2) 29 (24.3-33.3) 0 (0-0.1) Vietnamese 140 36b (30.8-42.0) 0.4 (0-1.1) 31 (25.7-36.5) 0.7 (0-1.7) a The numbers of subjects genotyped for the V12M, Q126Stop, Q141K, and P269S variants were 275, 375, 275, and 674, respectively. Login to comment
239 The V12M SNP has been reported to be associated with membrane localization (Mizuarai et al., 2004). Login to comment
259 Similarly, BCRP V12M has been reported to exhibit the same transport function as the wild type (Kondo et al., 2004), whereas another study has shown decreased activity caused by disrupted membrane localization (Mizuarai et al., 2004). Login to comment

PMID: 17297656 [PubMed] Tamura A et al: "Re-evaluation and functional classification of non-synonymous single nucleotide polymorphisms of the human ATP-binding cassette transporter ABCG2."

No. Sentence Comment

3 To re-evaluate the effect of single nucleotide polymorphisms (SNP) of ABCG2 in vitro, we created a total of seven variant cDNAs (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) by site-directed mutagenesis and stably expressed each of them in Flp-In-293 cells using the Flp recombinase system. Login to comment
7 Drug resistance profiles of Flp-In-293 cells expressing two major SNP variants (V12M and Q141K) toward the drug SN-38 demonstrated that the IC50 value (drug concentrations producing a 50% reduction of cell growth) for Q141K was approximately 50% of that for wild type. Login to comment
104 Characterization of WT ABCG2, V12M and Q141K expressed in Flp-In-293 cells. Login to comment
105 As shown in Fig. 2A, mRNA levels of WT ABCG2 as well as its major SNP variants (V12M and Q141K) were represented evenly in Flp-In cells. Login to comment
112 Figure 2B depicts the immunofluorescence images of Flp-In-293/Mock, Flp-In-293/ABCG2 (WT), Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells. Login to comment
116 Drug resistance profiles of Flp-In-293 cells expressing WT ABCG2, V12M and Q141K variants toward camptothecin analogs. Login to comment
117 To examine the drug resistance profiles, we incubated Flp-In-293/ABCG2 (WT), Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells with SN-38 and the new camptothecin analogs at different concentrations for 96 h, after which we observed the cell survival rates. Login to comment
118 Flp-In-293/ABCG2 (WT), Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells exhibited strong resistance to SN-38, SN-355 and SN-398, as represented by large IC50 values (Fig. 3). Login to comment
119 Interestingly, the V12M variant provided the cells with higher drug resistance to SN-38, SN-355 and SN-398 than did WT ABCG2 (Fig. 3). Login to comment
135 (V12M) or Flp-In-293/ABCG2 (Q141K) cells exhibited resistance toward SN-22, SN-343, SN-348, SN-349, SN-351, SN-352, SN-353, SN-364, SN-397, SN-443 or SN-444. Login to comment
136 These results suggest that camptothecin analogs lacking the hydroxyl or amino group at position 10 or 11 are not substrates for WT ABCG2 or the V12M and Q141K variants. Login to comment
152 Considered overall, the minor SNP variants were less effective in drug resistance than the V12M and Q141K variants. Login to comment
155 For this purpose, we expressed WT ABCG2, V12M, Q141K, S248P, F431L, F489L, R482G and R482T in Sf9 insect cells and prepared plasma membranes as described previously,(16,35) as the plasma membrane of Sf9 cells has lower endogenous background ATPase activity than Flp-In-293 cells. Login to comment
159 Honjo et al. first identified non-synonymous SNP of V12M and Q141K. Login to comment
160 (23) The V12M polymorphism in exon 2 (34G >A) affects the N-terminal intracellular region of the protein. Login to comment
162 The V12M polymorphism was found in all ethnic groups tested, with the highest allele frequency in Mexican-Indians (90% of only five individuals tested), but only 1.7% in a Swedish population. Login to comment
164 Thus, there is a large difference in the allele frequency of the V12M polymorphism among different ethnic groups. Login to comment
169 The effect of camptothecin analogs on the growth of Flp-In-293/ABCG2 (wild type), Flp-In-293/ABCG2 (V12M) or Flp-In-293/ABCG2 (Q141K) cells. Login to comment
176 Resistance profile (IC50) of ABCG2 Compound IC50 (nM) Mock Wild type V12M Q141K F208S S248P F431L S441N F489L SN-38 0.9 40.0 (44.4) 40.0 (44.4) 17.0 (18.9) 0.6 (0.7) 3.0 (3.3) 10.0 (11.1) 0.7 (0.8) 3.1 (3.4) Mitoxantorone 5.2 >100 (>19) 92.0 (17.7) 45.0 (8.7) 4.5 (0.9) 11.0 (2.1) 21.0 (4.0) 4.6 (0.9) 11.0 (2.1) Doxorubicin 32.0 78.0 (2.4) 100.0 (3.1) 110.0 (3.4) 20.0 (0.6) 20.0 (0.6) 40.0 (1.3) 21.0 (0.7) 45.0 (1.4) Daunorubicin 12.0 30.0 (2.5) 50.0 (4.2) 50.0 (4.2) 12.0 (1.0) 21.0 (1.8) 14.0 (1.2) 12.0 (1.0) 19.0 (1.6) Etoposide 110.0 200.0 (1.8) 220.0 (2.0) 200.0 (1.8) 110.0 (1.0) 120.0 (1.1) 120.0 (1.1) 130.0 (1.2) 170.0 (1.5) Vincristine 1.4 4.0 (2.9) 5.0 (3.6) 4.5 (3.2) 0.6 (0.4) 4.0 (2.9) 1.4 (1.0) 0.8 (0.6) 2.8 (2.0) Relative resistances to mock cells are described in parentheses. Login to comment
202 As one of the specific aims of the present study, we functionally classified the non-synonymous polymorphisms (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) in terms of their protein expression level, drug resistance profile and prazosin-stimulated ATPase activity. Login to comment
206 As shown in Fig. 5B, it is obvious that WT, V12M and Q141K form one group where protein expression, methotrexate and porphyrin transport, and resistance to SN-38 and mitoxantrone are positive, but contribution to doxorubicin- and daurorubicin- Fig. 4. Login to comment
221 (32,33) As demonstrated in Fig. 3, the new camptothecin analogs that were non-substrates for ABCG2 circumvented ABCG2-mediated drug resistance without any influence from major SNP (i.e. V12M and Q141K). Login to comment

PMID: 17373578 [PubMed] Yoshioka S et al: "The identification of two germ-line mutations in the human breast cancer resistance protein gene that result in the expression of a low/non-functional protein."

No. Sentence Comment

21 In our previous study, we identified three nonsynonymous SNPs within the BCRP gene, G34A substituting Met for Val-12 (V12M), C376T substituting a stop codon for Gln-126 (Q126Stop), and C421A substituting Lys for Gln141 (Q141K). Login to comment
42 The cells were selected with 120 ng/mL of methotrexate, and the resulting mixed populations of resistant cells were designated as PA/WT, PA/V12M, PA/ G51C, PA/Q141K, PA/T153M, PA/I206L, PA/F208S, PA/ S248P, PA/F431L, PA/N590Y and PA/D620N, respectively. The PA/F208S clones and PA/F431L clones were obtained by limiting dilution. Login to comment
43 Cell Growth Inhibition Assay Anticancer agent resistance levels in both the parental PA317 cells and in the various BCRP transfectants were Table I. Frequencies of Germ-line Mutations/SNPs Within The BCRP Gene Variation Frequency (%) Number Population Reference Nucleotide Amino acid G34A V12M 19 29 Japanese 17 G151T G51C 0.1a 350 Japanese C376T Q126Stop 1.2 124 Japanese 17 C421A Q141K 26.6 124 Japanese 17 C458T T153M 3.3 30 Cell line 32 C496G Q166E 0.3a 200 Japanese A616C I206L 20 10 Hispanic 33 T623C F208S 0.3a 200 Japanese T742C S248P 0.5a 200 Japanese T1291C F431L 0.6b 260 Japanese 34 A1768T N590Y 1.1 88 Caucasians 33 G1858A D620N 1.1 90 unknown 35 a Determined in this study. Login to comment
45 V12M Q141K D620N N590Y F431L S248P F208S I206L T153M G51C Q166E OUT MEMBRANE IN Fig. 1. Login to comment
75 SN-38 Resistance Levels of PA317 Transfectantsa Cell type IC50 (nmol/L) Degree of resistance PA317 11 T 0.2 1 PA/WT 550 T 16 50 PA/V12M 490 T 13 45 PA/Q141K 110 T 5.9 10 PA/T153M 260 T 15 24 PA/Q166E 680 T 40 62 PA/F208S 10 T 0.7 1 PA/F431L 34 T 0.9 3 PA/D620N 190 T 5.7 17 a Cells were cultured for 5 days with various concentrations of SN-38. Login to comment
85 Similar to previous findings (14), PA/V12M cells were observed to express similar amounts of BCRP compared with PA/WT cells, whereas PA/Q141K cells expressed significantly lower amounts of BCRP than PA/WT (Fig. 2a). Login to comment
130 The resulting mixed populations of cells were designated a PA/WT, PA/V12M, PA/G51C, PA/Q141K, PA/ T153M, PA/I206L, PA/F208S, PA/S248P, PA/F431L, PA/ N590Y and PA/D620N. Login to comment

PMID: 17375082 [PubMed] Hardwick LJ et al: "The emerging pharmacotherapeutic significance of the breast cancer resistance protein (ABCG2)."

No. Sentence Comment

145 Imai et al. (2002a) sequenced cDNA from 11 human tumours and identified SNPs G34A (V12M) and C421A (Q141K), a splice variant 944-949 deletion (A315- T316), and later, an additional C376T (G126Stop) polymorphism. Login to comment

PMID: 17494054 [PubMed] Hu LL et al: "BCRP gene polymorphisms are associated with susceptibility and survival of diffuse large B-cell lymphoma."

No. Sentence Comment

18 BCRP G34A (Val12Met) and C421A (Gln141Lys) polymorphisms occurred at high frequency in most ethnic populations and have been shown to be associated with the expression and activity of BCRP protein. Login to comment
21 Based on these evidences, we hypothesize that BCRP G34A (Val12Met) and C421A (Gln141Lys) polymorphisms should have potential effect on the susceptibility and prognosis of diseases. Login to comment

PMID: 17504223 [PubMed] Xia CQ et al: "Evaluation of drug-transporter interactions using in vitro and in vivo models."

No. Sentence Comment

119 The function of seven single nucleotide polymorphisms (SNPs) in BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N BCRP) was determined using membrane vesicles from HEK293 cells infected with the recombinant adenoviruses containing the corresponding BCRP cDNAs [45]. Login to comment
121 Furthermore, the transport rate of estrone sulfate, dehydroepiandrosterone sulfate (DHEAS), methotrexate, and p-aminohippurate was almost the same for the wild type, V12M, Q141K, A149P, R163K, Q166E, and P269S BCRP variants when it is normalized by the expression levels of BCRP protein. Login to comment

PMID: 17505995 [PubMed] Fischer S et al: "ATP-binding cassette transporter ABCG2 (BCRP) and ABCB1 (MDR1) variants are not associated with disease susceptibility, disease phenotype response to medical therapy or need for surgeryin Hungarian patients with inflammatory bowel diseases."

No. Sentence Comment

60 Detection of MDR1 and ABCG2 polymorphisms The sequence variants (SNPs) of the two ABC transporters studied were: ABCB1 (MDR1): c.2677G/T/A or G2677T/A (Ala893Ser/Thr, exon 21, SNP database ID: rs2032582) and c.3435C/T or C3435T (silent base-substitution I1145I, exon 26, SNP database ID: rs1045642); ABCG2 (BCRP/MXR): c.34G/A or G34A (Val12Met, exon 2, SNP database ID: rs2231137; c.421C/A or C421A (Gln141Lys, exon 5, SNP database ID: rs2231142). Login to comment

PMID: 17507636 [PubMed] Weiss JR et al: "Concordance of pharmacogenetic polymorphisms in tumor and germ line DNA in adult patients with acute myeloid leukemia."

No. Sentence Comment

60 Gene information and K statistics for matched AML and buccal DNA samples (N = 80) Gene Single nucleotide polymorphism location Chromosome rs nos. j Asymptotic error Confidence interval No. of evaluable cases (%) No. of nonmatching genotype calls ABCB1-03 Ex27-55A>C>G>T; I1144M 7q21.1 rs1045642 1.00 77 (96.3) 0 ABCB1-05 Ex22-9A>C>G>T; A892S 7q21.1 rs2032582 0.96 0.031 0.89-1.02 76 (95.0) 2 ABCB1-24 Ex13+12 A>G; G412G 7q21.1 rs1128503 0.98 0.023 0.95-1.02 76 (95.0) 1 ABCC1 Ex8 T825C; V275V 16p13.1 rs246221 1.00 76 (95.0) 0 ABCC1 Ex28 G4002A; S1334S 16p13.1 rs2230671 1.00 78 (97.5) 0 ABCC1 Ex9 T1062C; L562L 16p13.1 rs35587 0.98 0.022 0.93-1.02 77 (96.3) 1 ABCG2 Ex5 C421A; Q141K 4q22 rs2231142 1.00 75 (93.8) 0 ABCG2 Ex2 G34A; V12M 4q22 rs2231137 1.00 75 (93.8) 0 CAT-01 À329T>C 11p13 rs1001179 1.00 78 (97.5) 0 GPX1-01 Ex1-226C>T; P200L 3p21.3 rs1050450 0.96 0.029 0.90-1.02 79 (98.8) 2 SOD2-01 Ex2+24C>T; V16A 6q25.3 rs1799725 0.98 0.020 0.94-1.02 77 (96.3) 1 GSTA1-01 À4621T>C 6p12.1 rs3957357 1.00 78 (97.5) 0 GSTP1-01 Ex5-24A>G; I105V 11q13 rs947894 0.96 0.030 0.90-1.02 78 (97.5) 2 GSTM1 Gene deletion 1p13.3 1.00 77 (96.3) 0 GSTT1 Gene deletion 22q11.23 1.00 77 (96.3) 0 CYP3A4-02 À391A>G 7q21.1 rs2740574 0.94 0.053 0.89-1.05 77 (96.3) 1 CYP2C8 A1196G; R399K 10q23.33 rs10509681 0.96 0.040 0.88-1.04 77 (96.3) 1 CYP2C8 C792G; M264I 10q23.33 rs1058930 0.96 0.041 0.88-1.04 77 (96.3) 1 MGMT-01 Ex4-13A>G; I143V 10q26 rs2308321 1.00 80 (100.0) 0 XPD312 Ex10-16G>A; D312N 19q13.3 rs1799793 1.00 73 (91.3) 0 XPD751 Ex23-61A>C; K751Q 19q13.3 rs13181 0.98 0.022 0.93-1.02 76 (95.0) 1 XRCC1 Ex10-4A>G; Q399R 19q13.2 rs25487 1.00 74 (92.5) 0 CDA A79C; K27Q 1p36.2-p35 rs2072671 1.00 77 (96.3) 0 NOTE: Values of n: j > 0.75 (excellent agreement beyond chance), j between 0.40 and 0.75 (fair to good agreement), j < 0.40 (poor agreement). Login to comment
62 j Asymptotic error Confidence interval No. of evaluable cases (%) No. of nonmatching genotype calls ABCB1-03 Ex27-55A>C>G>T; I1144M 7q21.1 rs1045642 1.00 77 (96.3) 0 ABCB1-05 Ex22-9A>C>G>T; A892S 7q21.1 rs2032582 0.96 0.031 0.89-1.02 76 (95.0) 2 ABCB1-24 Ex13+12 A>G; G412G 7q21.1 rs1128503 0.98 0.023 0.95-1.02 76 (95.0) 1 ABCC1 Ex8 T825C; V275V 16p13.1 rs246221 1.00 76 (95.0) 0 ABCC1 Ex28 G4002A; S1334S 16p13.1 rs2230671 1.00 78 (97.5) 0 ABCC1 Ex9 T1062C; L562L 16p13.1 rs35587 0.98 0.022 0.93-1.02 77 (96.3) 1 ABCG2 Ex5 C421A; Q141K 4q22 rs2231142 1.00 75 (93.8) 0 ABCG2 Ex2 G34A; V12M 4q22 rs2231137 1.00 75 (93.8) 0 CAT-01 À329T>C 11p13 rs1001179 1.00 78 (97.5) 0 GPX1-01 Ex1-226C>T; P200L 3p21.3 rs1050450 0.96 0.029 0.90-1.02 79 (98.8) 2 SOD2-01 Ex2+24C>T; V16A 6q25.3 rs1799725 0.98 0.020 0.94-1.02 77 (96.3) 1 GSTA1-01 À4621T>C 6p12.1 rs3957357 1.00 78 (97.5) 0 GSTP1-01 Ex5-24A>G; I105V 11q13 rs947894 0.96 0.030 0.90-1.02 78 (97.5) 2 GSTM1 Gene deletion 1p13.3 1.00 77 (96.3) 0 GSTT1 Gene deletion 22q11.23 1.00 77 (96.3) 0 CYP3A4-02 À391A>G 7q21.1 rs2740574 0.94 0.053 0.89-1.05 77 (96.3) 1 CYP2C8 A1196G; R399K 10q23.33 rs10509681 0.96 0.040 0.88-1.04 77 (96.3) 1 CYP2C8 C792G; M264I 10q23.33 rs1058930 0.96 0.041 0.88-1.04 77 (96.3) 1 MGMT-01 Ex4-13A>G; I143V 10q26 rs2308321 1.00 80 (100.0) 0 XPD312 Ex10-16G>A; D312N 19q13.3 rs1799793 1.00 73 (91.3) 0 XPD751 Ex23-61A>C; K751Q 19q13.3 rs13181 0.98 0.022 0.93-1.02 76 (95.0) 1 XRCC1 Ex10-4A>G; Q399R 19q13.2 rs25487 1.00 74 (92.5) 0 CDA A79C; K27Q 1p36.2-p35 rs2072671 1.00 77 (96.3) 0 NOTE: Values of n: j > 0.75 (excellent agreement beyond chance), j between 0.40 and 0.75 (fair to good agreement), j < 0.40 (poor agreement). Login to comment

PMID: 17509035 [PubMed] Kim HS et al: "The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine."

No. Sentence Comment

0 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine Ho-Sook Kim,1 Yu Eun Sunwoo,1 Ji Young Ryu,1 Ho-Jin Kang,1 Hye-Eun Jung,1 Im-Sook Song,1 Eun-Young Kim,1,2 Joo-Cheol Shim,1,3 Ji-Hong Shon1,2 & Jae-Gook Shin1,2 1 Department of Pharmacology and Pharmacogenomics Research Centre, Inje University College of Medicine, 2 Department of Clinical Pharmacology and 3 Department of Psychiatry, Inje University Busan Paik Hosptial, Busan, Korea Correspondence Jae-Gook Shin, MD, PhD, Department of Pharmacology and Clinical Pharmacology, Pharmacogenomics Research Centre, Inje University College of Medicine, 633-165 Gaegum-dong, Jin-gu, Busan 614-735, Korea. Login to comment
2 Received 19 September 2006 Accepted 15 March 2007 Published OnlineEarly 17 May 2007 Aims To evaluate the effects of three ABCG2 variants (Q141K, V12M and Q126X), which are known to have altered transport properties in vitro, on the disposition of lamivudine in healthy subjects. Login to comment
10 Conclusions Lamivudine appeared to be a substrate of ABCG2 in vitro, but the disposition of lamivudine was not significantly influenced by known in vitro functional variants of ABCG2, Q141K, V12M and Q126X in healthy subjects. Login to comment
23 It has also been reported that the ABCG2 G34A allele, resulting in a Val12Met substitution, causes the apical plasma membrane dislocalization of ABCG2 and produces a protein with significantly reduced ability to transport several drugs [15]. Login to comment
53 Weighted nonlinear regression analysis was performed in the fitting using Sigma plot (version 9.0; Systat Software Inc., Richmond, CA, USA) Subjects Unrelated Korean subjects (n = 183) had been genotyped for theABCG2 variants G34A(Val12Met), C376T (Gln126stop) and C421A (Gln141Lys). Login to comment
62 ABCG2 gene to determine the presence of the Val12Met, Gln126Stop and Gln141Lys alleles. Login to comment
85 After washing Table 2 Sequences of primers used for the amplification and sequencing analysis of ABCG2 genotype and the denaturation temperatures used in the PCR Name Primer sequence (5Ј,3Ј) Size PCR ( Tm; °C) ABCG2 V12M F: Biotin-CTCTCCAGATGTCTTCCAGTAATG 278 54 R: GCCAAAACCTGTGAGGTTCA S: CATTGGTGTTTCCTTGTGA ABCG2 Q126X F: GTCTTAGCTGCAAGGAAAGATCCA 174 54.5 R: Biotin-ACTATCAGCCAAAGCACTTACCC S: AATGTAATTCAGGTTACGTG ABCG2 Q141K F: TGATGTTGTGATGGGCACTC 69 54 R: Biotin-GTTGCAAGCCGAAGAGCTG S: GACGGTGAGAGAAAACTT F, forward primer; R, reverse primer; S, sequencing primer; Tm, melting temperature; PCR, polymerase chain reaction. Login to comment
116 Effect of ABCG2 variants on the pharmacokinetics of lamivudine To study the influence of ABCG2 variants on lamivudine pharmacokinetics, we included subjects with the Val12Met, Gln126Stop or Gln141Lys ABCG2 variants. Login to comment
135 The Val12Met polymorphism has also been associated with change in membrane localization and produces a protein with significantly decreased activity in transporting several Table3 Pharmacokineticparametersoflamivudineaftersingleoraladministrationof100mglamivudineinsubjectswithwild,Lys141/Lys141,Gln126/Stop126and Met12/Met12variantofABCG2 WildMet12/Met12Gln126/Stop126Lys141/Lys141 Meandifferencebetweenvariantsandwild P-valueMet12/Met12Gln126/Stop126Lys141/Lys141 Cmax(ngml-1 )742Ϯ297808Ϯ193840Ϯ151655Ϯ30966(-210,342)98(-198,394)-87(-389,215)0.68 Cmax,normal(ngml-1 )*736Ϯ303850Ϯ208926Ϯ230746Ϯ320114(-171,399)190(-133,513)10(-300,320)0.57 tmax(h)0.8Ϯ0.41.0Ϯ0.30.7Ϯ0.30.8Ϯ0.40.2(-0.2,0.6)-0.1(-0.5,0.3)0(-0.4,0.4)0.63 t1/2(h)5.5Ϯ2.47.1Ϯ2.05.5Ϯ2.17.7Ϯ4.91.6(-0.8,4)0(-2.6,2.6)2.2(-1.5,5.9)0.59 AUCinf(ngh-1 ml-1 )2480Ϯ5022552Ϯ6982422Ϯ2392207Ϯ101972(-552,696)-58(-555,439)-273(-1053,507)0.85 AUCinf,normal(ngh-1 ml-1 )*2440Ϯ3972604Ϯ5822654Ϯ3192573Ϯ1326164(-345,673)214(-214,642)133(-807,1073)0.69 CLtotal/F(lkg-1 h-1 )0.60Ϯ0.120.59Ϯ0.120.54Ϯ0.070.66Ϯ0.25-0.01(-0.14,0.12)-0.06(-0.18,0.06)0.06(-0.13,0.25)0.76 CLR(lkg-1 h-1 )0.29Ϯ0.050.26Ϯ0.050.26Ϯ0.050.28Ϯ0.09-0.03(-0.08,0.02)-0.03(-0.09,0.03)-0.01(-0.08,0.06)0.85 Vd/F(lkg-1 )4.8Ϯ2.65.9Ϯ1.44.2Ϯ1.24.7Ϯ2.41.1(-1.2,3.4)-0.6(-3.2,2.0)-0.1(-2.6,2.4)0.66 *Cmax,normalandAUCinf,normal:CmaxandAUCinfnormalizedto70kgbodyweight.EachvalueindicatesmeanϮSD(95%confidenceinterval). Login to comment
138 The ABCG2 Val12Met and Gln141Lys variants are common in Koreans, with allelic frequencies of 23 and 27.5%, respectively. Login to comment
157 Anderson et al. have recently shown that the intracellular concentration of lamivudine-triphosphate is not associated with ABCG2 Val12Met, Glu141Lys [33]. Login to comment
165 However, the Val12Met, Gln126stop and Gln141Lys polymorphisms of ABCG2 studied here, which have been previously shown to cause functional differences in the protein, did not alter the disposition of a single oral dose of 100 mg lamivudine in healthy volunteers. Login to comment

PMID: 17534875 [PubMed] Han JY et al: "Associations of ABCB1, ABCC2, and ABCG2 polymorphisms with irinotecan-pharmacokinetics and clinical outcome in patients with advanced non-small cell lung cancer."

No. Sentence Comment

81 of patients Genotype frequencies{ Allele frequencies§ w/w w/m m/m w m ABCB1 1236C > T Synonymous 105 14 57 34 0.405 0.595 2677G > T Ala893Ser 105 22 37 (GT) 10 (TT) 0.457 0.338 (T) 2677G > A Ala893Thr 15 (GA) 14 (TA) 0.205 (A) 7 (AA) 3435C > T Synonymous 105 43 51 11 0.652 0.348 ABCC2 À24C > T - 107 57 47 3 0.752 0.248 1249G > A Val417Ile 107 86 19 2 0.893 0.107 3972C > T Synonymous 107 51 48 8 0.701 0.299 ABCG2 34G > A Val12Met 106 60 41 5 0.759 0.241 421C > A Gln141Lys 105 59 42 4 0.762 0.238 w indicates wild type allele; m, mutant type allele. Login to comment

PMID: 17569884 [PubMed] Luke MM et al: "A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease."

No. Sentence Comment

99 Unadjusted Association of 5 SNPs With Severe CAD in Study 1 and Study 2 SNP ID Gene Symbol Chromosome Study Major Allele* Minor Allele* Type of SNP* Case AF† Control AF† OR‡ CI P Value§ rs3798220 LPA 6 1 A G I4399M 0.04 0.01 3.79 1.97-7.29 Ͻ0.001 2 A G 0.04 0.02 2.25 1.27-3.97 0.010 rs3814843 CALM1 14 1 T G 3ЈUTR 0.05 0.03 1.66 1.11-2.49 0.012 2 T G 0.06 0.04 1.74 1.13-2.67 0.020 rs4796603 HAP1 17 1 A T T58S 0.83 0.79 1.34 1.10-1.63 0.004 2 A T 0.83 0.78 1.36 1.09-1.68 0.012 rs6453373 AP3B1 5 1 A T E585V 0.94 0.92 1.51 1.11-2.04 0.008 2 A T 0.93 0.90 1.50 1.09-2.05 0.022 rs2231137 ABCG2 4 1 G A V12M 0.97 0.95 1.60 1.08-2.37 0.020 2 G A 0.96 0.94 1.62 1.10-2.38 0.028 *The polymorphic nucleotides on the sense strands are shown. Login to comment

PMID: 17662239 [PubMed] Telbisz A et al: "Membrane cholesterol selectively modulates the activity of the human ABCG2 multidrug transporter."

No. Sentence Comment

30 There are several polymorphic variants of ABCG2 present in large percentage in the human population (e.g. V12M, Q141K), and the possible alterations in the transport capacity and substrate handling of these variants have been examined in numerous experimental systems [18-24]. Login to comment

PMID: 17938643 [PubMed] Erdilyi DJ et al: "Synergistic interaction of ABCB1 and ABCG2 polymorphisms predicts the prevalence of toxic encephalopathy during anticancer chemotherapy."

No. Sentence Comment

23 According to the first theory this SNP and other variations (2677G4T/A and 1236C4T) in linkage disequilibrium are linked to a putative functional polymorphism that causes the differences observed.10 On the other hand it was shown that the 3435T mRNA is characterized by decreased stability, while the linked alleles themselves have no effect on gene expression.11 The ABCG2 34G4A and 421C4A are rare non-synonymous polymorphisms resulting in V12M and Q141K variations. Login to comment

PMID: 18154452 [PubMed] Sharom FJ et al: "ABC multidrug transporters: structure, function and role in chemoresistance."

No. Sentence Comment

355 Over 80 SNPs, missense, nonsense and frameshift mutations in the ABCG2 gene have been identified in different ethnic groups [23,170], including V12M (N-terminal cytosolic region), Q141K (NBD) and Q126stop (in which no active protein is produced). Login to comment
359 Compared with wild-type ABCG2, the Q141K variant displayed lower ATPase activity and lower mitoxantrone efflux when expressed in HEK-293 cells, whereas the V12M and D620N proteins showed little change [172]. Login to comment
360 Somewhat different results were reported by another group for the V12M and Q141K variants [173]. Login to comment
361 A recent study examined seven ABCG2 variants in detail, and found that cells expressing both V12M and Q141K had reduced resistance towards the drug SN-38 [174]. Login to comment

PMID: 18159130 [PubMed] Tamura A et al: "In vitro evaluation of photosensitivity risk related to genetic polymorphisms of human ABC transporter ABCG2 and inhibition by drugs."

No. Sentence Comment

8 In the present study, we expressed ABCG2 genetic variants, i.e., V12M, Q141K, S441N, and F489L, as well as the wild type (WT) in Flp-In-293 cells to examine the hypothesis. Login to comment
10 To further elucidate the signiˆcance of ABCG2 in cellular porphyrin homeostasis, we observed cellular accumulation and compartmentation of porphyrin and pheophorbide a by means of a new ‰uorescence microscopy technology, and found that accumulation of porphyrin and pheophorbide a in the cytoplasm compartment was maintained at low levels in Flp-In-293 cells expressing ABCG2 WT, V12M, or Q141K. Login to comment
98 Genetic polymorphisms of human ABCG2 and pheophorbide a-photosensitivity In vitro experiments SNP data IC50 (mM) Photosensitivity ratio (fold) Ethnic group N Allele frequency (z) Reference WT 3.0 1.0 - - - - V12M 4.1 0.7 Caucasian 546 5.6 22, 13, 21, 20, 14 Japanese 259 17.6 18, 22, 20 African 181 6.3 22, 20 Q141K 2.9 1.0 Caucasian 717 11.0 22, 13, 21, 15, 20, 14 Japanese 354 30.6 18, 22, 20 African 1213 1.4 22, 15, 14 S441N 0.5 6.0 Japanese 100 0.5 20 F489L 1.7 1.8 Japanese 160 0.6 19, 20 Pheophorbide a-photosensitivity ratios and IC50 values were determined from the data shown in Fig. 2B. 432 Ai TAMURA, et al. a Fluoroskan Ascent FL (Thermo Labsystems, Helsinki, Finland) (excitation at 405 nm; emission at 612 nm). Login to comment
99 Results Expression of ABCG2 WT and SNP variants in Flp-In-293 cells: In the present study, we aimed to examine the impact of hitherto reported major SNPs (V12M, Q141K, S441N, or F489L) on the photo-sensitivity. Login to comment
110 Figure 1B depicts the immuno‰uorescence images of Flp-In-293 cells expressing ABCG2 WT and those SNP variants (i.e., V12M, Q141K, S441N, and F489L) as well as mock vector-transfected cells (Flp-In-293/ Mock). Login to comment
114 In contrast, strong green ‰uorescence was observed at the plasma membrane and within intracellular compartments in Flp-In-293 cells expressing ABCG2 WT as well as the SNP variants of V12M, Q141K, and F489L. Login to comment
121 In contrast, intracellular accumulations of pheophorbide a in both Flp-In-293/ABCG2 (V12M) and Flp-In-293/ABCG2 (Q141K) cells were signiˆcantly lower, being similar to the levels observed in Flp-In-293/ABCG2 (WT) cells. Login to comment
122 It is suggested that two variants, V12M and Q141K, actively extruded pheophorbide a out of cells as did ABCG2 WT, 1. Login to comment
123 Expression of human ABCG2 WT, V12M, Q141K, S441N, and F489L in Flp-In-293 cells. Login to comment
130 Photosensitivity of Flp-In-293 cells expressing ABCG2 WT and SNP variants: Figure 2B demonstrates the cellular photosensitivity proˆles of Flp-In-293 cells expressing ABCG2 WT, V12M, Q141K, S441N, and F489L, as well as that of Flp-In-293/Mock cells. Login to comment
136 Flp-In-293/Mock and Flp-In-293/ABCG2 (S441N) cells were very sensitive to light, whereas Flp-In-293/ABCG2 (V12M), Flp-In-293/ABCG2 (Q141K), and Flp-In-293/ABCG2 (WT) cells were signiˆcantly more resistant. Login to comment
141 A, Flp-In-293 cells expressing human ABCG2 WT and SNP variants (V12M, Q141K, S441N, and F489L) were incubated with pheophorbide a at diŠerent concentrations (0, 0.63, 1.25, and 2.5 mM) at 379C for 4 hours. Login to comment

PMID: 18180275 [PubMed] Poonkuzhali B et al: "Association of breast cancer resistance protein/ABCG2 phenotypes and novel promoter and intron 1 single nucleotide polymorphisms."

No. Sentence Comment

32 Among the coding single nucleotide polymorphisms (SNPs), G34A (V12M) in exon 2 and C421A (Q141K) in exon 5 occur in most racial groups but with a higher allele frequency in Asians and Hispanics. Login to comment

PMID: 18202831 [PubMed] Mao Q et al: "BCRP/ABCG2 in the placenta: expression, function and regulation."

No. Sentence Comment

138 Notably, the single nucleotide polymorphisms (SNPs) G34A and C421A, resulting in alterations of BCRP protein at position 12 (V12M) and 141 (Q141K), respectively, occur at a relatively high frequency in most ethnic populations. Login to comment

PMID: 18237272 [PubMed] Nakagawa H et al: "Ubiquitin-mediated proteasomal degradation of non-synonymous SNP variants of human ABC transporter ABCG2."

No. Sentence Comment

208 In a previous study using the Flp recombinase system [33], we functionally characterized the non-synonymous polymorphisms (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) in terms of their protein expression level, drug resistance profile and prazosin-stimulated ATPase activity. Login to comment

PMID: 18249138 [PubMed] Hazai E et al: "Homology modeling of breast cancer resistance protein (ABCG2)."

No. Sentence Comment

245 However, in our model, R482 cannot form interaction with rhodamine, but L484 is in interacting distance Table 3 Mutations on BCRP and their effect on its function Mutation Effect/results Reference V12M Did not effect Hemato and MTX transport Tamura et al. (2006) G51C Did not effect Hemato and MTX transport Tamura et al. (2006) K86M Inactivates transporter (dominant negative effect on ATPase activity); alters subcellular distribution Henriksen et al. (2005a) K86M Transporter inactive, but still able to bind ATP Ozvegy et al. (2002) Q126stop Defective porphyrin transport Tamura et al. (2006) Q141K Did not effect Hemato and MTX transport Tamura et al. (2006) T153M Did not effect Hemato and MTX transport Tamura et al. (2006) Q166E Did not effect Hemato and MTX transport Tamura et al. (2006) I206L Did not effect Hemato and MTX transport Tamura et al. (2006) F208S Defective porphyrin transport Tamura et al. (2006) S248P Defective porphyrin transport Tamura et al. (2006) E334stop Defective porphyrin transport Tamura et al. (2006) F431L Effects MTX transport Tamura et al. (2006) S441N Defective porphyrin transport Tamura et al. (2006) E446-mutants No drug resistance Miwa et al. (2003) R482G, R482T Effects MTX transport Tamura et al. (2006) R482T Substrate drug transport and inhibitor efficiency is not mediated by changes in drug-binding Pozza et al. (2006) R482G, R482T Substitution influence the substrate specificity of the transporter Ozvegy et al. (2002) R482G, R482T Altered substrate specificity Honjo et al. (2001) R482G Methotrexate not transported Chen et al. (2003b) Mitomo et al. (2003) R482G Resistance to hydrophilic antifolates in vitro, G482-ABCG2 mutation confers high-level resistance to various hydrophilic antifolates Shafran et al., (2005) R482G Three distinct drug, binding sites Clark et al. (2006) R482G Altered substrate specificity, granulocyte maturation uneffected Ujhelly et al. (2003) R482 mutants Higher resistance to mitoxantrone and doxorubicin than wt Miwa et al. (2003) R482X Affects substrate transport and ATP hydrolysis but not substrate binding Ejendal et al. (2006) F489L Impaired porphyrin transport Tamura et al. (2006) G553L; G553E Impaired trafficing, expression, and N-linked glycosylation Polgar et al. (2006) L554P Dominant negative effect on drug sensitivity Kage et al. (2002) N557D Resistance to MTX, but decreased transport of SN-38; N557E no change in transport compared to wt Miwa et al. (2003) F571I Did not effect Hemato and MTX transport Tamura et al. (2006) N590Y Did not effect Hemato and MTX transport Tamura et al. (2006) C592A Impaired function and expression Henriksen et al. (2005b) C592A/C608A Restored plasma mb expression; MTX transport normal, BODIPY-prazosin impaired Henriksen et al. (2005b) C603A Disulfide bridge; no functional or membrane targeting change Henriksen et al. (2005b) C608A Impaired function and expression Henriksen et al. (2005b) D620N Did not effect Hemato and MTX transport Tamura et al. (2006) H630X No change in transport Miwa et al. (2003) Cand N-terminal truncated Impaired trafficing Takada et al. (2005) with the ligand. Login to comment

PMID: 18253130 [PubMed] Lemos C et al: "Drug transporters: recent advances concerning BCRP and tyrosine kinase inhibitors."

No. Sentence Comment

45 Breedveld et al (2005) showed that Table 1 BCRP substrates and polymorphisms Substrates Classical anticancer drugs Novel targeted drugs Mitoxantrone Canertinib (CI-1033)a Anthracyclinesb Imatiniba Camptothecins Nilotiniba Antifolatesb Gefitiniba Erlotinib Flavopiridol Polymorphismsc Variant Amino-acid change Effect G34A Val12Met (V12M) No change C376T Gln126stop (Q126T) No active BCRP protein C421A Gln141Lys (Q141K) Decreased protein levels and drug resistance Increased gefitinib-associated toxicity (diarrhoea) Increased imatinib accumulation in vitro, but no changes in the pharmacokinetic parameters of imatinib in vivo G1322A Ser441Asn (S441N) Decreased protein levels and different subcellular localisation BCRP ¼ breast cancer resistance protein. Login to comment
117 Finally, another BCRP SNP found in this Japanese population, G34A, which replaces valine by methionine at position 12 (V12M), showed similar protein expression and drug resistance levels as the wild-type (Imai et al, 2002). Login to comment

PMID: 18309947 [PubMed] Rudin CM et al: "Pharmacogenomic and pharmacokinetic determinants of erlotinib toxicity."

No. Sentence Comment

28 Recent studies suggest that gefitinib and erlotinib are substrates of ABCG2.32-35 Two nonsynonymous ABCG2 SNPs, 421 CϾA (Q141K, rs2231142) and 34GϾA (V12M, rs2231137), are common.36-39 The 141K polymorphism has been associated with lower expression and activity of ABCG2 and with higher accumulation of both gefitinib and erlotinib.35,36,40 A recent clinical study showed an association between 141K and diarrhea in patients treated with gefitinib.41 We have recently identified four functional polymorphisms in the 5Ј-regulatory region of ABCG2 (Poonkuzhali et al, manuscript submitted for publication). Login to comment

PMID: 18363541 [PubMed] Tamura A et al: "Drug-induced phototoxicity evoked by inhibition of human ABC transporter ABCG2: development of in vitro high-speed screening systems."

No. Sentence Comment

230 Plasma membrane Outside Inside ATP-binding cassette H2 N COOH V12M G51C Q126stop Q141K T153M R160Q Q166E I206L F208S S248P E334stop F431L F489L S441N R482G R482T F571I R575stop N590Y D620N T542A A528T D296H P269S A. Login to comment
231 0.0 0.1 0.2 0.3 0.4 0.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T ATP-dependenthematoporphyrintransport (nmol/min/mgprotein) B. interactions should also take into consideration the presence of multiple flavonoids. Login to comment
245 Based on the presently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells. Login to comment
249 To further elucidate the significance of ABCG2 in cellular porphyrin homeostasis, we observed the cellular accumulation and compartmentation of porphyrin and pheophorbide a by means of a new fluorescence microscopy technology, and found that the accumulation of porphyrin and pheophorbide a in the cytoplasmic compartment was significantly higher in Flp-In-293 cells expressing S441N and F489L variants, as compared with those expressing WT, V12M, or Q141K [88]. Login to comment
252 Amino acid Porphyrin transport* Allele frequency (%)‡ cDNA position Location Wild-type allele Variant alllele V12M ++ 2.0 - 90.0 34 Exon 2 G A Q126stop - 0.0 - 1.7 376 Exon 4 C T Q141K ++ 0.0 - 35.5 421 Exon 5 C A T153M ++ 3.3 458 Exon 5 C T Q166E ++ N.D. 496 Exon 5 C G I206L ++ 10.0 616 Exon 6 A C F208S - N.D. 623 Exon 6 T C S248P - N.D. 742 Exon 7 T C E334stop - N.D. 1000 Exon 9 G T F431L ++ 0.8 1291 Exon 11 T C S441N - 0.5 1322 Exon 11 G A F489L + 0.5 - 0.8 1465 Exon 12 T C F571L ++ 0.5 1711 Exon 14 T A N590Y ++ 0.0 - 1.0 1768 Exon 15 A T D620N ++ 0.5 1858 Exon 16 G A *Transport of hematoporphyrin is indicated by either '+` (positive) or '-' (negative). Login to comment

PMID: 18370231 [PubMed] Bosch TM et al: "Pharmacogenomics of drug-metabolizing enzymes and drug transporters in chemotherapy."

No. Sentence Comment

139 Mizuarai et al. (77) analyzed the effect of the polymorphisms G34A and C8825A, leading to an amino acid change of V12M and Q141K, respectively, on the transporter function of the protein. Login to comment
140 Drug resistance to indolocarbazole, a topoisomerase I inhibitor, of cells expressing V12M or Q141K was less than 1/10 compared to wild-type ABCG2-transfected cells and was accompanied by increased drug accumulation and decreased drug efflux in the variant ABCG2-expressing cells. Login to comment
141 A possible explanation for this altered function of the ABCG2 enzyme is the fact that the ABCG2 transporter is not localized to the apical membrane in the V12M clone. Login to comment

PMID: 18370855 [PubMed] Polgar O et al: "ABCG2: structure, function and role in drug response."

No. Sentence Comment

82 Some of these are in the coding region of ABCG2 and alter the protein sequence, such as V12M, Q141K, I206L and N590Y. Login to comment
175 Membrane Out In 200 100 300 400 500 600 ATP site N-terminus C-terminus V12M Q141K I206L GXXXG, G406/G410 R482 G553 C603 N596 N590Y protein synthesis. Login to comment

PMID: 18408567 [PubMed] Urquhart BL et al: "Breast cancer resistance protein (ABCG2) and drug disposition: intestinal expression, polymorphisms and sulfasalazine as an in vivo probe."

No. Sentence Comment

21 In addition, several nonsynonymous single nucleotide polymorphisms (SNPs) of the ABCG2 gene have been described including ABCG2 34G > A (V12M) located in exon 2 and 421C > A (Q141K) in exon 5. Login to comment
62 Site-directed mutagenesis was utilized to create the nonsynonymous allelic variants, 34G > A (V12M) and 421C > A (Q141K). Login to comment

PMID: 18454051 [PubMed] Saraiya B et al: "Sequential topoisomerase targeting and analysis of mechanisms of resistance to topotecan in patients with acute myelogenous leukemia."

No. Sentence Comment

91 For ABCG2, primers were designed to amplify regions containing the following four SNPs: G34A (V12M, exon 1), C376T (stop, exon 3), A616C (I206L, exon 5), C421A (Q141K, exon 12), and A1768T (N590Y, exon 14). Login to comment
144 A SNP was identified in two patients (enrolled in cohorts 2 and 5, respectively), involving a coding region G-to-A substitution that yields a V12M substitution in the ABCG2 protein (refSNP ID: rs2231137). Login to comment

PMID: 18464048 [PubMed] Gradhand U et al: "Pharmacogenomics of MRP transporters (ABCC1-5) and BCRP (ABCG2)."

No. Sentence Comment

250 It should be noted that many xeno- and endobiotic BCRP Figure 5 Predicted membrance topology of BCRP (ABCG2) based on hydrophobicity analysis. Locations of the non-synonymous polymorphisms are indicated with arrows. See Table 5 for allele frequencies and description of funtional consequences. NH2 COOH NBD Val12Met Gly51Cys Gln126* Ala149Pro Gln141Lys Thr153Met Arg160Gln Arg163Lys Gln166Glu Phe506Ser Phe507Leu Val508Leu Met509* Phe489Leu Ser441Asn Phe431Leu Glu334* Ile206Leu Ala315del Thr316del Phe208Ser Asp296His Ser248Pro Pro269Ser Phe571Ile Arg575* Asn590Tyr Asp620Asn in out Membrane BCRP (ABCG2) NBD Val12Met NBDNBD Val12Met substrates are also transported by other efflux transporters, especially P-glycoprotein, thus extrapolating BCRP related in vitro data to the in vivo situation may be difficult. Login to comment
278 This SNP which is more frequently found in Asian populations than in Caucasians or Africans (Table 5), leads to the amino acid change, Val12Met. Login to comment
318 Available data in relation to BCRP pharmacogenetics suggest at least one of the known non-synonymous polymorphisms (421C>A/Gln141Lys) and possibly a few others (34G>A/Val12Met and 1322G>T/Ser441Asn) may be of functional and clinical importance. Login to comment

PMID: 18509645 [PubMed] O'Bryant CL et al: "A dose-ranging study of the pharmacokinetics and pharmacodynamics of the selective apoptotic antineoplastic drug (SAAND), OSI-461, in patients with advanced cancer, in the fasted and fed state."

No. Sentence Comment

273 A mutation results in markedly decreased protein expression, and low level drug resistance, as compared to wild-type BRCP c For ABCG-2 #34 the of the A mutation frequency in Caucasians is 4.7%; and for ABCG-2 #421 the A mutation frequency in Caucasians is 25.9% Pt # ABCG-2 #34a ABCG-2 #421b Racec Val12 Met mutation Sequencing result Gln141 Lys mutation Sequencing result 01015 No Wild-type: G/G No Wild-type: C/C White 01016 No Wild-type: G/G Yes Heterozygote: C/A White 01017 Yes Homozygote: A/A No Wild-type: C/C Asian 01018 No Wild-type: G/G Yes Heterozygote: C/A White 01019 No Wild-type: G/G No Wild-type: C/C White 01020 Yes Heterozygote: A/G No Wild-type: C/C White 01021 No Wild-type: G/G Yes Heterozygote: C/A White 01022 No Wild-type: G/G No Wild-type: C/C Black 01023 No Wild-type: G/G Yes Heterozygote: C/A White 01024 No Wild-type: G/G No Wild-type: C/C White 01026 No Wild-type: G/G No Wild-type: C/C White 01027 No Wild-type: G/G No Wild-type: C/C White 01028 No Wild-type: G/G No Wild-type: C/C White 01029 No Wild-type: G/G No Wild-type: C/C White 01031 No Wild-type: G/G Yes Homozygote: A/A White 01032 No Wild-type: G/G No Wild-type: C/C White 01033 No Wild-type: G/G No Wild-type: C/C White A prior study of OSI-461 demonstrated that Cmax and AUC values increased in an approximate linear fashion as the dose was increased from 100 to 400 mg BID with a signiWcant amount of interpatient variability [35]. Login to comment

PMID: 18668433 [PubMed] Koshiba S et al: "Human ABC transporters ABCG2 (BCRP) and ABCG4."

No. Sentence Comment

225 Based on the currently available data on SNPs and acquired mutations, a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) were created by site-directed mutagenesis and expressed in Sf9 insect cells (Tamura et al. 2006, 2007). Login to comment

PMID: 18673259 [PubMed] Nakamura T et al: "Pharmacogenetics of intestinal absorption."

No. Sentence Comment

76 Among the SNPs identified so far, two nonsynonymous SNPs, 34G>A and 421C>A, in the coding region, resulting in Val12Met and Gln141Lys, respectively, are relatively frequently identified and well-studied. Login to comment
77 Honjo et al. sequenced 90 genomic DNA samples and identified Val12Met and Gln141Lys at a frequency of 12.2% and 6.1%, respectively [86]. Login to comment
78 The Val12Met and Gln141Lys polymorphisms were also identified in a sequence analysis of ABCG2 cDNA clones isolated from 11 human tumor cell lines and were confirmed to have allelic frequencies of 19.0% and 26.6%, respectively, by a genomic DNA analysis in 124 Japanese [85]. Login to comment
83 In Vitro Studies Associated with Common SNPs of Drug Transporter Genes Exon Polymorphism Effect dbSNP Cell Expression Function Reference ABCC2 Exon 1 -24C>T 5`-UTR rs717620 116A>T Tyr2Phe rs927344Exon 2 159A>G synonymous rs17222596 Exon 7 736A>C Met246Leu rs17222744 Exon 8 998A>G Asp333Gly rs17222674 Exon 9 1058G>A Arg353His rs7080681 1219C>T synonymous rs17216198 1249G>A Val417Ile rs2273697 LLC-PK1 Protein (n.s.) Membrane localization (n.s.) Transport activity (n.s.) Hirouchi et al. [51] 1434G>T synonymous 1434G>A synonymous rs4267009 Exon 10 1457C>T Thr486Ile rs17222589 Exon 11 1483A>G Lys495Glu rs17222561 Exon 13 1686T>G Phe562Leu rs17216233 2009T>C Ile670Thr rs17222632Exon 16 2073C>A synonymous rs17222624 Exon 17 2153A>G Asn718Ser rs3740072 Exon 19 2546T>G Leu849Arg rs17222617 Exon 20 2677G>C Glu893Gln rs3740071 2901C>A Tyr967stop rs17222547 2934G>A synonymous rs3740070 Exon 22 2944A>G Ile982Val rs17222554 3107T>C Ile1036Thr rs17216149Exon 23 3188A>G Asn1063Ser rs17222540 Exon 24 3396T>C synonymous rs17216345 3542G>T Arg1181Leu rs8187692 3561G>A synonymous rs17216324 Exon 25 3563T>A Val1188Glu rs17222723 Exon 27 3817A>G Thr1273Ara rs8187699 3872C>T Pro1291Leu rs17216317 3895A>C Lys1299Gln rs4148400 3927C>T synonymous rs4148401 Exon 28 3972C>T synonymous rs3740066 4062C>T synonymous rs17216275Exon 29 4110C>T synonymous rs7899457 4242C>T synonymous rs17216296Exon 30 4290G>T synonymous rs1137968 4410G>A synonymous rs8187706Exon 31 4488C>T synonymous rs8187707 4527C>T synonymous rs8187709Exon 32 4544G>A Cys1515Tyr rs8187710 ABCG2 PA317 mRNA (n.s.) Protein (n.s.) Drug sensitivity (n.s.) Topotecan uptake (n.s.) Imai et al. [85] mRNA (n.s.) Protein (n.s.) Apical localization (impaired) Drug sensitivity ( ) Indolocarbazole uptake ( ) Indolocarbazole efflux ( ) Mizuarai et al. [88] Exon 2 34G>A Val12Met rs2231137 LLC-PK1 Apical localization (n.s.) . Login to comment
93 Exon Polymorphism Effect dbSNP Subject Expression Function Reference Exon 24 3396T>C synonymous rs17216345 3542G>T Arg1181Leu rs8187692 3561G>A synonymous rs17216324 3563T>A Val1188Glu rs17222723 Healthy (Finnish) Pravastatin PK (TT TA) Niemi et al. [48] HIV patient (Caucasian) Nelfinavir intracellular AUC (TT TA) Colombo et al. [58] Exon 25 Patient Acute anthracycline-induced cardiotoxicity (TT<TA) Chronic anthracycline-induced cardiotoxicity (TT TA) Wojnowski et al. [59] Exon 27 3817A>G Thr1273Ara rs8187699 3872C>T Pro1291Leu rs17216317 3895A>C Lys1299Gln rs4148400 3927C>T synonymous rs4148401 3972C>T synonymous rs3740066 Women undergoing cesarean section Placental mRNA (GG GA AA) Placental protein (GG GA AA) Meyer zu Schwabedissen et al. [52] DNT patient Tumoral protein (GG GA) Peritumoral protein (GG GA) Vogelgesang et al. [54] Patient 9-nitrocamptotecin PK and toxicity (CC CT TT) 9-aminocamptotecin PK and toxicity (CC CT TT) Zamboni et al. [55] Exon 28 Colorectal cancer patient (Japanese) Tumoral mRNA (CC CT TT) Drug sensitivity (CC CT TT) Tumor growth rate (CC CT TT) Nishioka et al. [57] 4062C>T synonymous rs17216275Exon 29 4110C>T synonymous rs7899457 4242C>T synonymous rs17216296Exon 30 4290G>T synonymous rs1137968 Exon 31 4410G>A synonymous rs8187706 4488C>T synonymous rs8187707 HIV patient (Caucasian) Nelfinavir intracellular AUC (CC CT) Colombo et al. [58] 4527C>T synonymous rs8187709 4544G>A Cys1515Tyr rs8187710 Healthy (Finnish) Pravastatin PK (GG GA) Niemi et al. [48] HIV patient (Caucasian) Nelfinavir intracellular AUC (GG GA) Colombo et al. [58] Exon 32 Patient Acute anthracycline-induced cardiotoxicity (GG<GA) Chronic anthracycline-induced cardiotoxicity (GG GA) Wojnowski et al. [59] ABCG2 34G>A Val12Met rs2231137 Nasopharyngeal cancer patient Irinotecan PK (GG GA+AA) SN-38 PK (GG GA+AA) SN-38G PK (GG GA+AA) Zhou et al. [56] HIV patient (Caucasian) Nelfinavir intracellular AUC (GG GA) Colombo et al. [58] Exon 2 Patient (Japanese) Placental mRNA (GG GA AA) Placental protein (GG GA AA) Kobayashi et al. [91] (Table 3) contd…. Login to comment
99 In the report of Mizuarai et al., Val12Met but not Gln141Lys affected apical membrane localization of ABCG2 in transfectant- LLC-PK1 cells, whereas Morisaki et al. reported impaired membrane trafficking or incorrect membrane insertion of Gln141Lys ABCG2 in HEK-293 cells. Login to comment
101 Reduced drug resistance to ABCG2 substrates was also observed in Val12Met ABCG2-transfected LLC-PK1 cells, but not significantly in Val12Met ABCG2-transfected HEK-293 cells. Login to comment

PMID: 18681776 [PubMed] Cusatis G et al: "Pharmacogenomic importance of ABCG2."

No. Sentence Comment

27 Several other SNPs have been identified in coding regions of the gene, and at least three additional nonsynonymous SNPs have been identified, occurring at positions 34 (V12M, exon 2), 616 (I206L, exon 6) and 1768 (N590Y, exon 15). Login to comment

PMID: 18855611 [PubMed] Zhou SF et al: "Clinical pharmacogenetics and potential application in personalized medicine."

No. Sentence Comment

618 Only a small portion of them are non-synonymous (V12M, Q141K, Q166E, I206L, F208S, S248P, D296H, L525R, A528T, F571I, and Y590N) and there is one frameshift (1515delC) mutation observed in the coding region of ABCG2. Login to comment
619 Among the above variations, 34G>A (V12M) AND 421C>A (Q141K) have been testified to be polymorphic in numerous populations [267, 271]. Login to comment
620 The V12M polymorphism located in exon 2 influenced the N-terminal intracellular region of the protein. Login to comment
622 The V12M polymorphism was discovered in all ethnic groups tested, found with the highest allele frequency in Mexican-Indians (90%, but only 10 individuals were tested), while only 2% in a Swedish population [272]. Login to comment
623 Upon the combination of several population studies, a consistent and significant difference can be seen between the overall allele frequencies of V12M in Caucasian, African American and Japanese populations [271]. Login to comment
630 Studies have discovered that the expression levels of Q141K ABCG2 protein is lower than the wild-type, or the V12M variant when expressed in PA317 or HEK-293 cells [273]. Login to comment
631 It was also found that a portion of Q141K remained intracellular despite having a low level of expression, as both V12M and Q141K BCRP could reach the plasma membrane in the HEK-293 cells [273]. Login to comment
635 ABCG2 is expressed in polarized LLC-PKI cells, and a study has demonstrated that the V12M variant has an intracellular localization whereas the wild-type ABCG2 and Q141K show mainly apical staining [275]. Login to comment
636 The localization of other variants including V12M, A149P, R163K, Q166E, P269S and S441N was also examined. Login to comment
637 All polymorphisms, including V12M and Q141K, had an apical localization, and only the S441N variant displayed an intracellular staining [275]. Login to comment
639 Further studies are required to clarify the mechanism of a reduced protein expression for Q141K, and the change of cellular localization for the V12M and Q141K variants found under specific conditions. Login to comment
641 There was a 10-fold decrease in drug resistance compared with the wild-type ABCG2 when the V12M or Q141K-transfected LLC-PKI cells were challenged by mitoxantrone or topotecan [275]. Login to comment
645 Experiments were undertaken to observe between the vanadate-sensitive ATPase activity of ABCG2 V12M and Q141K variants, using Sf9 (Spodoptera frugiperda) cell membranes [276]. Login to comment
646 There was a 1.3 and 1.8-fold lower basal ATPase activity, respectively, for V12M and Q141K compared to wild-type [276]. Login to comment
647 On the other hand, the V12M (and D620N) ABCG2 displayed a comparable ATPase activity as the wild-type protein. Login to comment

PMID: 19002564 [PubMed] Polgar O et al: "The 315-316 deletion determines the BXP-21 antibody epitope but has no effect on the function of wild type ABCG2 or the Q141K variant."

No. Sentence Comment

62 We have previously used the same expression system to study non-synonymous SNPs, such as Q141K, V12M, and D620N, and found that Q141K results in impaired function [13]. Login to comment
64 We have previously used the same expression system to study non-synonymous SNPs, such as Q141K, V12M, and D620N, and found that Q141K results in impaired function [13]. Login to comment

PMID: 19023099 [PubMed] Luke MM et al: "Gene variants associated with ischemic stroke: the cardiovascular health study."

No. Sentence Comment

12 The Val12Met SNP in ABCG2 was associated with stroke in both white (hazard ratio, 1.46; 90% CI, 1.05 to 2.03) and black (hazard ratio, 3.59; 90% CI, 1.11 to 11.6) participants of CHS. Login to comment
14 Conclusions-The Val12Met SNP in ABCG2 (encoding a transporter of sterols and xenobiotics) was associated with incident ischemic stroke in white and black participants of CHS. Login to comment
76 ABCG2 Val12Met (rs2231137) was the only SNP associated with incident ischemic stroke in both white and black participants of CHS. Login to comment
82 The most notable finding, consistent in both whites and blacks, was the association between the Val allele of ABCG2 Val12Met and increased risk of incident ischemic stroke. Login to comment
84 The first of these 3 gene variants was the Val allele of ABCG2 Val12Met (rs2231137). Login to comment
97 The Val Allele Homozygotes of ABCG2 Val12Met, Compared With the Met Allele Carriers Are Associated With Increased Risk of Incident Ischemic Stroke in Both White and Black Participants of CHS Model 1* Model 2* ABCG2 Genotype Events, n Total, n HR (90% CI) P HR (90% CI) P White ValVal 370 3398 1.58 (1.12-2.23) 0.02 1.50 (1.06-2.12) 0.03 ValMetϩMetMet 24 335 1 (Reference) 1 (Reference) ValMet 23 321 MetMet 1 14 Black ValVal 66 592 3.80 (1.16-12.4) 0.03 3.62 (1.11-11.9) 0.04 ValMetϩMetMet 2 70 1 (Reference) 1 (Reference) ValMet 2 69 MetMet 0 1 *Model 1 was adjusted for baseline age and sex. Login to comment
100 Comparison of Kaplan-Meier estimates of the cumulative incidence of ischemic stroke among Val allele homozygotes of the ABCG2 Val12Met and among Met allele carriers in white (A) and in black (B) participants of CHS. Login to comment
113 Notably, the Val allele of the Val12Met SNP in ABCG2 (which encodes a transporter of sterols and anticancer drugs) was associated with increased risk of incident ischemic stroke in both white and black participants of CHS. Login to comment

PMID: 19032367 [PubMed] Kim IS et al: "ABCG2 Q141K polymorphism is associated with chemotherapy-induced diarrhea in patients with diffuse large B-cell lymphoma who received frontline rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone chemotherapy."

No. Sentence Comment

2 Of the ABCG2 polymorphisms, V12M and Q141K alter the functional activity of the ABCG2 transporter and influence the drug response and various toxicities to chemotherapeutic agents. Login to comment
3 We therefore evaluated the impact of the ABCG2 V12M and Q141K polymorphisms on the therapeutic outcomes and toxicities of primary rituximab plus cyclophosphamide/doxorubicin/vincristine/prednisone (R-CHOP) therapy in 145 Korean patients with diffuse large B-cell lymphoma (DLBCL). Login to comment
4 ABCG2 V12M and Q141K genotyping was carried out by pyrosequencing of polymerase chain reaction products. Login to comment
5 The clinical characteristics, treatment outcomes, toxicities of the patients, and the predictive value of the polymorphisms on response, survival, and adverse events to R-CHOP for 145 patients were analyzed according to the ABCG2 V12M and Q141K polymorphisms. No differences were observed according to ABCG2 Q141K and V12M genotype in patient characteristics, disease characteristics, response, survival, or hematology toxicity profiles in patients with DLBCL who received frontline R-CHOP chemotherapy. Login to comment
15 (7-11) In particular, two non-synonymous polymorphisms, c.34G>A (p.Val12Met, V12M) and c.421C>A (p.Gln141Lys, Q141K), have been detected at relatively high frequencies in most ethnic groups, including Asians, Caucasians, and Africans. Login to comment
17 (15) A recently published study found that the ABCG2 V12M and Q141K polymorphisms are associated with susceptibility to and survival from DLBCL. Login to comment
18 (16) In the present study, we evaluated the impact of the ABCG2 Q141K and V12M polymorphisms on the therapeutic outcomes and adverse reactions of primary R-CHOP therapy in 145 patients with DLBCL, including treatment response, overall survival (OS) and event-free survival (EFS), hematological toxicities, and non-hematological toxicities. Login to comment
35 ABCG2 Q141K and V12M genotyping was carried out by pyrosequencing of the polymerase chain reaction (PCR) products from the ABCG2 gene to determine the presence of the Q141K and V12M polymorphisms. Login to comment
39 Patient characteristics and treatment outcomes according to the ABCG2 Q141K and V12M polymorphisms ABCG2 Q141K P-value ABCG2 V12M P-value QQ QK KK VV VM MM No. patients (%) 67 (46.2%) 69 (47.6%) 9 (6.2%) 71 (49.0%) 63 (43.4%) 11 (7.6%) Sex (no. Login to comment
43 Sequences and information of primers used for pyrosequencing Name Primer sequence (5' to 3') Size (bp) Polymerase chain reaction (Tm; °C) ABCG2 V12M F: CTCTCCAGATGTCTTCCAGTAATG 110 59 R: Biotin-TCCTTCAGTAAATGCCTTCAGGT S: TCGAAGTTTTTATCCCA ABCG2 Q141K F: Biotin-ACTGCAGGTTCATCATTAGCTAGA 238 60 R: CCGTTCGTTTTTTTCATGATTC S: CGAAGAGCTGCTGAGAA F, forward; R, reverse; S, sequencing; Tm, melting temperature. Login to comment
55 The primary objective of the current study was to correlate the ABCG2 Q141K and V12M polymorphisms with the response and survival outcomes, including OS and EFS to R-CHOP therapy. Login to comment
56 The secondary objectives were to correlate the ABCG2 Q141K and V12M polymorphisms with the hematological and non- hemtological toxicities of R-CHOP therapy. Login to comment
57 The clinical characteristics, treatment outcomes, and toxicities of the patients were compared using χ2 -tests, Fisher`s exact tests, or Mann-Whitney U-tests according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
58 Logistic regression analysis was conducted to determine the predictive value of the polymorphisms on response and adverse reaction to R-CHOP for the 145 patients who had available both the ABCG2 Q141K and V12M polymorphism data. Login to comment
59 The variables included stage (stages 1 and 2 vs 3 and 4), IPI score (0-2 vs 3-5), age (<60 vs ≥60 years), performance status (Eastern Cooperative Oncology Group [ECOG] 0 and 1 vs ≥2), lactate dehydrogenase level (normal vs beyond normal range), extranodal involvement (≤1 vs ≥2 sites), B symptoms (absence vs presence), hematological toxicity (grade 0-II vs III-IV or grade 0 vs grade I-IV), non-hematological toxicity (grade 0-II vs III-IV or grade 0 vs grade I-IV), and ABCG2 Q141K (QQ, QK, and KK) and ABCG2 V12M (VV, VM, and MM) genotypes. Login to comment
66 Results Frequency of ABCG2 Q141K and V12M polymorphisms. Login to comment
68 The distribution of the VV, VM, and MM genotypes of the ABCG2 V12M polymorphism was 49.0, 43.4, and 7.6%, respectively (Table 1). Login to comment
70 Patient characteristics according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
72 In brief, no differences in the patient and disease characteristics were observed according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
73 Response to frontline R-CHOP therapy according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
75 As shown in Table 1, no significant difference in the response rate or the ORR was observed according to the ABCG2 Q141K and V12M polymorphisms. No statistically significant difference in the response rate or ORR was observed according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
76 Survival analysis according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
79 When comparing OS and EFS according to the ABCG2 Q141K and V12M polymorphisms, neither the Q141K nor V12M polymorphisms had any impact on OS or EFS (Fig. 1). Login to comment
80 Side effects according to the ABCG2 Q141K and V12M polymorphisms. Login to comment
82 No significant differences of such hematological toxicities as anemia, leukocytopenia, neutropenia, and thrombocytopenia were observed according to the ABCG2 Q141K and V12M alleles. Login to comment
87 Discussion Among several naturally occurring ABCG2 polymorphisms, V12M in exon 2 and Q141K in exon 5 occur in most racial groups, but they occur with a higher allellic frequency in Asians. Login to comment
88 In the present study, the frequencies of two polymorphisms, V12M and Q141K, were 0.293 and 0.300, respectively, and these values were comparable to those reported in the literature for Asians (0.230-0.241 and 0.150-0.360, respectively). Login to comment
91 However, the allele frequency of ABCG2 V12M in the present study was higher than that of the Korean healthy controls, and the association between ABCG2 V12M and disease susceptibility should be further investigated (Table 5). Login to comment
92 The present study demonstrated that the ABCG2 Q141K and V12M polymorphisms were not predictive of the response, OS, or EFS to R-CHOP chemotherapy in patients with DLBCL. Login to comment
93 No association of the ABCG2 Q141K and V12M polymorphisms with response and survival was noted in the present study for the following reasons: (1) the relatively small number of patients; (2) the relatively short period of follow up may not have been enough to see a significant difference in survival; and (3) other unknown chemoresistance mechanisms are probably important in the mechanism of R-CHOP action, and this would be expected to affect the response and survival of DLBCL patients. Login to comment
103 Hematological and non-hematological toxicity outcomes according to the ABCG2 Q141K and V12M polymorphisms (grade 0-II vs grade III-IV) ABCG2 Q141K P-value ABCG2 V12M P-value QQ QK or KK VV VM or MM No. patients (%) 67 (46.2%) 78 (53.8%) 71 (49.0%) 74 (51.0%) Grade III-IV, n (%) Anemia 9 (13.4%) 9 (11.5%) 0.730 10 (14.1%) 8 (10.8%) 0.550 Leukocytopenia 29 (43.3%) 32 (41.0%) 0.784 33 (46.5%) 28 (37.8%) 0.292 Neutropenia 38 (56.7%) 39 (50.0%) 0.419 38 (53.5%) 39 (52.7%) 0.921 Thrombocytopenia 4 (6.0%) 11 (14.1%) 0.109 9 (12.7%) 6 (8.1%) 0.367 Grade III-IV, n (%) Fever 8 (11.9%) 20 (25.6%) 0.037 16 (22.5%) 12 (16.2%) 0.335 Mucostis 11 (16.4%) 22 (28.2%) 0.091 19 (26.8%) 14 (18.9%) 0.260 Infection 9 (13.4%) 21 (27.5%) 0.046 13 (18.3%) 17 (23.0%) 0.488 Nausea and vomiting 2 (3.0%) 5 (6.4%) 0.337 3 (4.2%) 4 (5.4%) 0.740 Diarrhea 2 (3.0%) 9 (11.5%) 0.052 4 (5.6%) 7 (9.5%) 0.384 Alopecia 27 (40.3%) 38 (48.7%) 0.309 32 (45.1%) 33 (44.6%) 0.954 Neurotoxicity 2 (3.0%) 4 (5.1%) 0.518 3 (4.2%) 3 (4.1%) 0.959 Bold and italic values significant at P < 0.05. Login to comment

PMID: 19111841 [PubMed] Noguchi K et al: "Functions of the breast cancer resistance protein (BCRP/ABCG2) in chemotherapy."

No. Sentence Comment

847 C421A (Q141K) BCRP SNP In a previous study, we screened for BCRP SNPs among a population of Japanese individuals and in human cancer cell lines where we identified three variant BCRP cDNAs harboring the following substitutions: G34A (V12M), C421A (Q141K) and an amino acid deletion of residues 944-949 that lacks Ala-315 and Thr-316 (Δ315-6) [54]. Login to comment
853 In contrast to the above results, the G34A BCRP-transfected PA317 (PA/V12M) cells showed comparable protein expression levels and drug resistance levels to the wild-type BCRP-transfected cells. Login to comment
874 Among these SNPs, with the exception of C376T and C421A, only a few have been studied Table 1 Identified SNPs within the BCRP gene Variation Effect Domain A-1379G - Δ-654/-651 - G-286C - T-476C - Δ-235A - A-113G - A-29G - G34A V12M N-terminal T114C No change N-terminal G151T G51C N-terminal C369T No change NBD C376T Q126stop NBD C421A Q141K NBD C458T T153M NBD C474T No change NBD C496G Q166E NBD A564G No change NBD A616C I206L NBD T623C F208S NBD T742C S248P Linker G1000T E334stop Linker G1098A No change Linker T1291C F431L TMD A1425G No change TMD T1465C F489L TMD A1768T N590Y TMD G1858A D620N TMD G2237T - G2393T - NBD, nucleotide-binding domain; TMD, transmembrane domain. Login to comment
876 The G34A SNP generating an amino acid substitution at position 12 (V12M) has been observed in the Japanese population [54]. Login to comment
878 Transfection studies of the V12M BCRP have shown, however, that the expression levels and drug-resistance associated with this variant are comparable to the wild type BCRP and therefore that this SNP has no significant impact on the BCRP protein activity [54]. Login to comment

PMID: 19200005 [PubMed] Porcelli L et al: "Intracellular trafficking of MDR transporters and relevance of SNPs."

No. Sentence Comment

149 Polymorphisms and Mutations Affecting the Cellular Localization of MDR Transporters Transporter Variant Amino-acid Change Localization References Intracellular + plasma membrane [99] C421A Q141K Plasma membrane [97, 98, 101] Intracellular + plasma membrane [98, 101] G34A V12M Plasma membrane [97, 99] ABCG2 G1322A S441N Intracellular [97, 98] ABCC1 G128C C43S Intracellular + plasma membrane [116] 4175-4180del RM1392-1393del Intracellular (ER) [118] C2302T R768W Intracellular (ER) [119] A3517T I1173F Intracellular (ER) [120, 121] C2366T S789F Intracellular + plasma membrane [122] ABCC2 G4348A A1459T Intracellular + plasma membrane [122] 293 transfected cells. Login to comment
176 Another nonsynonymous ABCG2 SNP, G34A, which replaces valine by methionine at position 12 (V12M), was identified by Imai et al. Login to comment
178 PA317 cells transfected with this variant (PA/V12M) showed similar levels of ABCG2 protein expression compared with PA/WT, along with similar levels of resistance to the anticancer drugs SN-38, mitoxantrone and topotecan [96]. Login to comment
187 [97] observed a similar cellular localization of V12M and wild-type ABCG2, at the apical membrane of transiently transfected LLC-PK1 cells. Login to comment
188 Although the authors don`t have a good answer to explain the discrepancy, they suggest that the cellular localization of V12M ABCG2 might be affected by the culture conditions of LLC-PK1 cells [97]. Login to comment
190 [98] reported a similar cellular localization of the V12M variant and the wild-type ABCG2 at the plasma membrane and within intracellular compartments in Flp-In-293 cells. Login to comment
191 Of note, these authors showed that the V12M variant provided the cells with higher drug resistance to SN-38 than did the wild-type ABCG2 [98]. Login to comment
192 A plasma membrane localization of the V12M and wild-type ABCG2 in HEK-293 cells was also described by Morisaki et al. Login to comment
217 From these studies it is clear that only the S441N and, possibly, the V12M and Q141K variants might affect ABCG2 localization within the cell. Login to comment

PMID: 19584153 [PubMed] Kim DH et al: "Clinical relevance of a pharmacogenetic approach using multiple candidate genes to predict response and resistance to imatinib therapy in chronic myeloid leukemia."

No. Sentence Comment

203 In the present study, the ABCG2 genotype V12M (rs2231137) was found to be significantly associated with cytogenetic response to imatinib therapy. Login to comment

PMID: 19605531 [PubMed] Cotte S et al: "ABC-transporter gene-polymorphisms are potential pharmacogenetic markers for mitoxantrone response in multiple sclerosis."

No. Sentence Comment

42 TaqManTM PCR was performed for ABCG2 V12M (reference SNP rs2231137) and Q141K (rs2231142) using Platinum qPCR SuperMix-UDG (Invitrogen, Karlsruhe, Germany) on a 7500 Real Time PCR system (Applied Biosystems, Darmstadt, Germany). Login to comment
70 Retrospective clinical correlation of genotype and MX response Patient samples were genotyped for ABCB1 2677 G4T, 3435C4T, ABCG2 V12M and Q141K and retrospectively correlated with clinical MX response. Login to comment
102 Of five different ABCG2 SNPs with potential functional significance investigated, only reference SNP (rs) 2231137 (G4A) leading to a V12M substitution and rs2231142 (C4A) resulting in a Q141K substitution were observed. Login to comment
110 A high degree of linkage disequilibrium was found between ABCG2 V12M and Q141K [linkage D` = 0.854, (Gaunt et al., 2007)]. Login to comment
207 For ABCG2, only V12M and Q141K polymorphisms could be detected, in vitro leading to disruption of apical membrane localization (V12M) or decreased ATPase function (Q141K) Table 3 Association of ABC-transporter genotype with therapeutic response to MX monotherapy, exact Cochran-Armitage test (P = 0.039) (panel A), or MX/GC combination therapy (P = 0.348) (panel B) Total, n (%) Responder, n (%) Non-Responder, n (%) A: MX monotherapy ABCB1/ABCG2-H 24 (15.5) 15 (62.5) 9 (37.5) ABCB1/ABCG2-I 98 (63.2) 78 (79.6) 20 (20.4) ABCB1/ABCG2-L 33 (21.3) 28 (84.8) 5 (15.2) Total 155 121 (78.1) 34 (21.9) B: MX/GC combination therapy ABCB1/ABCG2-H 21 (13.6) 12 (57.1) 9 (42.9) ABCB1/ABCG2-I 100 (64.9) 58 (58.0) 42 (42.0) ABCB1/ABCG2-L 33 (21.4) 21 (63.6) 12 (36.4) Total 154 91 (59.1) 63 (40.9) Retrospective analysis using EDSS, relapse rate and MSFC as main outcome parameters to define responders and non-responders, respectively. Login to comment

PMID: 19696792 [PubMed] Cha PC et al: "Single nucleotide polymorphism in ABCG2 is associated with irinotecan-induced severe myelosuppression."

No. Sentence Comment

48 In addition to this SNP, rs7977213 in SLCO1B3 as well as the UGT1A7*3 variant Table 1 Demographical characteristic of patients First study Second study Combined study Case (N¼23) Control (N¼58) Case (N¼7) Control (N¼20) Case (N¼30) Control (N¼78) Age 62.04 (37-77) 60.29 (34-77) 60.29 (40-81) 67.60 (50-84) 61.63 (37-81) 62.21 (34-84) % of men 61 71 57 42 60 65 Types of cancers Lung 12 52% 10 17% 2 29% 4 17% 14 47% 14 18% Cervical 6 26% 2 3% 0 0% 0 0% 6 20% 2 3% Colorectal 3 13% 35 60% 3 43% 13 57% 6 20% 48 62% Gastric 1 4% 4 7% 1 14% 2 9% 2 7% 6 8% Ovarian 0 0% 2 3% 1 14% 1 4% 1 3% 3 4% Breast+cervical 1 4% 0 0% 0 0% 0 0% 1 3% 0 0% Pancreatic 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% Esophageal 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% Breast 0 0% 1 2% 0 0% 0 0% 0 0% 1 1% No information 0 0% 2 0% 0 0% 0 0% 0 0% 2 3% Types of regimens CPT-11 1 4% 11 19% 1 14% 2 9% 2 6% 13 17% Other drug combinations 22 96% 47 81% 6 86% 18 91% 28 94% 65 83% Associations of 170 SNPs with severe myelosuppression in subjects who received irinotecan therapy Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio UGT1A9 rs3832043 UGT1A9*1b or *22 9T 10T 0.63 0.63 1.00E+00 8.05EÀ01 7.33EÀ01 0.76 UGT1A7 rs17868323 Exon 1 (Lys 129 Asn) T G 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 1A7_R131Kaa Exon 1 (R131K) (UGT1A7*2) C A 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 1A7_R131Kba Exon 1 (R131K) (UGT1A7*2) G A 0.54 0.63 3.72EÀ01 1.00E+00 1.16EÀ01 2.68 UGT1A7 rs11692021 Exon 1 (Arg 208 Trp) (UGT1A7*3) T C 0.65 0.76 1.71EÀ01 1.00E+00 6.72EÀ03 15.56 UGT1A1 rs887829 Intron (tagged UGT1A1*28, promoter indel) G A 0.96 0.90 3.53EÀ01 1.64EÀ01 1.00E+00 5.15 UGT1A1 rs4148323 Exon 1 (Arg 71 Gly) (UGT1A1*6) G A 0.76 0.78 8.34EÀ01 4.51EÀ01 2.14EÀ02 12.00 UGT1A1 rs35350960 Exon 1 (Gln 229 Pro) (UGT1A1*27) C A 1.00 0.99 1.00E+00 1.00E+00 1.00E+00 NA BCHE rs697356 3' near gene G C 0.30 0.40 2.74EÀ01 4.95EÀ01 4.46EÀ01 1.64 BCHE rs1007845 3' near gene G A 0.83 0.78 6.67EÀ01 6.13EÀ01 1.00E+00 1.40 BCHE rs2048493 Intron 2 C G 0.78 0.62 6.41EÀ02 5.08EÀ02 4.29EÀ01 2.74 BCHE rs4639017 Intron 1 C G 0.72 0.60 2.07EÀ01 2.07EÀ01 7.17EÀ01 2.07 ABCC5 rs6810123 3' near gene A G 0.33 0.41 3.72EÀ01 1.00E+00 2.07EÀ01 2.07 ABCC5 rs12638772 3' near gene A G 0.36 0.32 7.07EÀ01 2.50EÀ01 1.00E+00 2.36 ABCC5 rs7613247 3' near gene A G 0.93 0.94 1.00E+00 1.00E+00 1.00E+00 1.15 ABCC5 rs2176825 3' near gene A G 0.25 0.37 1.81EÀ01 5.07EÀ01 2.07EÀ01 1.98 ABCC5 rs13066518 3' near gene T A 0.33 0.39 4.78EÀ01 1.00E+00 4.50EÀ01 1.62 ABCC5 rs3749443 3' near gene A G 0.20 0.18 1.00E+00 1.00E+00 7.90EÀ01 1.29 ABCC5 rs1402001 3' near gene A G 0.52 0.57 6.03EÀ01 7.95EÀ01 2.30EÀ01 2.10 ABCC5 rs6790814 3' near gene C G 0.66 0.76 2.33EÀ01 4.63EÀ01 1.25EÀ01 4.42 ABCC5 rs9838667 3' near gene T G 0.34 0.46 2.12EÀ01 5.64EÀ01 3.05EÀ01 1.85 ABCC5 rs2280392 3' near gene G A 0.25 0.23 8.35EÀ01 3.40EÀ01 8.02EÀ01 2.84 ABCC5 rs1879257 3' near gene A G 0.43 0.32 2.02EÀ01 3.07EÀ01 3.27EÀ01 2.02 ABCC5 rs3817403 3' near gene A G 0.87 0.90 7.82EÀ01 1.00E+00 1.00E+00 1.19 ABCC5 rs3805111 3' near gene T C 0.09 0.10 7.85EÀ01 1.00E+00 7.72EÀ01 1.24 ABCC5 rs3805108b 3' near gene A G 0.11 0.19 2.50EÀ01 6.69EÀ01 4.00EÀ01 1.97 ABCC5 rs2872247 3' near gene T G 0.76 0.70 4.49EÀ01 6.30EÀ01 6.67EÀ01 1.30 ABCC5 rs2293001 3' near gene T C 0.48 0.54 6.00EÀ01 7.79EÀ01 5.56EÀ01 1.44 ABCC5 rs4148572 Intron 2 C G 0.33 0.22 1.60EÀ01 1.36EÀ01 3.30EÀ01 4.20 ABCC5 rs4148568 Intron 2 A G 0.13 0.18 6.37EÀ01 5.85EÀ01 7.89EÀ01 NA ABCC5 rs4148564 Intron 2 A G 0.89 0.82 3.44EÀ01 3.00EÀ01 1.00E+00 1.89 ABCC5 rs4148560 Intron 2 A T 0.78 0.80 8.30EÀ01 7.96EÀ01 1.36EÀ01 4.20 ABCC5 rs7624838 Intron 2 T C 0.50 0.52 8.63EÀ01 7.82EÀ01 1.00E+00 1.26 ABCG2 rs2231164 Intron 14 C T 0.36 0.39 8.56EÀ01 5.57EÀ02 4.46EÀ01 NA ABCG2 rs2622611 Intron 10 T G 0.16 0.18 8.20EÀ01 3.29EÀ01 1.00E+00 NA ABCG2 rs1871744 Intron 6 T C 0.55 0.69 9.76EÀ02 3.22EÀ01 1.71EÀ01 2.73 ABCG2 rs2231142 Exon 5 (Gln 141 Lys) C A 0.78 0.78 1.00E+00 1.00E+00 1.00E+00 0.79 ABCG2 rs2231137 Exon 2 (Val 12 Met) G A 0.67 0.79 1.53EÀ01 3.19EÀ01 1.36EÀ01 4.20 ABCG2 rs1564481 Intron 1 C T 0.72 0.62 2.77EÀ01 3.15EÀ01 6.67EÀ01 1.74 ABCG2 rs2622624 Intron 1 A G 0.41 0.29 1.93EÀ01 2.78EÀ01 3.35EÀ01 2.41 ABCG2 rs2622604 Intron 1 T C 0.28 0.09 2.35EÀ03 7.81EÀ02 6.66EÀ03 4.40 ABCB1 rs1882478 Intron 27 C T 0.59 0.55 7.27EÀ01 4.31EÀ01 7.57EÀ01 1.57 ABCB1 rs6979885 Intron 27 G A 0.89 0.91 1.00E+00 1.00E+00 1.00E+00 1.19 ABCB1 rs2235047 Intron 27 T G 0.50 0.52 8.63EÀ01 7.82EÀ01 1.00E+00 1.26 ABCB1 rs1045642 Exon 27 (Ile 3 Ile) T C 0.37 0.44 4.80EÀ01 1.00E+00 4.34EÀ01 1.67 ABCB1 rs1002205 Intron 26 C G 0.52 0.60 3.75EÀ01 4.21EÀ01 7.14EÀ01 1.70 ABCB1 rs6949448 Intron 26 T C 0.35 0.40 5.91EÀ01 1.00E+00 6.09EÀ01 1.42 ABCB1 rs2235067 Intron 23 A G 0.07 0.11 5.60EÀ01 1.00E+00 5.36EÀ01 1.83 ABCB1 rs2373588 Intron 22 T C 0.43 0.39 5.98EÀ01 7.20EÀ01 7.99EÀ01 1.53 ABCB1 rs7787082 Intron 22 A G 0.50 0.50 1.00E+00 7.72EÀ01 7.72EÀ01 NA ABCB1 rs3789246 Intron 20 A G 0.09 0.19 1.50EÀ01 5.51EÀ01 2.69EÀ01 2.31 ABCB1 rs1922242b Intron 17 A T 0.78 0.68 2.45EÀ01 3.24EÀ01 4.90EÀ01 1.74 ABCB1 rs2235046 Intron 17 A G 0.72 0.59 1.51EÀ01 4.38EÀ02 1.00E+00 2.89 ABCB1 rs868755 Intron 9 C A 0.59 0.61 1.00E+00 1.00E+00 7.29EÀ01 1.36 ABCB1 rs4148734 Intron 8 C T 0.87 0.90 7.79EÀ01 5.42EÀ01 1.00E+00 1.55 ABCB1 rs2235018 Intron 6 A G 0.67 0.81 9.65EÀ02 2.09EÀ01 1.40EÀ01 4.13 ABCB1 rs10256836a Intron 5 C G 0.13 0.09 5.68EÀ01 1.00E+00 5.31EÀ01 1.73 ABCB1 rs10259849a Intron 5 C T 0.14 0.10 5.75EÀ01 1.00E+00 5.36EÀ01 1.65 ABCB1 rs1202172 Intron 5 T G 0.96 0.86 1.01EÀ01 8.01EÀ02 1.00E+00 4.00 Table 2 Continued Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio ABCB1 rs17327442 Intron 5 T A 0.89 0.94 5.12EÀ01 4.93EÀ01 1.00E+00 1.87 ABCB1 rs1202184 Intron 5 G A 0.24 0.33 3.44EÀ01 1.00E+00 2.25EÀ01 1.91 ABCB1 rs3789243 Intron 4 T C 0.50 0.31 2.81EÀ02 5.05EÀ02 1.38EÀ01 3.50 ABCB1 rs3213619 Exon 2 (5' UTR) C T 0.02 0.10 1.81EÀ01 1.00E+00 1.63EÀ01 5.02 ABCB1 rs4148732 Intron 1 A G 0.87 0.96 7.89EÀ02 6.87EÀ02 1.00E+00 3.67 ABCB1 rs13233308 Intron 1 T C 0.43 0.44 1.00E+00 7.60EÀ01 7.95EÀ01 0.82 ABCB1 rs1978095 Intron 1 T C 0.67 0.73 5.59EÀ01 6.21EÀ01 6.89EÀ01 1.36 ABCB1 rs2157929 Intron 1 T C 0.93 0.79 3.32EÀ02 5.60EÀ02 5.51EÀ01 3.81 ABCB1 rs10278483 Intron 1 T C 0.96 0.86 1.01EÀ01 1.36EÀ01 5.88EÀ01 3.34 CYP3A5 rs776746 Intron 3 (CYP3A5*3) A G 0.22 0.32 2.50EÀ01 6.67EÀ01 3.26EÀ01 1.79 CYP3A4 rs28371759c Exon 10 (Pro 293 Leu) (CYP3A4*18) 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CYP3A4 rs12721627b Exon 7 (Ser 185 Thr) (CYP3A4*16) C G 1.00 0.96 3.23EÀ01 3.22EÀ01 1.00E+00 NA ABCC2 rs12268782 5' near gene A G 0.22 0.13 2.26EÀ01 1.00E+00 1.81EÀ01 2.21 ABCC2 rs2804398 Intron 7 T A 0.83 0.84 8.14EÀ01 7.90EÀ01 1.00E+00 1.29 ABCC2 rs2756109 Intron 7 G T 0.63 0.65 8.55EÀ01 1.00E+00 1.00E+00 1.12 ABCC2 rs2273697 Exon 10 (Ile 417 Val) G A 0.83 0.92 8.91EÀ02 5.96EÀ02 1.00E+00 3.33 ABCC2 rs11190291a Intron 11 T C 0.17 0.08 8.91EÀ02 1.00E+00 5.96EÀ02 3.33 ABCC2 rs2002042 Intron 19 T C 0.33 0.39 4.78EÀ01 2.78EÀ01 1.00E+00 3.52 ABCC2 rs17222723c Exon 25 (Glu 1188 Val) T A 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA ABCC2 rs3740065b Intron 29 T C 0.65 0.60 5.96EÀ01 6.18EÀ01 9.90EÀ02 6.36 ABCC2 rs12762549 3' near gene C G 0.48 0.36 2.13EÀ01 1.00E+00 6.81EÀ02 3.35 ABCC2 rs2862691 3' near gene T C 0.19 0.25 5.26EÀ01 6.05EÀ01 6.11EÀ01 NA ABCC2 rs11598781 3' near gene T C 0.17 0.27 2.30EÀ01 1.00E+00 1.40EÀ01 2.29 ABCC2 rs11190303 3' near gene T C 0.24 0.33 2.62EÀ01 5.33EÀ02 1.00E+00 NA SLCO1B3 rs12228798 Intron 1 C T 0.82 0.83 1.00E+00 7.77EÀ01 2.27EÀ01 NA SLCO1B3 rs7977213 Intron 2 G C 0.43 0.18 1.29EÀ03 1.31EÀ03 2.55EÀ02 NA SLCO1B3 rs10841661 Intron 2 T C 0.48 0.23 2.73EÀ03 5.65EÀ03 4.79EÀ02 9.88 SLCO1B3 rs4149118 Intron 4 A G 0.59 0.48 3.31EÀ01 3.49EÀ01 5.40EÀ01 1.85 SLCO1B3 rs3764009a Intron 4 A G 0.68 0.69 1.00E+00 1.00E+00 1.00E+00 1.16 SLCO1B3 rs7311358 Exon 7 (Ile 233 Met) A G 0.68 0.69 1.00E+00 1.00E+00 1.00E+00 1.16 SLCO1B3 rs11045585b Intron 12 G A 0.13 0.21 2.76EÀ01 3.14EÀ01 6.06EÀ01 NA SLCO1B3 rs980084 Intron 12 G C 0.28 0.45 7.48EÀ02 3.80EÀ01 7.66EÀ02 2.67 SLCO1B3 rs3764006 Exon 14 (Gly 611 Gly) T C 0.87 0.70 2.74EÀ02 1.32EÀ01 9.75EÀ02 NA SLCO1B3 rs919840 3' near gene C G 0.97 0.90 2.99EÀ01 2.77EÀ01 1.00E+00 3.74 SLCO1B3 rs2117032 3' near gene T C 0.52 0.47 6.05EÀ01 7.68EÀ01 7.82EÀ01 1.35 SLCO1B3 rs7312051 3' near gene C T 1.00 0.91 1.26EÀ01 1.04EÀ01 1.00E+00 NA SLCO1B3 rs10841714 3' near gene C T 0.15 0.17 8.01EÀ01 1.00E+00 1.00E+00 NA SLCO1B3 rs2174012 3' near gene T C 0.62 0.63 1.00E+00 5.72EÀ01 4.55EÀ01 0.39 SLCO1B3 rs11045639a 3' near gene G A 0.65 0.72 4.46EÀ01 2.17EÀ01 7.25EÀ01 2.05 SLCO1B3 rs2900459 3' near gene G A 0.46 0.56 2.95EÀ01 1.43EÀ02 5.70EÀ01 5.96 SLCO1B3 rs4762693 3' near gene G A 0.65 0.72 4.46EÀ01 2.17EÀ01 7.25EÀ01 2.05 SLCO1B3 rs10734711 3' near gene A G 0.28 0.35 4.61EÀ01 2.78EÀ01 8.05EÀ01 3.52 SLCO1B1 rs12228427 5' near gene (LST-3TM12 Intron 9) A G 0.96 0.88 1.59EÀ01 1.36EÀ01 1.00E+00 3.34 SLCO1B1 rs1910163 5' near gene (LST-3TM12 Intron 12) A T 0.28 0.34 4.66EÀ01 7.25EÀ01 6.21EÀ01 1.44 SLCO1B1 rs6487207 5' near gene (LST-3TM12 Intron 11) T G 0.78 0.73 5.54EÀ01 8.11EÀ01 3.22EÀ01 NA SLCO1B1 rs1604539 5' near gene (LST-3TM12 Intron 12) T G 0.80 0.75 5.41EÀ01 6.18EÀ01 1.00E+00 1.42 SLCO1B1 rs7973691 5' near gene T C 0.80 0.83 8.21EÀ01 7.98EÀ01 1.00E+00 1.22 SLCO1B1 rs10743408 Intron 2 C G 0.24 0.18 4.97EÀ01 1.00E+00 3.06EÀ01 1.73 SLCO1B1 rs976754 Intron 2 T C 0.83 0.69 1.15EÀ01 8.67EÀ02 6.67EÀ01 2.54 SLCO1B1 rs2291073 Intron 3 T G 0.78 0.72 4.35EÀ01 8.11EÀ01 1.76EÀ01 NA SLCO1B1 rs4149037 Intron 4 A G 0.70 0.80 2.12EÀ01 2.07EÀ01 6.19EÀ01 2.07 SLCO1B1 rs4149056 Exon 5 (Ala 174 Val) T C 0.72 0.84 8.02EÀ02 2.04EÀ01 8.01EÀ02 NA SLCO1B1 rs2417967 Intron 11 A G 0.33 0.21 1.54EÀ01 1.00E+00 8.68EÀ02 2.41 SLCO1B1 rs7969341b Intron 14 T C 0.50 0.46 7.24EÀ01 1.58EÀ01 5.60EÀ02 3.80 SLCO1B1 rs4149085 3' UTR T C 0.74 0.66 4.53EÀ01 8.05EÀ01 1.76EÀ01 NA SLCO1B1 rs12372067 3' near gene C A 0.21 0.33 2.06EÀ01 1.00E+00 1.68EÀ01 2.42 SLCO1B1 rs12310063 3' near gene A C 0.67 0.76 3.21EÀ01 2.13EÀ01 1.00E+00 2.07 ABCC1 rs8050881 5' near gene A G 0.33 0.23 2.37EÀ01 1.00E+00 1.44EÀ01 2.13 ABCC1 rs4148330 5' near gene G A 0.48 0.34 1.46EÀ01 2.95EÀ01 2.13EÀ01 2.02 Continued Allele Frequency of allele 1 Fisher test`s P-values Gene name SNP ID Position of SNP/functional SNP 1 2 dCase eControl f1vs2 g11vs h22vs Odds ratio ABCC1 rs7190484 Intron 1 T C 0.43 0.34 3.67EÀ01 5.03EÀ01 4.62EÀ01 1.52 ABCC1 rs215098 Intron 1 C A 0.41 0.34 4.63EÀ01 1.96EÀ01 1.00E+00 2.30 ABCC1 rs215096 Intron 1 T C 0.89 0.87 1.00E+00 5.63EÀ01 2.89EÀ01 0.00 ABCC1 rs152023 Intron 1 G A 0.48 0.41 4.75EÀ01 3.79EÀ01 8.05EÀ01 1.79 ABCC1 rs6498595 Intron 1 G C 0.41 0.31 2.70EÀ01 2.73EÀ02 1.00E+00 4.76 ABCC1 rs7196970 Intron 1 C G 0.70 0.63 4.71EÀ01 3.25EÀ01 1.00E+00 1.73 ABCC1 rs12935283 Intron 1 A G 0.67 0.61 4.78EÀ01 3.19EÀ01 1.00E+00 1.79 ABCC1 rs246240 Intron 5 A G 0.60 0.58 1.00E+00 1.00E+00 1.00E+00 1.06 ABCC1 rs924138b Intron 5 T C 0.68 0.63 5.84EÀ01 6.17EÀ01 1.00E+00 1.38 ABCC1 rs2062541 Intron 6 C T 0.71 0.64 4.46EÀ01 4.45EÀ01 7.51EÀ01 1.60 ABCC1 rs11647513 Intron 6 C T 0.78 0.70 3.34EÀ01 2.14EÀ01 1.00E+00 2.13 ABCC1 rs35593 Intron 11 T C 0.71 0.75 8.37EÀ01 1.00E+00 1.00E+00 2.70 ABCC1 rs3765129 Intron 11 C T 0.98 0.84 2.69EÀ02 1.75EÀ02 1.00E+00 9.90 ABCC1 rs17287570 Intron 12 A C 0.73 0.91 6.32EÀ03 1.03EÀ02 2.75EÀ01 4.27 ABCC1 rs35597 Intron 12 A G 0.59 0.55 7.19EÀ01 5.85EÀ01 1.00E+00 1.45 ABCC1 rs35598a Intron 12 A G 0.82 0.86 6.21EÀ01 7.86EÀ01 2.78EÀ01 NA ABCC1 rs9932506 Intron 12 G A 0.72 0.75 6.94EÀ01 6.21EÀ01 1.00E+00 1.44 ABCC1 rs35604 Intron 12 G A 0.24 0.25 1.00E+00 1.00E+00 1.00E+00 1.63 ABCC1 rs35606 Intron 13 C T 0.82 0.86 6.17EÀ01 7.82EÀ01 2.86EÀ01 NA ABCC1 rs35620 Intron 14 G C 0.26 0.23 8.39EÀ01 1.00E+00 6.19EÀ01 1.39 ABCC1 rs35625 Intron 14 C T 0.41 0.34 4.70EÀ01 7.52EÀ01 4.72EÀ01 1.45 ABCC1 rs35626 Intron 15 T G 0.43 0.40 7.21EÀ01 5.08EÀ01 2.96EÀ01 1.93 ABCC1 rs4148353 Intron 15 T G 0.20 0.07 2.42EÀ02 1.00E+00 1.69EÀ02 4.02 ABCC1 rs35629 Intron 15 C T 0.80 0.76 5.46EÀ01 6.24EÀ01 1.00E+00 1.32 ABCC1 rs2269800 Intron 20 A G 0.74 0.66 4.53EÀ01 8.06EÀ01 2.78EÀ01 3.52 ABCC1 rs11864374 Intron 21 G A 0.78 0.77 8.41EÀ01 1.00E+00 1.00E+00 1.63 ABCC1 rs3887893 Intron 22 A G 0.48 0.46 8.62EÀ01 2.30EÀ01 5.85EÀ01 2.10 ABCC1 rs4148376 Intron 23 A G 0.93 0.95 1.00E+00 1.00E+00 1.00E+00 1.30 ABCC1 rs2238475 Intron 23 C A 0.11 0.18 3.45EÀ01 1.00E+00 4.21EÀ01 1.80 ABCC1 rs212079 Intron 26 G A 0.76 0.83 3.77EÀ01 1.00E+00 6.71EÀ02 8.55 ABCC1 rs2283512 Intron 26 G T 0.48 0.46 1.00E+00 7.68EÀ01 1.00E+00 1.32 ABCC1 rs212081 Intron 27 T C 0.20 0.22 8.34EÀ01 5.73EÀ01 4.61EÀ01 1.50 ABCC1 rs212084 Intron 28 G A 0.68 0.77 2.90EÀ01 3.02EÀ01 6.00EÀ01 1.81 ABCC1 rs212087 Intron 28 C T 0.57 0.70 1.41EÀ01 1.38EÀ01 3.45EÀ01 2.30 ABCC1 rs4148380 3' UTR G A 0.87 0.89 7.88EÀ01 7.75EÀ01 1.00E+00 1.22 ABCC1 rs212091 3' UTR G A 0.22 0.34 1.84EÀ01 2.68EÀ01 3.35EÀ01 4.04 ABCC1 rs12448760 3' near gene G A 0.82 0.89 2.95EÀ01 3.79EÀ01 1.00E+00 1.79 ABCC1 rs9932935 3' near gene (ABCC6 Intron 29) A T 0.96 0.91 5.12EÀ01 5.00EÀ01 1.00E+00 1.93 ABCC1 rs2066738 3' near gene (ABCC6 Intron 28) C T 0.74 0.90 1.50EÀ02 5.28EÀ02 7.81EÀ02 2.95 ABCC1 rs169845 3' near gene (ABCC6 Intron 27) G C 0.26 0.40 1.04EÀ01 3.28EÀ01 2.13EÀ01 2.07 ABCC1 rs2238471 3' near gene (ABCC6 Intron 26) A C 0.93 0.81 5.49EÀ02 5.79EÀ02 1.00E+00 3.78 ABCC1 rs3213471 3' near gene (ABCC6 Intron 24) A G 0.91 0.92 1.00E+00 7.33EÀ01 1.00E+00 1.32 ABCC1 rs3213473 3' near gene (ABCC6 Intron 24) T G 0.16 0.13 7.98EÀ01 1.00E+00 7.71EÀ01 1.27 CES2 rs3843712 5' near gene G A 0.18 0.12 4.41EÀ01 1.00E+00 4.00EÀ01 1.80 CES2 rs8062110 5' near gene G C 0.61 0.65 7.16EÀ01 1.00E+00 7.28EÀ01 1.39 CES2 rs4783744 5' near gene G A 0.66 0.62 8.37EÀ01 7.76EÀ01 1.00E+00 1.24 CES2 rs7194513 5' near gene G A 0.26 0.27 1.00E+00 3.14EÀ01 6.29EÀ01 NA CES2 rs28382812c Exon 1 (Ile 37 Ile) C T 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CES2 rs2241410 Intron 2 T G 0.10 0.11 7.85EÀ01 1.00E+00 7.71EÀ01 1.26 CES2 rs2303218 Intron 2 G A 0.09 0.21 1.03EÀ01 5.55EÀ01 1.15EÀ01 2.70 CES2 rs8192924c Exon 5 (His 270 Arg) G A 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA CES2 rs28382827c Exon 12 (Leu 613 Leu) C T 1.00 1.00 1.00E+00 1.00E+00 1.00E+00 NA Abbreviations: Chrom, chromosome; HWE, Hardy-Weinberg equilibrium; NA, not available; SNP, single nucleotide polymorphism. 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PMID: 19771428 [PubMed] Sai K et al: "Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients."

No. Sentence Comment

41 49G[T G 0.200 0.274 # IIIC [*1b-*3-*1c]e 34G[A(V12M), IVS9-30A[T 0.164 0.097 SLCO1B1 *1b 388A[G(N130D) 0.373 0.573 *15 Á 17 521T[C(V174A) S 0.191 0.153 a Number of chromosome b BJL consists of *1B (having -1789G[A), *1J (having -1789G[A and -371A[G) and *1L (having -1789G[A and -145C[G) previously defined [26] c *2 Group includes *2, *9, *12 and *14 haplotypes previously defined [26] d *10 Group includes *10 and *13 haplotypes previously defined [26] e Combination of ABCG2 haplotypes of three blocks [block (-1)-block 1-block 2] previously defined [28] haplotypes with 2677G[T (A893S), *2, *9, *12 and *14 [26], as the *2 group (*2 in this paper). Login to comment
49 49G[T] (0.251) and # IIIC [containing 34G[A (V12M) and IVS9-30A[T] (0.107). Login to comment
50 Note that # IIB and # IIIC are subgroups of block 1 *2 [421C[A (Q141K)] and block 1*3 [34G[A (V12M)], respectively [28]. Login to comment
157 ABCG2# IIIC contains a non-synonymous SNP 34G[A (V12M) which has no influence on BCRP expression or activity in vitro [36, 39-41]. Login to comment
159 In contrast, a report on Korean patients suggested the association of ABCG2 34G[A (V12M) with a higher incidence of grade 3 diarrhea in a combination therapy of irinotecan and cisplatin [24]. Login to comment

PMID: 19788499 [PubMed] Vahakangas K et al: "Drug transporters in the human blood-placental barrier."

No. Sentence Comment

99 Table 4 Significance of drug transporter polymorphisms in human placenta Protein Gene polymorphisms Type of study Significance in placenta Reference P-gp/MDR1 G2677A/T (Ala toThr/Ser) T-129C 100 human placentas Less P-gp protein Less P-gp protein 1 P-gp/MDR1 G2677T/A C3435T 73 human placentas from Caucasians No effect on MDR1 mRNA Homozygosity of 3435T and 2677T lead to lower protein levels 2 P-gp/MDR1 C3435T 44 human placentas T allele associated with a higher expression 3 P-gp/MDR1 C3435T and G2677A/T Human placental perfusion No effect on saquinavir transfer 3, 4 P-gp/MDR1 C3435T Human placental perfusion 3435T associated with increased transfer of quetiapine 5 MRP2 G1249A 58 human placentas Reduced expression of MRP2 mRNA in preterm placentas only 6 BCRP G34A (Val12Met) C421A (Gln141Lys) 99 human placentas No effect on protein level Protein decreased 7 References: (1) Tanabe et al. (2001), (2) Hitzl et al. (2004), (3) Rahi et al. (2008), (4) Mölsä et al. (2005), (5) Rahi et al. (2007), (6) Meyer zu Schwabedissen et al. (2005b), (7) Kobayashi et al. (2005). Login to comment

PMID: 19827267 [PubMed] Ishikawa T et al: "Human ABC transporter ABCG2 in cancer chemotherapy and pharmacogenomics."

No. Sentence Comment

222 COOH H2N N590Y V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L F489L D620N R482G R482T S441N F571I OUT IN R160Q R575stop ATP-binding site Figure 7. Continued A 005-024 pp JETO-0900616-TI (Review).indd 8/7/2009 3:59:50 19 Q141K has been associated with lower levels of protein expression and impaired transport in vitro (Imai et al., 2002; Kobayashi et al., 2005; Misuarai et al., 2004; Zamber et al., 2003; Morisaki et al., 2008; Kondo et al., 2004). Login to comment
228 Furthermore, the F208S, S248P, F431L, S441N, and F489L variants exhibited greatly altered protein expression levels and drug resistance profiles Figure 7. Continued WT V12M Q141K F208S S248P F431L S441N F489L R482G R482T Protein expression + + + - + + - + + + MTX transport + + + - - - - +/ - - Porphyrin transport + + + - - + - +/ + + SN-38 resistance + + + - +/ + - - + + MX resistance + + + - - - - - -- - - - - - - - +/ - - - - - - - - + + Doxorubicin resistance + + Daunorubicin resistance + + ATPase activity (Prazosin) + + WTV12M Q141K F431L F489L S248P F208S S441L R482G R482T ∆1.5 ∆3 ∆3.5 ∆5 ∆4 - - - - - - -- - - B 005-024 pp JETO-0900616-TI (Review).indd 8/7/2009 3:59:51 20 Journal of Experimental Therapeutics and Oncology Vol. 8 2009 (Tamura et al., 2007b). Login to comment
232 It is known that, in the ER, the N-linked glycans play pivotal roles in protein fold- 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) Methotrexate 0.0 0.5 1.0 1.5 0.0 0.5 1.0 1.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T Methotrexatetransport (nmol/min/mgprotein) MethotrexateMethotrexate Porphyrintransport (nmol/min/mgprotein) 0.0 0.1 0.2 0.3 0.4 0.5 0.0 0.1 0.2 0.3 0.4 0.5 Porphyrin Figure 7. Login to comment
251 The new camptothecin analogues that were non-substrates for ABCG2 circumvented ABCG2-mediated drug resistance without any influence from major SNPs, i.e., V12M and Q141K (Tamura et al. 2007b). Login to comment

PMID: 19835554 [PubMed] Franke RM et al: "Pharmacogenetics of drug transporters."

No. Sentence Comment

104 Several other SNPs have been identified in coding regions of the gene, and at least three additional non-synonymous SNPs have been identified occurring at positions 34 (V12M; exon 2), 616 (I206L, exon 6), and 1768 (N590Y, exon 15). Login to comment

PMID: 19949922 [PubMed] Cascorbi I et al: "Pharmacogenetics of ATP-binding cassette transporters and clinical implications."

No. Sentence Comment

224 Both identified 34G>A (V12M) and 421C>A (Q141K). Login to comment
232 Moreover, decreased transport rates were found in Sf9 insect cells, transfected with the V12M variant (119). Login to comment
239 0.235 c. 34 G>A V12M 0.17 0.04a 0.06b IVS 2 +16 A>G ? Login to comment
258 Interestingly, V12M was associated with elevated activity compared to the wild-type, whereas ABCG2 with premature stop-codon lacked any activity as expected (37). Login to comment

PMID: 19949923 [PubMed] Aszalos A et al: "Flow cytometric evaluation of multidrug resistance proteins."

No. Sentence Comment

258 The V12M and Q141K variants were described by Zamber et al. Login to comment

PMID: 19949928 [PubMed] Ross DD et al: "Impact of breast cancer resistance protein on cancer treatment outcomes."

No. Sentence Comment

70 A number of single nucleotide polymorphisms (SNPs) have been observed in the BCRP gene (77), and of those nonsynonymous SNPs observed in the coding region, the most common and most extensively studied are the G34A (exon 2) and C421A (exon 5) alleles, which cause alterations of amino acids 12 (V12M) and 141 (Q141K), respectively (78-81). Login to comment
90 found four nonsynonymous coding region SNPs among 92 Korean subjects (V12M, Q141K, P269S, Q126Stop), and four SNPs in the BCRP promoter region, one of which was in the HIF-1 response element (C-19031T) (86). Login to comment
93 Tamura et al. used multicolor fluorescence in situ hybridization to assure uniform mRNA expression of cDNAs of seven BCRP SNPs (V12M, Q141K, F208S, S248P, F431L, S441N and F489L) transduced into Flp-In-293 cells (87, 88). Login to comment
94 Protein expression from the F208S and S441N variants was found to be low; the V12M and Q141K alleles had IC50 s for SN-38 that were approximately half that of the wild-type; all the other alleles examined had significantly lower IC50 values for SN-38, mitoxantrone, doxorubicin, daunorubicin and etoposide when compared with wild type alleles (88). Login to comment

PMID: 19950006 [PubMed] Sissung TM et al: "Pharmacogenetics of membrane transporters: an update on current approaches."

No. Sentence Comment

61 Another SNP exists at nucleotide 34, resulting in a V12M amino acid change. Login to comment

PMID: 20347140 [PubMed] Hutson JR et al: "Placental P-glycoprotein and breast cancer resistance protein: influence of polymorphisms on fetal drug exposure and physiology."

No. Sentence Comment

142 The G34A and C421 SNPs result in amino acid changes (V12M and Q141K respectively). Login to comment

PMID: 20972558 [PubMed] Kim KA et al: "Effect of ABCG2 genotypes on the pharmacokinetics of A771726, an active metabolite of prodrug leflunomide, and association of A771726 exposure with serum uric acid level."

No. Sentence Comment

17 Several ABCG2 genetic variants have been reported; the most frequent ABCG2 polymorphisms detected among different ethnic groups are c.34G>A (rs2231137), which codes for V12M, and c.421C>A (rs2231142), which codes for Q141K [4]. Login to comment

PMID: 21054463 [PubMed] Kim KA et al: "ABCG2 polymorphisms, 34G>A and 421C>A in a Korean population: analysis and a comprehensive comparison with other populations."

No. Sentence Comment

21 The most frequent ABCG2 polymorphisms detected among different ethnic groups are 34G>A, which codes for V12M, and 421C>A, which codes for Q141K (14). Login to comment
39 Oligonucleotide primers used for PCR and pyrosequencing to detect ABCG2 polymorphisms SNP Amino acid change PCR primer Sequencing primer Size (bp) 34G>A Val12Met Forward 5'-GCTCATTGCCACACATTT-3' 5'-ATGTCGAAGTTTTTATCC-3' 188 Reverse B 5'-GAAGCCATTGGTGTTTCC-3' 421C>A Cln141Lys Forward B 5'- ATGTTGTGATGGGCACTCTGAC-3' 5'-GAAGAGCTGCTGAGAACT-3' 210 Reverse 5'-TATCCACACAGGGAAAGTCCTACT-3' B, biotinylated on 5'-end of primer. Login to comment
81 Comparisons of ABCG2 allele frequencies with other ethnic groups SNP Amino acid change Population (n) Frequency (%) Reference G34A V12M Korea (250) 19Æ8 Present study Southeast Asians (20) 45Æ0 14 Chinese (20) 20Æ0 14 Japanese (124) 19Æ0 15 Japanese (120) 17Æ5 27 Japanese (20) 15Æ0 14 Caucasian (150) 10Æ3 19 Ashkenazi Jewish (20) 10Æ0 14 Mexicans (20) 10Æ0 14 Dutch (100) 6Æ5 37 African-American (150) 6Æ3 27 Middle Eastern (40) 5Æ0 14 Caucasian (150) 3Æ7 27 Swedish (60) 1Æ7 36 C421A Q141K Korea (250) 27Æ8 Present study Japanese (20) 35Æ0 14 Chinese (20) 35Æ0 14 Chinese (95) 34Æ2 22 Japanese (120) 32Æ7 27 Japanese (124) 26Æ6 15 Southeast Asians (20) 15Æ0 14 Middle Eastern (40) 13Æ0 14 Dutch (100) 12Æ0 37 Caucasian (172) 11Æ3 22 Mexicans (20) 10Æ0 14 Swedish (60) 10Æ0 36 Caucasian (150) 8Æ7 19 Ashkenazi Jewish (20) 5Æ0 14 African-American (150) 2Æ3 27 was demonstrated that 421C>A carriers have a 1Æ3-fold decrease in ATPase activity compared to wild-type (19), and the bioavailability of sulfasalazine, diflomotecan and topotecan was significantly elevated by this polymorphism (29-31). Login to comment

PMID: 21188243 [PubMed] Ishikawa T et al: "Key Role of Human ABC Transporter ABCG2 in Photodynamic Therapy and Photodynamic Diagnosis."

No. Sentence Comment

167 Based on the currently available data on SNPs and acquired mutations, we have created a total of 18 variant forms of ABCG2 (V12M, G51C, Q126stop, Q141K, T153M, Q166E, I206L, F208S, S248P, E334stop, F431L, S441N, R482G, R482T, F489L, F571I, N590Y, and D620N) by site-directed mutagenesis and expressed them in insect cells [41, 90]. Login to comment
177 Gefitinib and imatinib are new anticancer drugs Outside Plasma membrane Inside H2N COOH V12M G51C Q126stop Q141K T153M R160Q Q166E I206L F208S S248P E334stop F431L F489L S441N R482G R482T F571I R575stop N590Y D620N T542A A528T D296H P269S ATP-binding cassette (a) 0 0.1 0.3 0.4 0.2 0.5 Mock WT V12M G51C Q126stop Q141K T153M Q166E I206L F208S S248P E334stop F431L S441N F489L F571I N590Y D620N R482G R482T ATP-dependenthematoporphyrin transport(nmol/min/mgprotein) (b) Figure 4: (a) Schematic illustration of human ABCG2 and its nonsynonymous polymorphisms. Login to comment

PMID: 21311724 [PubMed] Hampras SS et al: "Genetic polymorphisms of ATP-binding cassette (ABC) proteins, overall survival and drug toxicity in patients with Acute Myeloid Leukemia."

No. Sentence Comment

61 The rs2231137 (G34A) polymorphism results in valine to methionine substitution (V12M) in the amino acid sequence of the protein and findings across studies have been contradictory regarding its functional significance. Login to comment

PMID: 21449672 [PubMed] Kwan P et al: "Gene-wide tagging study of the association between ABCC2, ABCC5 and ABCG2 genetic polymorphisms and multidrug resistance in epilepsy."

No. Sentence Comment

34 For ABCG2, 77 kbp from positions 89,365,500 to 89,442,500 on chromosome 4 were tagged by 11 poly-morphisms (with forced inclusion of two coding SNPs: rs2231137 or V12M and rs2231142 or Q141K), capturing 29 of 39 alleles at r2 ≥ 0.8. Login to comment

PMID: 14965249 [PubMed] Haimeur A et al: "The MRP-related and BCRP/ABCG2 multidrug resistance proteins: biology, substrate specificity and regulation."

No. Sentence Comment

724 Another mutant, G34A, in which the Val at position 12 has been replaced with Met (Val12Met), exhibits properties comparable to the wild-type protein. Login to comment

PMID: 16041239 [PubMed] Colombo S et al: "Influence of ABCB1, ABCC1, ABCC2, and ABCG2 haplotypes on the cellular exposure of nelfinavir in vivo."

No. Sentence Comment

78 - 19346T > A 50 upstream Epidauros bc-v-081 c.19 delG exon 2 p.K7fsX28 Epidauros bc-v-007 c.34G > A exon 2 p.V12M Honjo et al., 2001 bc-v-008 rs2231137 c.71C > T exon 2 p.A24V Epidauros bc-v-009 c.114T > C exon 2 synonymous (p.S38S) Zamber et al., 2003 bc-v-071 rs12721644 IVS 2 + 35 A > G intron 2 Honjo et al., 2001 bc-v-058 rs4148152 IVS 2-12 A > G intron 4 Epidauros bc-v-014 rs2231141 c.421C > A exon 5 p.Q141K Imai et al., 2002 bc-v-015 rs2231142 c.496C > G exon 5 p.Q166E Epidauros bc-v-016 rs1061017 IVS 5 + 14 A > T intron 5 Epidauros bc-v-017 rs2231143 Statistics Association between AUC values and genotypes at single SNP loci was evaluated using a Kruskal-Wallis rank test complemented by a Spearman rank test for trend. Login to comment

PMID: 19349540 [PubMed] Innocenti F et al: "Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics."

No. Sentence Comment

115 % of Patients HWE Exact P (white)African American (n ϭ 11) White (n ϭ 67) Other (n ϭ 7) ABCB1 IVS9 -44AϾG 10276036 .012 A/A 45.4 37.3 0 A/G 36.4 34.3 57.1 G/G 18.2 28.4 42.9 ABCB1 1236CϾT 1128503 .012 C/C 45.5 38.8 0 C/T 54.5 34.3 57.1 T/T 0 26.9 42.9 ABCB1 IVS13 ϩ24CϾT 2235033 .027 C/C 27.3 29.9 0 C/T 45.4 35.8 57.1 T/T 27.3 34.3 42.9 ABCB1 IVS14 ϩ38AϾG 2235013 .027 A/A 18.2 29.9 0 A/G 54.5 35.8 57.1 G/G 27.3 34.3 42.9 ABCB1 2677GϾA/T (A893T/S) 2032582 .046 G/G 40.0 36.9 40.0 G/T 60.0 36.9 60.0 T/T 0 26.2 0 ABCB1 3435CϾT 1045642 .212 C/C 36.4 28.4 57.1 C/T 54.5 41.8 42.9 T/T 9.1 29.8 0 ABCG2 34GϾA (V12M) 2231137 .113 G/G 100 92.5 28.6 G/A 0 6.0 57.1 A/A 0 1.5 14.3 ABCG2 421CϾA (Q141K) 2231142 1.000 C/A 9.1 14.9 42.9 C/C 90.9 85.1 57.1 A/A 0 0 0 SLCO1B1*1b 388AϾG (N130D) 2306283 .624 A/A 18.2 31.3 0 A/G 63.6 46.3 71.4 G/G 18.2 22.4 28.6 SLCO1B1*5 521TϾC (V174A) 4149056 1.000 T/T 81.8 65.7 57.1 T/C 18.2 31.3 42.9 C/C 0 3.0 0 NOTE. Alleles for which a * nomenclature has not yet been assigned have been reported according to their genomic position related to the ATG start site. The reference sequences used for genotyping are the following: ABCG2, NM_004827; SLCO1B1, NM_006446; ABCB1, NM_000927; ABCC1, NM_004987; and ABCC2, NM_00039. Login to comment

PMID: 20368717 [PubMed] Bergmann TK et al: "Impact of CYP2C8*3 on paclitaxel clearance: a population pharmacokinetic and pharmacogenomic study in 93 patients with ovarian cancer."

No. Sentence Comment

135 This effect on clearance of a 'non-fixed` variable provides a competing and dynamic biological explanation for clearance that certainly should be Table 4 Clearance of unbound paclitaxel as function of observed genotypes Gene/allelea Effectb Reference homozygote Heterozygote Variant homozygote P-valuee SNP IDf Nc CLd (10th-90th) Nc CLd (10th-90th) Nc CLd (10th-90th) Candidate SNPs for confirmative analysis CYP2C8 1196A4G(*3) K399R 74 395 (297-490) 19 350 (238-458) 0.03* (0.04) rs10509681 ABCB1 1236C4T G412G 29 391 (270-569) 45 393 (299-490) 19 359 (291-437) 0.25 (0.25) rs1128503 2677G4T/Ag A893S/T 26 387 (270-490) 42(GT) 396 (299-490) 20(TT) 356 (294-437) 0.20 (0.26) rs2032582 3435C4T I1145I 11 403 (326-548) 44 387 (282-490) 38 378 (297-468) 0.83 (0.43) rs1045642 Candidate SNPs for exploratory analysis CYP2C8 792C4G(*4) I264M 86 391 (297-490) 7 321 (270-374) 0.04* (0.03) rs1058930 15577956G4T (*1B) - 49 395 (298-552) 43 373 (291-478) 1 461 0.75 (0.36) rs7909236 15578055A4C (*1C) - 69 382 (291-478) 24 393 (300-552) 0.48 (0.62) rs17110453 ABCB1 À1A4G - 1 458 29 396 (270-592) 63 379 (297-477) 0.56 (0.3) rs2214102 61A4G N21D 63 384 (282-490) 29 386 (298-478) 1 437 0.52 (0.77) rs9282564 1199G4A S400N 83 385 (291-490) 10 386 (322-461) 0.74 (0.99) rs2229109 CYP3A4 24616372T4C (*1B) - 85 383 (296-490) 7 397 (270-641) 0.67 (0.72) rs2740574 CYP3A5 219-237G4A Frameshift 84 388 (297-490) 9 360 (176-726) 0.30 (0.36) rs776746 SLCO1B3 699G4A M233I 1 326 19 377 (299-481) 73 388 (291-490) 0.99 (0.46) rs7311358 767G4C G256A 67 386 (298-481) 26 383 (291-490) 0.63 (0.89) rs60140950 CYP1B1 1294C4G (*3) V432L 30 389 (270-530) 36 401 (298-490) 27 361 (300-470) 0.77 (0.24) rs1056836 ABCC1 7356253C4G - 65 394 (297-548) 27 368 (291-470) 1 332 0.04* (0.15) rs504348 ABCC2 1249G4A V417I 67 381 (291-490) 24 396 (297-552) 2 415 (368-468) 0.21 (0.39) rs2273697 3563T4A V1188E 87 386 (296-490) 5 370 (176-569) 0.7 (0.7) rs17222723 4544G4A C1515Y 75 389 (296-490) 3 355 (176-569) 0.72 (0.52) rs8187710 ABCG2 421C4A Q141K 61 374 (291-478) 32 408 (315-548) 0.4 (0.09) rs2231142 34G4A V12M 87 385 (291-490) 4 395 (296-726) 0.68 (0.83) rs2231137 ABCC10 2759T4C I920T 46 386 (297-478) 43 386 (291-548) 4 373 (326-467) 0.88 (0.89) rs2125739 Abbreviations: CL, clearance of unbound paclitaxel; SNP, single-nucleotide polymorphism. Login to comment

PMID: 17001288 [PubMed] Owen A et al: "Pharmacogenetics of HIV therapy."

No. Sentence Comment

171 Pharmacogenetics of HIV therapy Owen et al. 699 Table 1 Polymorphisms that have been studied within the context of metabolism, transport and toxicity (but not progression and response) along with the reference ID (where available), the genotypic consequence and the observed phenotype for antiretroviral drugs Gene SNP (haplotype) Reference SNP Genotypic consequence Phenotypic consequence Confirmation CYP3A4 A - 392G (CYP3A4*1B) rs2740574 Promoter; altered expression No effect on nelfinavir or efavirenz Yes for nelfinavir; controversial for efavirenz T878C (CYP3A4*18) rs4986909 L293P; altered activity No effect on efavirenz No CYP3A5 A6986G (CYP3A5*3) rs776746 Splice defect No effect on nelfinavir, saquinavir or efavirenz AUC but altered urinary metabolic ratio of saquinavir Yes for efavirenz G14690A (CYP3A5*6) rs10264272 Splice defect No effect on nelfinavir or efavirenz Yes CYP2C19 G681A (CYP2C19*2) rs4244285 Truncated protein Higher nelfinavir AUC and trend toward decreased virological failure; no effect on efavirenz Yes for efavirenz; controversial for nelfinavir CYP2D6 A2549del (CYP2D6*3) NT21914757 Frameshift Trend to higher plasma levels of nelfinavir and efavirenz No G1846A (CYP2D6*4) rs3892097 Splice defect Trend to higher plasma levels of nelfinavir and efavirenz No T1707del (CYP2D6*6) rs5030655 Frameshift Higher plasma nelfinavir concentrations No CYP2B6 G516 T (CYP2B6*6, *7, *9, *13, *19 and *20) rs3745274 Q172H Higher plasma and intracellular efavirenz AUCs and increased neurotoxicity Yes, numerous studies C1459T (CYP2B6*5 and *7) rs3211371 R487C No effect on nelfinavir or efavirenz No ABCB1 IVS1 - 80delG rs3214119 N/A No influence on cellular nelfinavir No A61G rs9282564 N21D No influence on cellular nelfinavir No TAG1 rs3789243 N/A No influence on cellular nelfinavir No G1199A rs2229109 S400N No influence on cellular nelfinavir No TAG5 rs1128503 N/A No influence on cellular nelfinavir No TAG6 rs2235046 N/A No influence on cellular nelfinavir No IVS21 + T49C rs2032583 N/A No influence on cellular nelfinavir No C3435T rs1045642 Synonymous Some evidence of an influence on plasma and intracellular nelfinavir; decreased efavirenz plasma concentrations; currently under debate; increase in HDL cholesterol with efavirenz Controversial G2677T rs2032582 Ala893Ser No effect on efavirenz, ritonavir, nelfinavir, indinavir or viral decay and CD4 count Yes IVS26 + T59G rs2235047 N/A No influence on cellular nelfinavir No IVS26 + T80C rs2235048 N/A Increased intracellular nelfinavir concentrations No TAG11 rs1186746 N/A No influence on cellular nelfinavir No TAG12 rs1186745 N/A No influence on cellular nelfinavir No ABCC1 G816A P272P No influence on cellular nelfinavir No T825C rs246221 V275V No influence on cellular nelfinavir No T1062C rs35587 Synonymous No influence on cellular nelfinavir No IVS9 + A8G rs35588 N/A No influence on cellular nelfinavir No IVS10 + C64T N/A No influence on cellular nelfinavir No ABCC2 C - 24T rs717620 N/A No influence on cellular nelfinavir No G1249A rs2273697 V417I No influence on cellular nelfinavir No C1436G Synonymous No influence on cellular nelfinavir No IVS16 - G47A N/A No influence on cellular nelfinavir No T3563A rs8187694 V1188E No influence on cellular nelfinavir No C4488T rs8187707 Synonymous No influence on cellular nelfinavir No IVS31 + G12A rs8187708 N/A No influence on cellular nelfinavir No IVS31 + C74T N/A No influence on cellular nelfinavir No G4544A rs8187710 C1515Y No influence on cellular nelfinavir No G + 259T N/A No influence on cellular nelfinavir No ABCG2 - 19571_ - 19568delT- CAC rs4148162 Deletion No influence on cellular nelfinavir No A-19541G N/A No influence on cellular nelfinavir No G34A rs2231137 V12M No influence on cellular nelfinavir No IVS2 + 35G rs4148152 N/A No influence on cellular nelfinavir No C421A rs2231142 Q141K No influence on cellular nelfinavir No APOCIII C-482T Pending Promoter Hyperlipidaemia in presence of ritonavir Yes T-455C Pending Promoter Hyperlipidaemia in presence of ritonavir Yes C3238G rs5128 30 UTR variant Hyperlipidaemia in presence of ritonavir Yes APOE 2060T/2198T (APOEe2) rs429358 R112C/R158C Hyperlipidaemia in presence of ritonavir Yes 2060T/2198C (APOEe3) rs7412 R112C/R158R Hyperlipidaemia in presence of ritonavir Yes TNFa G - 238A rs361525 Promoter Rapid development of lipoatrophy Controversial SPINK-1 C112T rs17107315 N34S Associated with risk of pancreatitis Yes, in general population CFTR G1717 - 1A Splice defect Associated with risk of pancreatitis Yes, in general population IVS8 5T Splice defect Associated with risk of pancreatitis Yes, in general population HLA-B HLA-B*57.1 N/A Abacavir hypersensitivity Yes, but not in all populations HLA-DR HLA-DRB1*0101 N/A Nevirapine hypersensitivity No HSPA1L C2437T rs2227956 M493T Abacavir hypersensitivity No UGT1A1 A(TA)7TAA, - 43_ - 42in- sTA (UGT1A1*28) rs8175347 Promoter; insertion at TATA box Gilberts syndrome, hyperbilirubinaemia in presence of atazanavir and indinavir but not saquinavir Yes MT-CO1 C7028T Synonymous Haplogroup T associated with greater incidence of peripheral neuropathy No 700 Pharmacogenetics and Genomics 2006, Vol 16 No The NNRTI nevirapine can also cause a hypersensitivity syndrome characterized by a rash with systemic symptoms; occasionally liver injury may be part of the clinical picture, or alternatively, may actually be the only manifestation. 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PMID: 18058331 [PubMed] Wang JS et al: "The emerging importance of transporter proteins in the psychopharmacological treatment of the pregnant patient."

No. Sentence Comment

124 The two most frequent polymorphisms were the G34A in exon 2 that results in a V12M change, and a C421A transition in exon 5. Login to comment

PMID: 21619426 [PubMed] Stieger B et al: "Pharmacogenetics of drug transporters in the enterohepatic circulation."

No. Sentence Comment

94 Gene name Transporter SNP Protein Population size (n) In vitro function Ref. Intestinal uptake transporters SLC15A1 PEPT1 p.P586L 44 Reduced Vmax [81] p.F28Y 247 Increased Km [82] Intestinal efflux transporters ABCB1 MDR1 c.571G>A p.G191R N/A Reduced drug resistance [201] c.1199G>A p.S440N N/A Reduced activity (substrate dependent) [202] c.11199G>A c.1199G>t p.S440N p.S440I N/A N/A Increased drug resistance Reduced drug resistance [203] c.1292-3GT>TG p.C431L N/A Reduced drug resistance [204] c.2005C>T p.R669C N/A Reduced substrate affinity [202] c.2547A>G p.I849M N/A Increased transport activity [202] c.2677G>T p.A893S 60 Lower intracellular digoxin accumulation [205] c.2677G>T c.2677G>A p.A893S p.A893T N/A N/A Unchanged Unchanged [206] c.2677G>T p.A893S 46 No change in rhodamine 123 efflux from peripheral blood lymphocytes [207] c.2667G>T p.A893S N/A Reduced transport function [208] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased transport function Increased transport function [209] c.2667G>T c.2677G>A p.A893S p.A893T N/A N/A Increased activity (substrate dependent) Increased substrate affinity and transport activity [202] c.2667G>T p.A893S 48 No change in rhodamine 123 efflux activity in peripheral blood mononuclear cells [210] c.2956A>G p.M986V N/A Increased transport activity [202] c.2995G>A p.A999T N/A Increased substrate affinity and transport activity [202] c.3151C>G p.P1051A N/A Increased transport activity (substrate dependent) [202] c.3188G>C p.G1063A N/A Increased transport activity [202] ABCG2 ABCG2 c.34G>A p.V12M N/A Low transport protein expression in vitro [211] c.34G>A p.V12M N/A Unchanged [212] c.34G>A p.V12M N/A No change in HEK-293, lowered transport activity in Sf9 cells in vitro [213] c.34G>A p.V12M N/A Unchanged [214] c.421C>A p.Q141K N/A Lower transport protein expression, normal transport activity [212] c.421C>A p.Q141K N/A Reduced drug resistance and lower ATPase activity [213] c.421C>A p.Q141K N/A Reduced drug extrusion [215] c.421C>A p.Q141K N/A Reduced drug resistance [216] c.421C>A p.Q141K N/A Unchanged [217] c.421C>A p.Q141K N/A No change of intracellular porphyrin accumulation [218] c.421C>A p.Q141K N/A Reduced transport activity [219] c.421C>A p.Q141K N/A Reduced transport activity [55] c.421C>A p.Q141K N/A Increased Km [220] For more information on members of the SLC superfamily of transporters please consult [301] and for more information of ABC transporters please consult [302]. Login to comment

PMID: 20103563 [PubMed] Klaassen CD et al: "Xenobiotic, bile acid, and cholesterol transporters: function and regulation."

No. Sentence Comment

6588 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/Localization ABCG2 BCRP G34A V12M ↔ Normal/intracellular C376T Gln126STOP N.D. Login to comment

PMID: 19442037 [PubMed] Ieiri I et al: "Genetic polymorphisms of uptake (OATP1B1, 1B3) and efflux (MRP2, BCRP) transporters: implications for inter-individual differences in the pharmacokinetics and pharmacodynamics of statins and other clinically relevant drugs."

No. Sentence Comment

546 Kim HS, Sunwoo YE, Ryu JY, et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

PMID: 18418374 [PubMed] Rosner GL et al: "Pharmacogenetic pathway analysis of irinotecan."

No. Sentence Comment

97 Table 3 Associations between the principal components and polymorphisms Polymorphism PC1 PC2 PC3 PC4 PC5 PC6 PC7 PC8 PC9 UGT1A1, -53A(TA)6>7TAA, PROMOTER 0.086/0.5 0.301/0.2 0.007/4.9 0.019/1.8 0.216/0.2 0.009/3.4 0.314/0.2 0.204/0.2 0.123/0.4 UGT1A1, -3279G>T (UGT1A1*60), PBREM 0.021/1.7 0.056/0.7 0.043/0.9 0.027/1.3 0.588/0.1 0.001/24.8 0.482/0.1 0.527/0.1 0.046/0.8 UGT1A1, -3156G>A, PBREM 0.008/4.2 0.136/0.3 0.014/2.6 0.017/2.0 0.322/0.2 0.005/6.7 0.031/1.1 0.268/0.2 0.083/0.5 UGT1A7, 387G>T (N129K), EXON 1 0.007/4.6 0.139/0.3 0.001/26.7 0.050/0.8 0.050/0.8 0.103/0.4 0.116/0.4 0.186/0.3 0.114/0.4 UGT1A7, 622T>C (W208R), EXON 1 0.000/77.5 0.392/0.2 0.002/17.3 0.019/1.8 0.332/0.2 0.003/11.2 0.289/0.2 0.055/0.7 0.270/0.2 UGT1A9, -118(T)9>10, UGT1A9*1b, PROMOTER 0.003/12.3 0.258/0.2 0.001/36.4 0.017/2.0 0.054/0.7 0.025/1.4 0.067/0.6 0.279/0.2 0.066/0.6 UGT1A9, -2152C>T, PROMOTER 0.809/0.1 0.453/0.1 0.293/0.2 0.703/0.1 0.328/0.2 0.473/0.1 0.615/0.1 0.238/0.2 0.784/0.1 UGT1A9, -275T>A, PROMOTER 0.632/0.1 0.217/0.2 0.297/0.2 0.764/0.1 0.148/0.3 0.583/0.1 0.527/0.1 0.245/0.2 0.944/0.1 HNF1α, 79A>C (I27L), EXON 1 0.625/0.1 0.001/37.3 0.154/0.3 0.434/0.1 0.527/0.1 0.423/0.2 0.517/0.1 0.366/0.2 0.213/0.2 CYP3A4, -392A>G, CYP3A4*1B, 5ʹ-UTR 0.414/0.2 0.556/0.1 0.337/1.2 0.967/0.4 0.721/0.1 0.323/0.2 0.772/0.2 0.487/0.3 0.923/0.1 CYP3A5, 6986A>G, CYP3A5*3, INTRON 3 0.861/0.4 0.179/0.9 0.255/0.5 0.480/0.1 0.124/0.4 0.704/0.1 0.536/0.1 0.822/0.1 0.443/ 0.1 SLCO1B1, 388A>G (N130D), SLCO1B1*1b, EXON 4 0.079/0.5 0.106/0.4 0.023/1.6 0.097/0.4 0.580/0.1 0.379/0.2 0.317/0.2 0.038/1.0 0.269/0.2 SLCO1B1, 521T>C (V174A), SLCO1B1*15, EXON 5 0.878/0.1 0.614/0.6 0.600/0.1 0.433/0.2 0.751/0.2 0.159/0.5 0.942/0.1 0.145/0.3 0.066/0.6 ABCC2, -1549A>G, 5ʹ-Flanking region 0.383/0.2 0.001/47.4 0.301/0.2 0.308/0.2 0.171/0.3 0.749/0.1 0.705/0.1 0.253/0.2 0.643/0.1 ABCC2, -1019A>G, 5ʹ-Flanking region 0.583/0.1 0.002/15.4 0.254/0.2 0.249/0.2 0.398/0.2 0.732/0.1 0.681/0.1 0.226/0.2 0.809/0.1 ABCC2, -24C>T, 5ʹ-UTR 0.985/0.1 0.013/2.7 0.575/0.2 0.950/1.1 0.054/0.9 0.221/0.7 0.402/0.2 0.641/0.1 0.366/0.6 ABCC2, 1249G>A (V417I), EXON 10 0.443/0.1 0.045/0.9 0.934/0.1 0.358/0.2 0.521/0.1 0.329/0.2 0.495/0.1 0.002/14.9 0.706/0.1 ABCC2, -34T>C, INTRON 26 0.469/0.1 0.258/0.2 0.963/0.1 0.167/0.3 0.639/0.1 0.829/0.1 0.049/0.8 0.734/0.1 0.345/0.2 ABCC2, 3972C>T (I1324I), EXON 28 0.250/0.2 0.011/3.1 0.224/0.2 0.103/0.4 0.013/2.5 0.144/0.3 0.175/0.3 0.200/0.3 0.149/0.3 ABCC1, 1062T>C (N354N), EXON 9 0.136/0.3 0.179/0.3 0.221/0.2 0.120/0.4 0.139/0.3 0.684/0.1 0.013/2.3 0.228/0.2 0.082/0.5 ABCC1, -48C>T, INTRON 11 0.302/0.2 0.187/0.3 0.840/0.2 0.175/0.3 0.105/0.4 0.748/0.5 0.577/0.2 0.642/0.1 0.084/0.6 ABCC1, 1684T>C (L562L), EXON 13 0.405/0.2 0.018/2.0 0.414/0.2 0.098/0.4 0.579/0.1 0.436/0.1 0.805/0.1 0.037/1.0 0.233/0.2 ABCC1, -30C>G, INTRON 18 0.188/0.3 0.004/8.0 0.362/0.2 0.155/0.3 0.879/0.1 0.620/0.1 0.526/0.1 0.061/0.6 0.177/0.3 ABCC1, 4002G>A (S1334S), EXON 28 0.001/29.4 0.022/1.7 0.300/0.2 0.195/0.3 0.416/0.2 0.096/0.4 0.184/0.3 0.064/0.6 0.072/0.6 ABCC1, +18A>G, INTRON 30 0.023/1.6 0.198/0.3 0.424/0.2 0.825/0.1 0.365/0.2 0.296/0.2 0.217/0.2 0.403/0.2 0.236/0.2 ABCB1, -129T>C, 5ʹ-UTR 0.559/0.5 0.811/0.1 0.610/0.3 0.977/0.2 0.725/0.9 0.807/0.4 0.163/0.3 0.177/0.3 0.009/3.5 ABCB1, -25G>T, INTRON 4 0.229/0.3 0.774/0.1 0.832/0.5 0.826/1.1 0.635/0.1 0.877/0.2 0.368/0.2 0.661/0.1 0.832/0.1 ABCB1, -44A>G, INTRON 9 0.147/0.3 0.605/0.1 0.618/0.1 0.570/0.1 0.109/0.4 0.156/0.3 0.096/0.4 0.338/0.2 0.051/0.8 ABCB1, 1236C>T (G412G), EXON 12 0.182/0.3 0.437/0.1 0.382/0.2 0.482/0.1 0.090/0.5 0.280/0.2 0.106/0.4 0.376/0.2 0.153/0.3 ABCB1, +24C>T, INTRON 13 0.725/0.1 0.439/0.1 0.491/0.1 0.540/0.1 0.532/0.1 0.076/0.5 0.100/0.4 0.306/0.2 0.016/2.1 ABCB1, +38A>G, INTRON 14 0.627/0.1 0.538/0.1 0.669/0.1 0.540/0.1 0.532/0.1 0.054/0.7 0.100/0.4 0.306/0.2 0.033/1.1 ABCB1, 2677G>A/T (A893T/S), EXON 21 0.302/0.2 0.543/0.1 0.491/0.1 0.962/0.1 0.943/0.1 0.309/0.2 0.210/0.2 0.890/0.1 0.004/6.9 ABCB1, 3435C>T (I1145I), EXON 26 0.319/0.2 0.441/0.1 0.531/0.1 0.631/0.1 0.664/0.1 0.644/0.1 0.402/0.2 0.226/0.2 0.013/2.5 ABCG2, 34G>A (V12M), EXON 2 0.479/0.1 0.828/0.1 0.139/0.3 0.348/0.2 0.588/0.2 0.673/0.1 0.087/0.5 0.219/0.2 0.780/0.1 ABCG2, 421C>A (Q141K), EXON 5 0.565/0.1 0.397/0.2 0.421/0.2 0.435/0.1 0.628/0.1 0.256/0.2 0.708/0.1 0.533/0.1 0.787/0.1 CES2, -363C>G, 5ʹ-UTR 0.999/2.3 0.546/0.2 0.028/1.9 0.624/0.1 0.872/0.1 0.899/0.1 0.379/0.6 0.92/.1 0.586/0.1 CES2, +1361A>G, INTRON 1 0.381/1.0 0.549/0.2 0.616/0.8 0.118/0.4 0.546/0.1 0.629/0.1 0.275/0.3 0.26/0.2 0.352/0.2 Split to SN-38 and SN-38 to bile to gut to SN-38 IRN compartments SN-38 to SN-38G and SN-38G elimination Split to APC from IRN central compartment APC elimination EHR SN-38 recir-- culation without EHR SN-38 elimination IRN elimination The table shows the P values and Bayes factors, respectively, separated by a"/. Login to comment
193 UGT1A1, -53A(TA)6>7TAA, PROMOTER 0.709(6):0.286(7) 0.62(6):0.38(7) 15,32 UGT1A1, -3279G>T (UGT1A1*60), PBREM 0.47(G):0.53(T) 0.85(G):0.15(T) UGT1A1, -3156G>A, PBREM 0.69(G):0.31(A) 0.715(G):0.285(A) UGT1A1, 211G>A (G71R), UGT1A1*6, EXON 1 0(A):1(G) 0(A):1(G) UGT1A1, 686C>A (P229Q), UGT1A1*27, EXON 1 0(A):1(C) 0(A):1(C) UGT1A7, 387G>T (N129K), EXON 1 0.646(G):0.354(T) 0.522(G):0.478(T) Supplementary Data S1 onlinea UGT1A7, 391C>A (R131K), EXON 1 0.646(G):0.354(T) 0.522(G):0.478(T) UGT1A7, 622T>C (W208R), EXON 1 0.521(T):0.479(C) 0.729(T):0.271(C) UGT1A9, -118(T)9>10, UGT1A9*1b, PROMOTER 0.59(9):0.41(10) 0.56(9):0.44(10) 42 UGT1A9, -2152C>T, PROMOTER 0.91(C):0.09(T) Unknownb UGT1A9, -275T>A, PROMOTER 0.91(T):0.09(A) Unknownb HNF1α, 79A>C (I27L), EXON 1 0.75(A):0.25(C) Unknownb Supplementary Data S1 onlinea CYP3A4, -392A>G, CYP3A4*1B, 5ʹ-UTR 0.977(A):0.023(G) 0.321(A):0.679(G) 43 CYP3A5, 6986A>G, CYP3A5*3, INTRON 3 0.023(A):0.977(G) 0.633(A):0.367(G) SLCO1B1, 388A>G (N130D), SLCO1B1*1b, EXON 4 0.396(C):0.604(T) 0.717(C):0.283(T) Supplementary Data S1 onlinea SLCO1B1, 521T>C (V174A), SLCO1B1*15, EXON 5 0.083(C):0.917(T) 0.022(C):0.978(T) ABCC1, 1062T>C (N354N), EXON 9 0.458(C):0.542(T) 0.643(C):0.357(T) 44 ABCC1, +8A>G, INTRON 9 0.643(A):0.357(G) 0.433(A):0.567(G) ABCC1, -48C>T, INTRON 11 0.146(T):0.854(C) 0(T):1.0(C) ABCC1, 1684T>C (L562L), EXON 13 0.917(C):0.083(T) 0.848(C):0.152(T) ABCC1, -30C>G, INTRON 18 0.042(C):0.958(G) 0.217(C):0.783(G) ABCC1, 4002G>A (S1334S), EXON 28 0.688(C):0.312(T) 0.955(C):0.045(T) ABCC1, +18A>G, INTRON 30 0.213(T):0.787(C) 0.042(T):0.958(C) ABCC2, -1549A>G, 5ʹ-Flanking region 0.43(A):0.57(G) 0.485(A):0.515(G) 44 ABCC2, -1019A>G, 5ʹ-Flanking region 0.43(G):0.57(A) 0.365(G):0.635(A) ABCC2, -24C>T, 5ʹ-UTR 0.230(A):0.770(G) 0.06(A):0.940(G) ABCC2, 1249G>A (V417I), EXON 10 0.146(A):0.854(G) 0.239(A):0.761(G) ABCC2, -34T>C, INTRON 26 0.17(C):0.83(T) 0.25(C):0.75(T) ABCC2, 3972C>T (I1324I), EXON 28 0.380(A):0.620(G) 0.280(A):0.720(G) ABCB1, -129T>C, 5ʹ-UTR 0.620(C):0.938(T) 0.043(C):0.957(T) 44 ABCB1, -25G>T, INTRON 4 0.273(T):0.737(G) 0.385(T) :0.615(G) ABCB1, -44A>G, INTRON 9 0.409(C):0.591(T) 0.20(C):0.80(T) ABCB1, 1236C>T (G412G), EXON 12 0.523(C):0.477(T) 0.864(C):0.136(T) ABCB1, +24C>T, INTRON 13 0.50(T):0.50(C) 0.467(T):0.533(C) ABCB1, +38A>G, INTRON 14 0.429(A):0.571(G) 0.389(A):0.611(G) ABCB1, 2677G>A/T (A893T/S), EXON 21 0.614(G):0.386(T) 0.923(G):0.077(T) ABCB1, 3435C>T (I1145I), EXON 26 0.375(C):0.625(T) 0.848(C):0.152(T) ABCG2, 34G>A (V12M), EXON 2 0.017(A):0.983(G) 0.071(A):0.929(G) Supplementary Data S1 onlinea ABCG2, 421C>A (Q141K), EXON 5 0.045(A):0.955(C) 0.023(A):0.977(C) CES2, -363C>G, 5ʹ-UTR 0.810(C):0.190(G) 0.733(C):0.267(G) Supplementary Data S1 onlinea CES2, +1361A>G, INTRON 1 0.143(G):0.857(A) 0.438(G):0.562(A) CES2, 108C>G, 3ʹ-UTR 0.004(G):0.996(C) 0(G):1.0(C) PBREM, phenobarbital-responsive enhancer module; UTR, untranslated region. Login to comment

PMID: 16180115 [PubMed] Ito K et al: "Apical/basolateral surface expression of drug transporters and its role in vectorial drug transport."

No. Sentence Comment

210 Mizuarai et al. (120) reported that the V12M SNP mutant exhibited severely impaired apical expression in LLC-PK1 cells. Login to comment
211 The allele frequency of V12M reached as high as 10.3%, and actually 27 and 2 out of the 150 normal healthy Caucasians were hetero-and homozygotes of this SNP, respectively. Login to comment
212 Kondo et al. (119) also examined the cellular localization of a total of seven SNP variants of BCRP (V12M, Q141K, A149P, R163K, Q166E, P269S, and S441N) in LLC-PK1. Login to comment
214 In contrast to the report from Mizuarai et al., V12M was found to be normally localized on the apical membrane of LLC-PK1 cells (119). Login to comment
215 The reason why such a contradictory result was observed while using the same SNP variant of BCRP (V12M) in the same host cell (LLC-PK1) is currently unknown, but the different cell culture conditions in laboratories might be one possible cause. Login to comment

PMID: 23058041 [PubMed] Grandvuinet AS et al: "Intestinal transporters for endogenic and pharmaceutical organic anions: the challenges of deriving in-vitro kinetic parameters for the prediction of clinically relevant drug-drug interactions."

No. Sentence Comment

517 Kim HS et al. The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

PMID: 22869929 [PubMed] Huang L et al: "Deletion of abcg2 has differential effects on excretion and pharmacokinetics of probe substrates in rats."

No. Sentence Comment

24 Several additional SNPs, including V12M, Q126Stop, and P269S, affect expression or activities of the transporter, which may also have clinical implications (Kondo et al., 2004; Mizuarai et al., 2004; Tamura et al., 2006; Lee et al., 2007). Login to comment

PMID: 23066723 [PubMed] Hue-Roye K et al: "The JR blood group system (ISBT 032): molecular characterization of three new null alleles."

No. Sentence Comment

69 Nucleotide and predicted amino acid changes in ABCG2 in 13 serologically defined Jr(a-) samples Proband (D/P) Ethnicity/race Anti-Jra Nucleotide change (exon) Predicted amino acid change 1 (D) Japanese No c.376C>T (4) Gln126Stop 2 (D) Unknown Unknown c.376C>T (4) Gln126Stop 3 (P) Asian Yes c.376C>T (4) Gln126Stop 4 (P) Japanese Yes c.376C>T (4) Gln126Stop 5 (D) Caucasian Yes c.376C>T (4) Gln126Stop 6 (P) Caucasian Yes c.376C>T (4) Gln126Stop 7 (P) Japanese Yes c.376C>T (4) Gln126Stop 8 (P) Chinese Yes c.376C>T (4) Gln126Stop 9 (P) Caucasian Yes c.706C>T (7) Arg236Stop 10 (P) Caucasian Yes c.706C>T (7) Arg236Stop 11 (P) Caucasian Yes c.337C/T† (4) c.736C/T (7) Arg113Stop Arg246Stop 12 (P) Caucasian Yes c.784G>T† (7) Gly262Stop 13 (P) Caucasian Yes c.1591C>T† (13) c.34G>A (2) Gln531Stop Val12 Met † Novel allele. Login to comment

PMID: 22937733 [PubMed] Chen P et al: "The contribution of the ABCG2 C421A polymorphism to cancer susceptibility: a meta-analysis of the current literature."

No. Sentence Comment

31 Researches had shown that there were two frequently polymorphic SNPs in the BCRP gene: one in exon2 (G34A, resulting in a V12M change) and the other in exon5 (C421A, resulting in a Q141K substitution) respectively [15]. Login to comment
24 Researches had shown that there were two frequently polymorphic SNPs in the BCRP gene: one in exon2 (G34A, resulting in a V12M change) and the other in exon5 (C421A, resulting in a Q141K substitution) respectively [15]. Login to comment

PMID: 22248732 [PubMed] Natarajan K et al: "Role of breast cancer resistance protein (BCRP/ABCG2) in cancer drug resistance."

No. Sentence Comment

3631 In another study, the GG genotype of BCRP rs2231137, in relation to the heterozygous (AG) (G34A, encoding V12M) or homozygous (AA) variant genotypes, was significantly associated with a lower rate of complete cytogenetic response to imatinib [197]. Login to comment
3640 With regard to BCRP SNPs, among 145 Korean patients with DLBCL treated with the R-CHOP regimen, there was no influence of BCRP SNPs on clinical characteristics or treatment outcomes, but patients with the Q141K polymorphism (QK or KK), but not the V12M polymorphism discussed above for AML and CML, had more chemotherapy-related diarrhea [201]. Login to comment

PMID: 22237259 [PubMed] Liu G et al: "Pharmacogenetic analysis of BR.21, a placebo-controlled randomized phase III clinical trial of erlotinib in advanced non-small cell lung cancer."

No. Sentence Comment

35 We excluded the analysis of the ABCG2 34GϾA (V12M, rs2231137) polymorphism17 because it had a 2% minor allele frequency in our Caucasian-predominant population. Login to comment

PMID: 22246507 [PubMed] Zelinski T et al: "ABCG2 null alleles define the Jr(a-) blood group phenotype."

No. Sentence Comment

26 The third ABCG2 null genotype consists of a compound molecular background, with one allele giving rise to a p.Val12Met substitution coupled with a premature stop codon at amino acid 236 and a second allele encoding the p.Val12Met substitution coupled with the normal Arg236 amino acid. Login to comment
37 In studies with polarized LLC-PK1 cells (renal epithelial cells derived from porcine kidneys), cells expressing ABCG2 V12M were ten times more sensitive to topoisomerase inhibitor I than cells transfected with control vectors8, and in vesicles expressing the V12M variant, substrate efflux was also reduced compared with that in control cells transfected with control vectors. Login to comment
38 Further, analysis of ABCG2 V12M localization by immunofluorescence showed that ABCG2 was not present at the apical membrane8. Login to comment
39 In contrast, a previous study did not observe a decrease in urate transport nor a significant difference in the amount of protein in immunoblots of lysates from HEK293 cells expressing the V12M variant5. Login to comment
40 Further investigation of the subject in our study who was homozygous for the mutation encoding p.Val12Met and heterozygous for the one encoding p.Arg236* might have resolved this issue, but, unfortunately, this individual was not available for follow-up studies. Login to comment
42 This finding is not surprising, as the p.Val12Met substitution falls in a region likely to encode a signal peptide. Login to comment
43 Alternatively, it is possible that the p.Val12Met substitution alters the Jra antigenic epitope within the transmembrane domain (amino acids 390-655) of ABCG2. Login to comment
121 Table 1 Nucleotide and predicted protein changes in ABCG2 in six Jr(a-) subjects Subject Ancestrya Nucleotide Protein 1 Caucasian c.736C>T p.Arg246* 2 Caucasian c.736C>T p.Arg246* 3 Asian c.376C>T p.Gln126* 4 Asian c.376C>T p.Gln126* 5 Asian c.376C>T p.Gln126* 6 Asian c.34G>A c.706C>T p.Val12Met p.Arg236* All samples were used with permission under protocols approved by the New York Blood Center and the University of Manitoba`s Health Research Ethics Board. Login to comment

PMID: 22123128 [PubMed] Ieiri I et al: "Functional significance of genetic polymorphisms in P-glycoprotein (MDR1, ABCB1) and breast cancer resistance protein (BCRP, ABCG2)."

No. Sentence Comment

71 Impact of ABCG2 (BCRP) polymorphisms on PK/PD/disorders Gene marker ¤SNPs/haplotype¥ Functional effect of the study Drug Population Disease Ref.Pharmacokinetics Therapeutic efficacy Side effects SNPs assay Others ¤e.g., frequency and susceptibility¥ %15622CgT or ¤1143ChT, %15622ChT¥ haplotype * gefitinib patient NSCLC 68 421ChA * * A771726 HV 223 421ChA ¤141QhK, rs2231142¥ * patient gout 224 421ChA * imatinib patient CML 225 421ChA * patient uric acid 226 421ChA ¤141QhK, rs2231142¥ * patient gout 227 421ChA, 914ChA * methotrexate patient RA 228 421ChA * * sunitinib patient RCC 70 421ChA * rosuvastatin patient myocardial infarction 229 346GhA, 421ChA, 1143ChT, 15994GhA * danusertib patient 230 421ChA * rosuvastatin patient hypercholesterolemia 231 421ChA * patient gout 232 376ChT, 421ChA * gefitinib patient NSCLC 67 421ChA * telatinib patient 233 421ChA * 3 statines HV 234 rs2622604 * irinitecan patient myelosuppression 235 ¤%15622C/T, 1143C/T¥ haplotype * sunitinib patient 127 12VhM, 141QhK * mitoxantrone patient multiple sclerosis 236 421ChA * imatinib patient CML 237 421ChA * sulfasalazine HV 238 421ChA * erlotinib patient SCC 69 421ChA * patient gout 239 421ChA * atorvastatin, rosuvastatin HV 240 12VhM, 141QhK * R-CHOP patient DLBCL 241 12VhM * patient ischemic stroke 242 421ChA * imatinib patient solid malignancies 243 421ChA * patient gout 73 rs2622621, rs1481012 * patient colorectal cancer 244 421ChA * nitrofurantoin HV 245 421ChA * sulfasalazine HV 246 421ChA * doxorubicin patient breast cancer 168 421ChA * sulfasalazine HV 60 Q141K, V12M, Q126X * lamivudine HV 247 34ChA, 421ChA * patient DLBCL 248 421ChA * pitavastatin HV 64 Continued on next page: 141QhK¥ which has been associated with lower BCRP protein expression.52,55¥ Recently, 421ChA was found to greatly affect the stability of BCRP in the endoplasmic reticulum, leading to increased protein degradation via ubiquitination and proteasomal proteolysis.56,57¥ Therefore, 421ChA may lead to increased bioavailability after the oral administration of substrate drugs. Login to comment

PMID: 22509477 [PubMed] Mo W et al: "Human ABCG2: structure, function, and its role in multidrug resistance."

No. Sentence Comment

889 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment
895 The effect of ABCG2 V12M, Q141K and Q126X, known functional variants in vitro, on the disposition of lamivudine. Login to comment

PMID: 21625222 [PubMed] Singh RR et al: "ABCG2 is a direct transcriptional target of hedgehog signaling and involved in stroma-induced drug tolerance in diffuse large B-cell lymphoma."

No. Sentence Comment

25 One study identified two polymorphisms in ABCG2 gene, G34A (Val12Met) and C421A (Gln141Lys), and associated these polymorphisms with increased risk and poor overall survival of DLBCL (Hu et al., 2007). Login to comment

PMID: 22132966 [PubMed] Matsuo H et al: "ABCG2/BCRP dysfunction as a major cause of gout."

No. Sentence Comment

38 1119 ABCG2 : ATP binding casse e G2 SNP : single nucleo de polymorphism QTL : quan ta ve trait locus OR : odds ra o ABCG2 as a urate secre on transporter in humans Gene c analysis Func onal analysis ABCG2 muta on analysis of 90 hyperuricemic cases (all coding regions) ABCG2 muta ons (with amino acid altera ons) 6 muta ons c d Func onal analysis of urate transport via wild type ABCG2 (vesicle studies) a Iden fica on of urate transport ac vi es via ABCG2 b Func onal analysis of urate transport via mutated ABCG2 6 mutants e No effect (V12M) g Dysfunc onal genotype combina ons of ABCG2 as major causes of gout q Dysfunc onal SNP with high frequency (>30%) (Q141K) QTL analysis in 739 Japanese individuals h i j n Gout / hyperuricemia with ABCG2 homozygous, n = 2 heterozygous, n = 24 Loss of func on (Q126X, G268R, S441N, F506Sfs) Reduced func on (~50%) (Q141K) f p Genotype combina on analysis 10.1% of gout with ≤1/4 ABCG2 func on OR = 25.8, p = 3.39×10-21 o Haplotype analysis 13.5% of gout with disease haplotype OR = 5.97, p = 4.10×10-12 Associa on analysis of hyperuricemia (Q126X) OR = 3.61, p = 2.91× 10-7 l m Associa on analysis of gout (Q126X) OR = 4.25, p =3.04 × 10-8 Genotyping of nonfunc onal SNP (Q126X) hyperuricemia, n=228 k FIGURE 1 Flowchart for molecular-function-based clinicogenetic (FBCG) analysis of gout patients with ABCG2 polymorphic variants. Login to comment
53 Using the site-directed mutagenesis technique, we constructed ABCG2 mutants (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
65 The following six nonsynonymous mutations, including three SNPs, were found: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4 (Figure 2A). Login to comment
76 Maekawa et al.[17] reported that V12M, Q126X, and Q141K are quite common in the Japanese population, and allele frequencies for these SNPs were 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively. Login to comment
77 Using Hardy-Weinberg equilibrium and these data on a Japanese population reported by Maekawa et al.,[17] we estimated that the frequencies of Japanese individuals with these minor alleles were 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
80 The V12M variant did not show any changes in urate transport compared to wild-type ABCG2. Login to comment
97 We also found that V12M is exclusively assigned to a nonrisk haplotype. Login to comment

PMID: 22132963 [PubMed] Matsuo H et al: "Identification of ABCG2 dysfunction as a major factor contributing to gout."

No. Sentence Comment

36 Using the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
45 The following six non-synonymous mutations, V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4, were found (Figure 1A), and the first three mutations were SNPs. Login to comment
49 Results are expressed as means ± SD. V12M, and 2.8% for Q126X. Login to comment
50 With the Hardy-Weinberg equilibrium and the data reported by Maekawa et al. of the Japanese population,[5] we calculated estimates of the minor allele frequencies of Japanese individuals to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
53 The V12M variant did not show any changes in urate transport relative to wild-type ABCG2. Login to comment
68 Our findings showed that V12M is exclusively assigned to a non-risk haplotype and that the V12M variant does not exhibit altered urate transport activity (Figure 1B). Login to comment
69 These findings may help explain why V12M decreases gout risk (OR, 0.68; 95% CI, 0.49-0.94; p = 0.02). Login to comment

PMID: 22132962 [PubMed] Nakayama A et al: "ABCG2 is a high-capacity urate transporter and its genetic impairment increases serum uric acid levels in humans."

No. Sentence Comment

34 With the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, and Q141K), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment
47 We found the following six nonsynonymous mutations: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4, and the first three mutations are SNPs. Login to comment
48 Maekawa et al.[7] reported that these SNPs are quite common in the Japanese population, and allele frequencies for them are 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively. Login to comment
49 Using Hardy-Weinberg equilibrium and these data on a Japanese population reported by Maekawa et al.,[7] the frequencies of Japanese individuals with these minor alleles were estimated to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X, respectively. Login to comment

PMID: 21594610 [PubMed] Kaneko H et al: "Hyperuricemia cosegregating with osteogenesis imperfecta is associated with a mutation in GPATCH8."

No. Sentence Comment

182 Amino acid AF dbSNP II-2 II-3 VIII-2 1 AGL 100,336,361 C [ T Syn. 0.7 rs2230306 T/T -/T -/T 4 ABCG2b 89,034,551 G [ A Syn. 0.02 rs35622453 -/- -/- -/A 89,052,323 C [ A Q141K 0.31 rs2231142 -/A A/A -/- 89,061,114 G [ A V12M 0.19 rs2231137 -/A -/- -/A 4 SLC2A9b 9,909,923 C [ T P350L 0.33 rs2280205 -/T -/T -/- 9,922,130 G [ A R294H 0.72 rs3733591 -/A -/- -/A 9,998,440 G [ A Syn. 0.54 rs10939650 -/A A/A -/A 10,022,981 G [ A G25R 0.43 rs2276961 -/A -/A -/- 10,027,542 G [ A A17T 0.06 rs6820230 -/- -/A -/A 11 SLC22A12b 64,359,286 C [ T Syn. 0.21 rs3825016 -/T T/T -/T 64,360,274 C [ T Syn. 0.81 rs11231825 -/T -/- -/T 12 PFKM n.d. 16 UMODb n.d. 17 G6PC n.d. X HPRT1a n.d. X PRPS1a n.d. X MAOA 43,591,036 G [ T Syn. 0.3 rs6323 -/- T/T T/T a The gene is associated with purine metabolism b The gene is associated with renal excretion of urate - symbol represents in the patients` genotypes mean being identical to the reference nucleotides Syn synonymous nucleotide change, AF allelic frequency of the changed nucleotide, n.d. no SNPs are detected Discussion Phenotypic variabilities of OI mutations We identified a heteroallelic c.3235G[A mutation in COL1A1 exon 45 in a Japanese family with mild OI type I. Login to comment

PMID: 21531129 [PubMed] Wang F et al: "Prognostic value of the multidrug resistance transporter ABCG2 gene polymorphisms in Chinese patients with de novo acute leukaemia."

No. Sentence Comment

17 In particular, two SNPs of ABCG2, G34A (V12M) in exon 2 and C421A (Q141K) in exon 5, were found to be the most prevalent in Asian population. Login to comment
80 Of the six polymorphisms, the allele frequencies of two published non-synonymous SNPs, G34A (Val12Met; exon 2) and C421A (Gln141Lys; exon 5), were 0.505 and 0.152 in our study. Login to comment
104 Position Location Change % Genotype frequency(n) Allele % Allele frequency NT-016354.18 dbSNP (NCBI) Nucleotide Amino acid Wildtype Heterozygote Homozygote 13608835 rs2231137 Exon 2 TCCCAG/ATGTCA Val12Met 35.9 (66) 27.2 (50) 36.9 (68) A 50.5 13600044 rs2231142 Exon 5 ACTTAC/AAGTTC Gln 141Lys 69.6 (128) 30.4 (56) 0 A 15.2 13561218a N.D. Exon 16 GGCATC/TGATCT Ile619Ile 98.9 (182) 1.1 (2) 0 T 0.5 13576005 rs2231149 Intron10 TCAAGC/TTTATT N/A 78.8 (145) 21.2 (39) 0 T 10.6 13564503 rs2231162 Intron13 TGACTC/TTTAGT N/A 60.3 (111) 39.7 (73) 0 T 19.8 13563578 rs2231164 Intron14 TTCTTA/GAAATT N/A 71.2 (131) 28.8 (53) 0 G 14.4 NCBI, National Cancer Center for Biotechnology Information; N.D., not determined; N/A, not applicable. Login to comment

PMID: 21554546 [PubMed] Woodward OM et al: "ABCG transporters and disease."

No. Sentence Comment

59 R L L A A M AT T T R V S G G G F I T Q R R V K K S G E A D RR V V K K L L G E E E I IN NN D H Q Q R V V V V V L L S G F E N M TT QD D S K R V K L L G F P C Y R K S G F P P C N N A V L L S G G G I N A D R K P P S GG G R V VK K KK L L L LL L S S S GG G PPE E IIII N NN M A A A T D D Y N E A I P E S I D L L F T LS G EI MT D I I P FC L R IH A N T T T T T G L D S S K K K L L L S G G G F F F F Q P P I M M A A A A D H G G LS S S V L L L L L R R RQ Q I I Y Y YS S HE E A T V V V V L Q I S F I I II A A L G G Y K F R S S E E I I L G Y YY Y V V K H S P C M M D R T I II L L L F F YV S S P F N T I A Q Q L L L G F Y Y H S S PR W C N M I I A A A L L G F V V K H W T L I F F C C C D D D A A A QQ Q Q Q G G G G G G G G G G FF FF F F FF Y Y Y Y Y V V V V V VVV K KKK KK K K E E E E P P P P R W W TT TT T TT T T NNNN N N N N N M MM M L L L L L L L L LL LL I I I I I I AA A A A A A S S S S S S S S SS L L L L LL L L LL V V F G GCC T Q Q Q Q Y Y Y KK K K K H H EE E E E E EEE E P P P P R R RW N N N II I I I I I I A AAA A A A S SS S S S S L L LL L L L V V V V F F F F F F F G GG G C TT T T T T K K K K KKKK N NN LL D DDD DS S 395 469 565 644 414 450 495 505 584 625 Signature Walker A WalkerBQ EP MI A V V VF FG GTN N NS S S S P F HE V FG CTT K NN LLD SS AAA I V12M N-terminus C-terminus M MM MM T A A A A L F F Y V V S S S F 524476 Y Q126X G268R S441N F506fs Q141K 44 288 PP AA DD Fig. 2. Login to comment

PMID: 20873966 [PubMed] Poguntke M et al: "Drug transport by breast cancer resistance protein."

No. Sentence Comment

529 The effect of ABCG2 V12M, Q141K and Poguntke, Hazai, Fromm & Zolk Expert Opin. Drug Metab. Toxicol. Login to comment

PMID: 20368174 [PubMed] Matsuo H et al: "Common defects of ABCG2, a high-capacity urate exporter, cause gout: a function-based genetic analysis in a Japanese population."

No. Sentence Comment

46 The following six nonsynonymous mutations were found: V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4 (Table 1). Login to comment
48 Maekawa et al. reported that allele frequencies for these SNPs, which are quite common in the Japanese population, were 31.9% for Q141K, 19.2% for V12M, and 2.8% for Q126X, respectively (Table 1) (34). Login to comment
49 Using Hardy-Weinberg equilibrium and these data of a Japanese population reported by Maekawa et al. (34), we calculated estimates of the frequencies of Japanese individuals with these minor alleles to be 53.6% for Q141K, 34.7% for V12M, and 5.5% for Q126X. Login to comment
55 The V12M variant did not show any changes in urate transport or in protein amounts relative to wild-type ABCG2. Login to comment
77 The call rate, or the ability of the SNP to be reliably decoded, for V12M, Q126X, and LS N N SV FLC S P T AN FK G LM ETS S E V F I P Q G N T N G FV P A A AS LD V S N I C Y R V K K RKPVEKEILSNINGIKPGLNAILGPG GGKSSL LDVLA ARKDP S G T L S G D V L I G A P PR A N F K N S G Y Q D D V V M G T L T V R NE LV VC H Q F S A A A RL L T T TNEKNER HINRVIQELGLDKVADSKVGTQFIRGVG GERR KTSIGME L I T D P S I L F L D E P T T G L D S S T A N A V LL L L K R M S K Q G R I I F S T S I H Q P R Y M S I F K LFDSLTLLASGRLMFHGPAQEALGYFESAGYHCEAN YN T V A L N R E E D F K A T E II E P S K Q D K L I E L A EK I Y V N S S F Y K ETKAELHQLSGGEKKKKITVFKEISYTTSFCHQRWVK SRS AFFLDII N G D S A PD P L F K N LL G N P Q A S A I V G I I T L V A FI I Q V V L G Y AVEFLKNDST G I Q N R A G V L F F L T T Q C F S L V S S N G L S L M L I T P M S F I FV D L R P I C Y W L W Y I Y T Q S R F L NQ S L F P G A H E F Y S Y S E F R G Y I K V K S V Y I H L E V A S S V L M A A M F V A F M S Y M T M F K A T I M L H F I A V K G W I L V C A N L W V A T L M T C F VI F M M I F S G L L VNLTTIASAIAAGQS L S V V LKGL L F N Q L F P S L D Y G Q K V L C Y EEGTCTAYNCPNNGTAN G P G L K L L L K K SYF L Y D L G L M A P K Extracellular Intracellular 50 150 200 300 100 350 395 415 469 450 470 500 525 550 565 585 600 625 608 650 250 655 603 475 644 F506SfsX4 (F506fs) V12M Q126X Q141K S441N G268R V Q F S G Q # C signature Walker B motif Walker A motif C D E 4.0 4.5 5.0 5.5 6.0 C/C C/A A/A Male + female P= 2.02 x 10 -6 5.0 5.5 6.0 6.5 7.0 C/C C/A A/A Male P= 0.0144 Serumuric acid(mg/dl) 4.0 4.5 5.0 5.5 6.0 C/C C/A A/A Female P= 0.0137 (pmol/mgprotein) 0 20 40 60 80 100 120 140 160 180 200 + AMP + ATP B Serumuric acid(mg/dl) Serumuric acid(mg/dl) A [C]Uratetransport 14 G F M C-terminal N-terminal Fig. 2. Login to comment
89 Amino acid change SNP ID dbSNP (NCBI) Exon Type of mutation Number of hyperuricemia patients Allele frequency (%) (in hyperuricemia) Allele frequency* (%) (in Japanese population) Wild-type Heterozygote Homozygote Q141K rs2231142 5 Missense 29 47 14 41.67 31.9 V12M rs2231137 2 Missense 64 23 3 16.11 19.2 Q126X 4 Nonsense 80 10 0 5.56 2.8 G268R 7 Missense 89 1 0 0.56 N.D. S441N 11 Missense 89 1 0 0.56 0.3 F506SfsX4 13 Frameshift 89 1 0 0.56 0.3 * Data from Maekawa et al. (34). Login to comment
90 Q141K was 98.8%, 100%, and 99.2%, respectively. P values for Hardy-Weinberg equilibrium of V12M, Q126X, and Q141K were 0.08, 0.72, and 0.01, respectively. P values that suggested mistyping were not obtained. Login to comment
97 Our findings showed that V12M is exclusively assigned to a nonrisk haplotype (Table 3) and that the V12M variant does not exhibit altered urate transport activity (Fig. 2B). Login to comment
98 These findings may help explain why V12M decreases gout risk (OR, 0.68; 95% CI, 0.49-0.94; P = 0.02) (Table 2). Login to comment
115 Phenotype SNP Genotype* Allele frequency mode Case Control P value P value OR 95% CI 1/1 1/2 2/2 MAF 1/1 1/2 2/2 MAF Q126X 1 21 139 0.071 0 31 840 0.018 1.74 × 10-7 3.04 × 10-8 4.25 2.44-7.38 Gout Q141K 31 87 41 0.469 87 316 462 0.281 5.80 × 10-10 5.54 × 10-11 2.23 1.75-2.87 V12M 3 43 112 0.155 30 306 526 0.212 0.055 0.020 0.68 0.49-0.94 Q126X 2 24 202 0.061 0 31 840 0.018 1.91 × 10-6 2.91 × 10-7 3.61 2.14-6.08 Hyperuricemia Q141K 45 113 68 0.449 87 316 462 0.281 5.32 × 10-10 1.53 × 10-11 2.06 1.67-2.55 V12M 7 55 163 0.153 30 306 526 0.212 0.006 0.005 0.67 0.51-0.89 * Minor allele was referred to as allele 1 and major allele as 2. Login to comment
118 Allele 1 is A and allele 2 is G in V12M. Login to comment
120 Haplotype frequency analysis of V12M, Q126X, and Q141K. Login to comment
123 Allele Frequency P value OR 95% CI V12M Q126X Q141K Gout Control G C A 0.465 0.284 2.26 × 10-13 2.50 1.94-3.20 G T C 0.071 0.018 4.10 × 10-12 5.97 3.39-10.51 G C C 0.306 0.486 - - - A C C 0.155 0.212 - - - of ABCG2, such as rosuvastatin (42) and gefitinib (43), have been reported. Login to comment
181 Using the site-directed mutagenesis technique, we constructed mutants of ABCG2 (V12M, Q126X, Q141K, G268R, S441N, and F506SfsX4), which were used for urate transport analysis, on the expression vector for ABCG2. Login to comment

PMID: 16815813 [PubMed] Choudhuri S et al: "Structure, function, expression, genomic organization, and single nucleotide polymorphisms of human ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP) efflux transporters."

No. Sentence Comment

573 Recently, Kondo et al. (2004) reported the effect of single nucleotide polymorphisms (SNPs) in ABCG2 gene on its localization, expression level, and transport activity of the BCRP protein. The cellular localization was identified using the wild-type and seven different SNP variants of BCRP protein (Val12Met, Gln141Lys, Ala149Pro, Arg163Lys, Gln166Glu, Pro269Ser, and Ser441Asn), following their expression in LLC-PK1 cells. Login to comment
583 SNP analyses of the ABCG2 gene by Morisaki et al. (2005) revealed three nonsynonymous SNPs that resulted in amino acid substitution of the BCRP protein; these were Val12Met, Gln141Lys, and Asp620Asn. Login to comment

PMID: 21706123 [PubMed] Narita S et al: "Outcome, clinical prognostic factors and genetic predictors of adverse reactions of intermittent combination chemotherapy with docetaxel, estramustine phosphate and carboplatin for castration-resistant prostate cancer."

No. Sentence Comment

90 Primers Restriction enzyme Forward Reverse MAP4 Intron rs56313601 TGCATGGTTTCCTTTCCCCTA TCTCTGAAACGTGTGTGGCTT BccI MAPT Intron rs3744460 AAAGTGGAGGCGTCCTTGCGA CAGCTTCTTATTAATTATCTGC MnlI ABCG2 V12M rs2231137 GCTTTTCTGTCTGCAGAAAGAT GAAGCTGTCGCGGGGAAGCC TspRI CYP3A5 A6986G rs776746 ATGGAGAGTGGCATAGGAGATA TGTGGTCCAAACAGGGAAGAAATA SspI XRCC1 C194T rs1799782 ATGCTTGGCCAGTTCCGTGTGAAG CACCTGGGGATGTCTTGTTGATCC AluI XRCC1 A399G rs25487 TCCTCCACCTTGTGCTTTCT AGTAGTCTGCTGGCTCTGGG NciI ABCB1 C3435T rs1045642 TTGATGGCAAAGAAATAAAGC CTTACATTAGGCAGTGACTCG MboI ABCB1 Intron rs7779562 TGTTCTGCAATGAGAAGAATAA ATTGTAACACAAATTAATTATC TaqI Genetic variation affecting adverse reaction Next, we explored the association between each genotype and severe leukocytopenia. Login to comment

PMID: 19528366 [PubMed] Delou JM et al: "Unveiling the role of multidrug resistance proteins in hypertension."

No. Sentence Comment

54 It is well established that age and hypertension are the most powerful risk factors for stroke.66,67 In a very recent cardiovascular health study, in which 74 genetic variants were tested, it was found that a single nucleotide polymorphism of ABCG2 (Val12Met) was associated with increased risk of ischemic stroke in both white and black participants.68 The authors showed that homozygotes of the Val allele of ABCG2 were at higher risk of stroke than carriers of the Met allele. Login to comment

PMID: 18243305 [PubMed] Semsei AF et al: "Association of some rare haplotypes and genotype combinations in the MDR1 gene with childhood acute lymphoblastic leukaemia."

No. Sentence Comment

29 The two most frequently identified SNPs in the BCRP gene are in exon 2 (G34A, resulting in a V12M change) and exon 5 (C421A, resulting in a Q141K substitution). Login to comment

PMID: 17259654 [PubMed] Gemignani F et al: "Development of lung cancer before the age of 50: the role of xenobiotic metabolizing genes."

No. Sentence Comment

154 Associations between lung cancer risk and SNPs belonging to genes involved in the phase II of xenobiotic metabolism SNP name rs no. Homozygotes common allele Heterozygotes Homozygotes rarer allele Ptrend Ca Co Ca Co ORa 95% CI Ca Co ORa 95% CI ABCG2: Q141K rs2231142 225 242 44 47 0.99 (0.61-1.63) 1 1 2.77 (0.15-52.00) 0.87 ABCG2: V12M rs2231137 171 190 15 10 1.91 (0.77-4.75) 0 1 - - 0.45 ALDH2: 348T.C-MspI rs440 187 202 94 96 0.94 (0.64-1.37) 9 7 1.18 (0.41-3.42) 0.91 ALDH2: 355G.A rs886205 184 204 99 93 1.04 (0.71-1.52) 10 9 0.99 (0.37-2.68) 0.88 ALDH2: 483T.C-HaeIII rs441 187 209 89 94 0.91 (0.62-1.34) 9 7 1.20 (0.41-3.46) 0.85 ALDH2: 69G.A rs4646777 191 213 89 89 0.98 (0.67-1.44) 10 8 1.07 (0.39-2.95) 0.99 COMT: IVS2-98A.G rs6269 123 125 136 134 1.17 (0.80-1.70) 36 57 0.74 (0.43-1.25) 0.52 COMT: 186C.G-L136L rs4818 123 124 138 135 1.17 (0.80-1.70) 34 50 0.76 (0.44-1.31) 0.64 COMT: H62H rs4633 60 77 151 149 1.14 (0.73-1.77) 80 78 1.04 (0.63-1.71) 0.92 COMT: V158M-472G.A rs4680 83 81 144 146 1.07 (0.70-1.62) 59 75 0.98 (0.60-1.62) 0.97 GSTA2: S112T rs1051739 70 90 74 84 1.19 (0.74-1.92) 63 49 1.88 (1.11-3.17) 0.02 GSTA4: 668C.T rs405729 86 87 129 148 1.04 (0.69-1.57) 74 72 1.12 (0.70-1.81) 0.64 GSTA4: Q117Q rs1802061 251 227 24 40 0.56 (0.31-1.01) 5 1 3.94 (0.43-36.38) 0.36 GSTM1: A/B and null rs1065411 82 97 18 15 1.63 (0.73-3.67) 50 42 1.39 (0.80-2.42) 0.24 GSTM3: 3 bp del-Mnl I rs1799735 113 132 41 39 1.29 (0.74-2.26) 2 5 0.30 (0.04-2.13) 0.88 GSTM3: IVS8À30 rs1537234 76 83 120 112 1.19 (0.76-1.85) 48 63 0.88 (0.52-1.50) 0.74 GSTM3: V224I rs7483 149 132 120 142 0.75 (0.52-1.09) 26 40 0.57 (0.32-1.04) 0.04 GSTP1: 313A.G-I105V rs947894 127 133 118 130 0.98 (0.67-1.43) 27 22 1.29 (0.67-2.49) 0.63 GSTP1: 341C.T-A114V rs1799811 244 265 47 47 1.08 (0.67-1.76) 6 1 8.47 (0.87-82.09) 0.20 GSTT2: 153 bp 3# of STP rs2719 60 72 107 132 1.14 (0.71-1.82) 57 54 1.55 (0.89-2.68) 0.13 GSTT2: M139I rs1622002 275 296 19 16 1.05 (0.50-2.21) 0 0 - - 0.89 MDR1: 2677G.T-S892A rs2032582 97 112 134 117 1.16 (0.78-1.73) 53 67 0.97 (0.60-1.58) 0.97 MDR1: 3435T.C rs1045642 62 86 164 141 1.56 (1.02-2.40) 65 81 1.18 (0.72-1.94) 0.50 MDR1: G411G rs1128503 96 106 134 125 1.03 (0.69-1.54) 46 64 0.82 (0.49-1.35) 0.50 MnSOD2: 1183C.T-V16A rs1799725 80 84 118 117 1.15 (0.75-1.77) 57 63 1.00 (0.60-1.66) 0.94 NAT1: 1088T.A rs1057126 190 180 77 101 0.67 (0.45-0.99) 7 12 0.87 (0.31-2.45) 0.08 NAT1: 1095A.C rs15561 155 140 74 104 0.63 (0.42-0.95) 18 22 0.83 (0.40-1.70) 0.10 NAT1: À344C.T rs4986988 219 219 14 17 0.85 (0.38-1.90) 2 1 1.23 (0.09-16.00) 0.80 NAT1: À40A.T rs4986989 248 256 17 23 0.81 (0.40-1.65) 2 1 1.64 (0.13-21.32) 0.75 NAT1: 445G.A-V149I rs4987076 243 259 18 26 0.75 (0.37-1.49) 3 1 1.85 (0.16-22.03) 0.64 NAT1: 459G.A-T153T rs4986990 245 264 17 25 0.78 (0.39-1.56) 2 1 1.62 (0.12-21.42) 0.65 NAT1: 559C.T-R187Stop rs5030839 227 238 1 2 0.90 (0.08-10.51) 0 0 - - 0.93 NAT1: 560G.A-R187Q rs4986782 270 300 5 3 2.17 (0.46-10.26) 0 0 - - 0.33 NAT2: 282C.T-Y94 rs1041983 135 144 114 120 1.13 (0.77-1.65) 34 33 1.28 (0.72-2.26) 0.36 NAT2: 341T.C-I114T rs1801280 69 73 101 96 1.16 (0.72-1.86) 51 47 1.02 (0.58-1.81) 0.86 NAT2: 481C.T-L161L rs1799929 113 105 127 161 0.73 (0.49-1.06) 43 36 1.07 (0.61-1.89) 0.65 NAT2: 590G.A-R197Q rs1799930 141 156 106 106 1.30 (0.88-1.91) 18 24 0.91 (0.46-1.83) 0.56 NAT2: 803A.G-L268R rs1208 96 88 117 139 0.73 (0.48-1.11) 52 64 0.69 (0.42-1.16) 0.13 NAT2: 857G.A-G286E rs1799931 244 258 15 12 1.34 (0.58-3.13) 0 0 - - 0.49 NQO1-DIA4: P187S rs1800566 202 207 75 97 0.74 (0.50-1.10) 17 11 1.89 (0.81-4.38) 0.96 NQO1-DIA4: R139W rs4986998 274 295 23 21 1.16 (0.59-2.27) 0 0 - - 0.67 SULT1A1: M223V rs1801030 282 302 0 1 - - 0 0 - - - SULT1A1: R213H-HaeII rs4149396 91 95 100 96 0.95 (0.61-1.47) 2 11 0.23 (0.05-1.18) 0.30 SULT1A2: 357 bp 3# of STP C.T rs11401 210 212 64 67 1.11 (0.72-1.71) 11 12 1.20 (0.48-2.98) 0.56 UGT1A7: N129K-R131K N/A 113 117 125 139 0.97 (0.65-1.43) 38 42 1.05 (0.61-1.81) 0.94 UGT1A7: W208R rs1126802 118 111 130 143 0.77 (0.52-1.12) 45 59 0.66 (0.39-1.10) 0.08 Ca, cases; Co, controls. ORa odd-ratio adjusted for age, sex, country and tobacco smoking. In bold, statistically significant results (P , 0.05). Login to comment

PMID: 16509759 [PubMed] Bosch TM et al: "Genetic polymorphisms of drug-metabolising enzymes and drug transporters in the chemotherapeutic treatment of cancer."

No. Sentence Comment

2327 Characteristics of drug transporter genes (with the most important polymorphisms)[167-169] Gene Location Protein Exons Amino Polymorphisms Location Effect (chromosome) acids (exon) ABCB1 7q21 P-gp/MDR1 29 1280 *6 (C3435T) 26 Silent *7 (G2677T/A) 21 A893S *8 (C1236T) 12 Silent G1199A 11 S400N ABCC2 10q24 MRP2 32 1545 C-24T 5'-UTR Unknown C1249A 10 V417I C2302T 18 R768W C2366T 18 S789F T2439+2C 18 Splice site ND 26 W1254Y,A,C,F C3972T 28 Silent A4145G 29 Q1382R G4348A 31 G1440S ABCG2 4q22 BCRP 16 655 G34A 2 V12M C8825A 5 Q141K BCRP = breast cancer resistance protein; MDR1 = multidrug resistance 1; MRP2 = multidrug resistance protein 2; ND = no data; P-gp = P-glycoprotein. Login to comment
2381 [168] Overall, no clinical effects have been observed topoisomerase I inhibitor, of cells expressing V12M for the different MRP2 genotypes and pharmacoki- or Q141K was less than one-tenth compared with netics and pharmacodynamics of anti-cancer drugs. Login to comment
2384 membrane in the V12M clone; however, it is not known if the altered transport function of ABCG2 5.3 Breast Cancer Resistance Protein influences drug transport in vivo. Login to comment
2400 polymorphisms G34A and C8825A, leading to an amino acid change of V12M and Q141K, respec- The levels of ABCG2 mRNA expression in cell tively (see table VII), on the transporter function of lines were found to be significantly correlated with the protein. Login to comment

PMID: 24581936 [PubMed] Au A et al: "Association of genotypes and haplotypes of multi-drug transporter genes ABCB1 and ABCG2 with clinical response to imatinib mesylate in chronic myeloid leukemia patients."

No. Sentence Comment

36 Two most common ABCG2 polymorphisms are 34 G>A, which codes for Val12Met and 421 C>A which codes for Glu141Lys (Zamber et al., 2003). Login to comment

PMID: 23166586 [PubMed] Kasza I et al: "Expression levels of the ABCG2 multidrug transporter in human erythrocytes correspond to pharmacologically relevant genetic variations."

No. Sentence Comment

67 The most common SNPs in ABCG2 [V12M (c.34G.A, p.12Val.Met in exon 2, SNP database ID: rs2231137) and Q141K (c.421C.A, p.141Gln.Lys in exon 5, SNP database ID: rs2231142] were genotyped using the LightCycler480 (Roche Diagnostics, Basle, Switzerland) allelic discrimination system as described previously in detail [45]. Login to comment
89 For this purpose we quantified the expression of the erythrocyte ABCG2 in 47 unrelated, healthy individuals that were also screened for the presence of two most prevalent ABCG2 polymorphic variants found in the Caucasian population (V12M and Q141K) [29]. Login to comment
102 There was no significant difference between homozygous wild-type individuals and heterozygous V12M carriers, although the number of the carriers of this variant was relatively low. Login to comment
103 As a summary of the ABCG2 polymorphism analysis data, among the 47 donors we found 11 individuals with the heterozygous presence of the DNA sequence coding for the Q141K variant (carrier frequency: 23.4%, allele frequency: 11.766.6%), and 3 individuals with the heterozygous presence of the V12M variant (carrier frequency: 6.4%; allele frequency: 3.263.6%). Login to comment
136 Labels: individuals carrying wild-type ABCG2 (WT), polymorphic (Q141K, V12M) ABCG2 alleles, or a heterozygous stop mutation (STOP). Login to comment

PMID: 23379683 [PubMed] Lee Y et al: "Computational analysis and predictive modeling of polymorph descriptors."

No. Sentence Comment

125 BCRP G34A (Val12Met) and C421A (Gln141Lys) polymorphisms occurred at high frequency in most ethnic populations and have been associated with the expression and activity of BCRP protein [48]. Login to comment
126 It has distinctive features including racial differences; for instance, BCRP V12M, Q141K, P269S and Q126Stop were detected in Korean at frequencies of 23, 28, 0.2 and 1.9%, respectively [49]. Login to comment

PMID: 23546589 [PubMed] Takada T et al: "[Transporter-mediated regulation of pharmacokinetics of lifestyle-related substances]."

No. Sentence Comment

24 c3f; ⏚ ᣸ 3fa; c8; e9; f3; b9; dd; fc; bf; fc; ABCG2 Ĳe; SNPs ௼ ad8;c3f;⏚⊈Kc7;fb;Kdb;ba8;ea;b9;af; ˯f;d3b;fd2;᠓Kc5;௼ ௱௺Me5;఑Ĵc;Ĵb; ad8;c3f;⏚⊈Kc7;ఌKdb;ba8;Ĳf;,d05;ca2;Kc5;௼௤௦a00; ℁İc;௢Ĵb;ఐ௦Ĳb;,Pa5;e80;ఌ ad8;d7;ea;f3;bdf;Ĳe;ᤪbdf;Έe;ɏa;Ĳa;௽ Ĳe;Jb0;᛻⌕8e0;Ĳb;d77;8e0;௳Ĵb;௼ὃ௨఑Ĵc;௺௤ıf;İc;,fd1;e74;Ĳe; Ẇa76;Ĳb;ఐĴa;΋a;f1d;ḄĲa;⌕8e0;Ĳe;b58;ᙠఊ̙a;ᖂ௯Ĵc;௺௤ıf;&#ff0e; 2004 e74;,5f0;e7e;Ĳe;Ẇa76;b0;eb;fc;d7;ఐĴa;,d2;c8;b2c; 4 Cd3; ⁐f53;╩ΊĲb;ʠa;Me5;Ĳe;Kdb;ba8;Kc5;8e0;΋a;f1d;b50;İc;b58;ᙠ௳Ĵb;5ef;Pfd;ឋ İc;ᛇȠa;௯Ĵc;ıf;İc;, 26) ᎛Xdc;♚9df;Ĳb;Ĳf;ɏa;İf;Ĳe;΋a;f1d;b50;İc;Ȟb; ĳe;Ĵc;௺İa;Ĵa;,ᐹf53;ḄĲa;Kc5;8e0;΋a;f1d;b50;Ĳf;Ȝc;b9a;௯Ĵc;௺௤Ĳa; İb;௷ıf;&#ff0e;ıd;௭௻,d30;Pde;̳c;e0a;Ĳb;İa;௤௺f38;〈9fa;cea;Ĳe;᣸3fa; Ĳb;fc2;Ĵf;Ĵb; ABCG2/breast cancer resistance protein (BCRP) ΋a;f1d;b50;İc;௭Ĳe;♚9df;Ĳb;b58;ᙠ௳Ĵb;௭௼, ABCG2 Ĳb;Ĳf;a5f;Pfd;᜕4d5;ఔf34;௦ϗb;ea6;Ĳe; ad8;௤΋a;f1d;b50;ɏa;ɂb;İc;b58;ᙠ௳ Ĵb;௭௼,Ae2;Me5;Ĳe;f38;〈9fa;cea;௼Ĳe;bd4;f03;İb;఑c3f;⏚Ĳf; ABCG2 Ĳe;9fa;cea;Ĳb;Ĳa;Ĵa;f97;Ĵb;௼ὃ௨఑Ĵc;ıf;௭௼Ĳa;௽Ĳe;ᳮᵫĲb;ఐ Ĵa;,b46;ὅ఑Ĳf; ABCG2 Ĳb;_a2;௳Ĵb;ʳc;a0e;ఔ⍈ఉıf;(௵Ĳa; ĳf;Ĳb;,ıd;Ĳe;f8c;Ĳe; GWAS Ĳb;İa;௤௺ఊ⊈e05;c3f;⏚ᎠĲe;᜕ 4d5;Ĳb;_a2;⌿௳Ĵb;΋a;f1d;b50;௼௱௺ ABCG2 Ĳf;ᛇȠa;௯Ĵc;௺௤ Ĵb;) &#ff0e; 27&#e30f; 29) ABCG2/BCRP Ĳf;ıd;Ĳe;Ȝd;Ĳe;΅a;Ĵa;,ɏa;ᒐὊឋĲb;_a2;e0e; ௳Ĵb;8e0;b50;௼௱௺˿a;΂b;௯Ĵc;ıf;c8;e9;f3;b9;dd;fc;bf;fc;௻௢Ĵb; İc;,e83;bc4;Ĳa;d44;e54;ᑖe03;௼e83;௤9fa;cea;a8d;b58;ឋఔᨵ௳Ĵb;௭௼ İc;b21;b2c;Ĳb;ʔe;఑İb;௼Ĳa;Ĵa;,Ife;ᙠ௻Ĳf;ɏa;Ed8;Ĳa;⌤Fb9;İb;఑Ẇ a76;İc;⍈ఉ఑Ĵc;௺௤Ĵb;&#ff0e;Ae5;ʠc;eba;Ĳb;İa;௫Ĵb; ABCG2 ΋a;f1d; b50;ɏa;ɂb;Ĳe;a2;ec;eb;ϗb;ea6;Ĳf; ad8;İf;,˿a;Ife;[cf;5ca;ఁa5f;Pfd;᜕ᓄఔ f34;Ĵf;Ĳa;௤ 34G&#ff1e;A(V12M)Ĳf; 19.2%,bf;f3;d1;af;cea; ˿a;Ife;[cf;İc;d04;Ȗa;ᑖĲb;f4e;e0b;௳Ĵb; 421C&#ff1e;A(Q141K)Ĳf; 31.9%,d42;b62;b3;c9;f3;İc;˯f;௲a5f;Pfd;b20;ʀd;௼Ĳa;Ĵb; 376C&#ff1e;T (Q126X)Ĳf; 2.8%௻௢Ĵb;௼ᛇȠa;௯Ĵc;௺௤Ĵb;&#ff0e; 30) ௭Ĵc; ఑Ĳe;௦௵,ϗb;ea6;İc; ad8;İf;a5f;Pfd;f4e;e0b;ఔf34;௦ 421C&#ff1e;A (Q141K)Ĳb;௸௤௺Ĳf;Qe8;e8a;ḄĲb;ఊఐİf;Ẇa76;௯Ĵc;௺İa; Ĵa;,Uac;ᱥ4d5;ɦb;Ĳe;᜕4d5;௼௱௺Ĳf;,b9;eb;d5;a1;b5;e9;b8;f3;Ĳe; d88;ᓄba1;ᔾ5ce;Ĳe;e0a;᧏,ed;b9;d0;b9;bf;c1;f3;ఌd5;eb;d0;b9;bf;c1; f3;Ĳe;d4c;5e3;ᢗe0e;᧲Ĳe; AUC(Uac;ᱥ⊈e2d;fc3;ea6;ߟ᧲╹Bf2;dda; e0b;☢a4d;)ఌ Cmax(ᨬ ad8;⊈e2d;fc3;ea6;)Ĳe;e0a;᧏İc;Yb3;bdf;௯ Ĵc;௺௤Ĵb;&#ff0e;௭Ĳe;ఐ௦Ĳb;,Uac;ᱥc8;e9;f3;b9;dd;fc;bf;fc; ABCG2 Ĳe;Uac;ᱥ4d5;ɦb;ᑴfa1;8e0;b50;௼௱௺Ĳe;[cd;⌕ឋĲf;a8d;b58; ௯Ĵc;௺௤ıf;ఊĲe;Ĳe;,d2;c8;Ĳb;İa;௫Ĵb;˯f;ᳮḄ9fa;cea;ఌ˯f;ᳮ a5f;Pfd;Ĳb;௸௤௺Ĳf;e0d;ʔe;௻௢௷ıf;&#ff0e; ABCG2 Ĳb;ఐĴb;c3f;⏚f38;〈Ĳb;௸௤௺ʳc;a0e;௳Ĵb;ıf;ఉ, ABCG2 ˿a;Ife;d30;Pde;İb;఑abf;Xfd;௱ıf;d30;Pde;̳c;c0f;Pde;ఔᵨ௤ıf; f38;〈b9f; a13;ఔʹc;௷ıf;d50;ʧc;,ABCG2 Ĳf;˯f;ᳮḄfc3;ea6;௻Ĳf; bfd;Ȥc;௱Ĳa;௤ ad8;bb9;[cf;ឋfb;f4e;Yaa;Ȥc;ឋĲe;c3f;⏚f38;〈ఔ>c5;௦௭ ௼İc;ʔe;఑İb;௼Ĳa;௷ıf;(c3f;⏚Ĳe;eb6;Ye3;ea6;Ĳe;bd4;f03;Ḅ ad8;௤ ad8; pH e0b;௻c42;ఉ఑Ĵc;ıf; Km ᎠĲf; 8.24&#b1;1.44 mM ௻௢ Ĵa;,⊈e05;c3f;⏚Ꭰ(f8b;௨௾ 7.0 mg/dL&#ff1d;d04; 420 mM) ௼bd4;ఇ௺Ĳf;Ĵb;İb;Ĳb; ad8;௤) &#ff0e; 31) ĳe;ıf;,᜕ᶒf53;Ye3;᪆Ĳe;d50; ʧc;,ed6;Ĳe;f38;〈9fa;cea;௼Ȝc;Ed8;,c3f;⏚f38;〈Ĳb;İa;௤௺ఊ Q141K ௻Ĳf;a5f;Pfd;İc;Ȗa;e1b;,Q126X ௻Ĳf;a5f;Pfd;İc;d88;ᜫ௳ Ĵb;௭௼İc;̙a;௯Ĵc;ıf;&#ff0e; ௸௹௤௺,Ae5;ʠc;eba;Ĳe;Ꮙeb7;a3a;Aad;5d7;a3a;ὅĲe;b5;f3;d7;eb;ఔ ᵨ௤௺,⊈e05;c3f;⏚Ꭰ௼ ABCG2 ΋a;f1d;b50;ɏa;ɂb;Ĳe;_a2;fc2;Ĳb; ௸௤௺ʳc;a0e;௱ıf;d50;ʧc;,Q141K ᜕ᶒĲe;fdd;ᢝᦪİc;ɏa;௤ ĳb;௽,⊈e05;c3f;⏚Ꭰİc;e0a;᧏௱௺௤ıf;&#ff0e; 31) ĳe;ıf;,cf;d7;ed; bf;a4;d7;ϗb;ea6;Ye3;᪆Ĳb;ఐĴa;,Q126X ௼ Q141K Ĳe;e21;᜕ᶒ 4. Proposed Model of ABCG2-mediated Urate Secretion31) 458 Vol. 133 (2013) Ĳf;Ȝc;௲Cd3;⁐f53;e0a;Ĳb;Ĳf;b58;ᙠ௱Ĳa;௤௭௼İc;̙a;௯Ĵc;ıf;&#ff0e;ıd; ௭௻,e21;᜕ᶒĲe;ϗb;ea6;Ĳb;௸௤௺Ae5;ʠc;eba;ᵱឋĲe;Kdb;ba8;Kc7;f8b; ௼Ꮙe38;ὅ௻bd4;f03;௱ıf;d50;ʧc;,Q126X ௼ Q141K Ĳe;d44;ĳf; ᔠĴf;ıb;İb;఑?a8;b9a;௯Ĵc;Ĵb;c3f;⏚f38;〈d3b;ឋĲe;f4e;e0b;Ĳb;f34;௤, aa;c3;ba;bd4;௻̙a;௯Ĵc;Ĵb;Kdb;ba8;˿a;Kc7;ea;b9;af;İc;♿℉Ĳb; ad8;ĳe;Ĵb; ௭ ௼ İc; ʔe; ఑ İb; ௼ Ĳa; ௷ ıf; &#ff0e; 31) ௭ Ĵc; ఑ Ĳe; d50; ʧc; Ĳf; , ABCG2 İc;˯f;f53;ᑁĲb;İa;௫Ĵb;c3f;⏚Ĳe;f53;᜜ఆĲe;᣸cc4;Ĳb;_a2; e0e;௱௺İa;Ĵa;,ıd;Ĳe;a5f;Pfd;f4e;e0b;Ĳf;⊈e05;c3f;⏚Ꭰ31,32)5ca;ఁKdb; ba8;˿a;Kc7;ea;b9;af;31)Ĳe;e0a;᧏ఔఊıf;఑௳௭௼ఔ̙a;௳ఊĲe;௻ ௢௷ıf;&#ff0e;ABCG2 Ĳf;̩d;Qd3;,̮e;Qd3;,c0f;ῲĲa;௽Ĳe;♊aef;̳c; Ĳb;˿a;Ife;௱,f38;〈9fa;cea;Ĳe;f53;᜜ఆĲe;᣸3fa;Ĳb;fc2;Ĵf;Ĵb;௭௼İc; Me5;఑Ĵc;௺௤Ĵb;௭௼,c3f;⏚Ĳf;c3f;e2d;Ĳe;ĳf;Ĳa;఑ıa;cde;e2d;Ĳb;ఊ ᣸ cc4; ௯ Ĵc; Ĵb; ௭ ௼ İc; ᛇ Ƞa; ௯ Ĵc; ௺ ௤ ıf; ௭ ௼ İb; ఑ , ABCG2 Ĳf;௭Ĵc;఑Ĳe;d44;e54;İb;఑Ĳe;c3f;⏚ᑖccc;Ĳb;_a2;e0e;௱௺ ௤Ĵb;5ef;Pfd;ឋİc;ὃ௨఑Ĵc;ıf;(Fig. 4) &#ff0e; 31) 5-2. Login to comment

PMID: 24021215 [PubMed] Stacy AE et al: "Molecular pharmacology of ABCG2 and its role in chemoresistance."

No. Sentence Comment

40 The two most frequent polymorphisms identified were the G34A (resulting in V12M) and C421A (resulting in a Q141K substitution) transitions (Fig. 3), found in 18 and 35.5% of the studied population, respectively (Kobayashi et al., 2005). Login to comment

PMID: 24338217 [PubMed] Zhao J et al: "Association of single nucleotide polymorphisms in MTHFR and ABCG2 with the different efficacy of first-line chemotherapy in metastatic colorectal cancer."

No. Sentence Comment

32 Genotyping Genomic DNA was isolated from whole blood using the FUJIFILM DNA extraction kit. Based on previous published studies, the single nucleotide polymorphisms selected for testing were MTHFR 677C[T (rs1801133, Ala 222 Val) and 1298A[C (rs1801131, Glu 428 Ala), and ABCG2 34G[A (rs2231137, Val 12 Met) and 421C[A (rs2231142, Gln 141 Lys). Login to comment

PMID: 24388985 [PubMed] Deppe S et al: "Impact of genetic variability in the ABCG2 gene on ABCG2 expression, function, and interaction with AT1 receptor antagonist telmisartan."

No. Sentence Comment

37 Site-directed mutagenesis Non-synonymous ABCG2 single nucleotide polymorphisms (SNPs) G34A (V12M), C421A (Q141K), T742C (S248P), T1291C (F431L), T1465C (F489L) as well as somatic mutation A1444G (R482G) were inserted into the ABCG2 cDNA sequence in the pTRE-Tight-BI-AcGFP1-ABCG2 plasmid using the QuickChange&#d2; Lightning Site-Directed Mutagenesis Kit (Agilent Technologies, Waldbronn, Germany) with specific primers according to the manufacturer`s instructions (Supplemental Fig. 1). Login to comment
91 The average PhA-associated fluorescence in non-induced HEK293-Tet-On cells transiently transfected with the various ABCG2 variants was not significantly different as compared with that observed in HEK293-Tet-On cells transfected with ABCG2 wild-type (wild-type (100 &#b1; 12.1%), V12M (106.7 &#b1; 2.0%), Q141K (97.1 &#b1; 9.3%), S248P (99.1 &#b1; 9.8%), F431L (104.7% &#b1; 10.9%), R482G A B C D Fig. 2. Login to comment
99 PhA-associated fluorescence was similar in doxycycline-induced AcGFP1-positive HEK293-Tet-On cells transfected with the ABCG2 variants V12M (11.8 &#b1; 0.9%), Q141K (17.9 &#b1; 5.8%), and R482G (17.0 &#b1; 2.8%). Login to comment
104 Inhibitory efficacy of telmisartan was not altered by the ABCG2 polymorphisms V12M and Q141K but tended to be lower in the ABCG2 variants S248P and F431L (Fig. 4A and C). Login to comment

PMID: 24586633 [PubMed] Balan S et al: "Genetic association analysis of ATP binding cassette protein family reveals a novel association of ABCB1 genetic variants with epilepsy risk, but not with drug-resistance."

No. Sentence Comment

62 For ABCG2 three functional variants viz: rs2231142 (Gln141Lys; missense), rs72552713 (Gln126Ter; stop gain) and rs2231137 (Val12Met; missense) were screened. Login to comment

PMID: 24777822 [PubMed] Jani M et al: "Structure and function of BCRP, a broad specificity transporter of xenobiotics and endobiotics."

No. Sentence Comment

87 Four variants are found with allele frequencies above 3 % in at least one of the studied population (African American, Asian, and Caucasian): Val12Met (V12M), Gln141Lys (Q141K), Phe208Ser (F208S), and Asp590Tyr (N590Y). Login to comment
91 Q141K and V12M are two variants that are much more highly represented across different ethnicities, although the V12M mutation is not known to alter significantly BCRP function or expression (Tamura et al. 2006; Kondo et al. 2004; Honjo et al. 2002). Login to comment
92 More recently, V12M has been associated with acute lymphoblastic leukemia and gefitinib-induced toxicity (Zhai et al. 2012; Tamura et al. 2012). Login to comment
95 Histone deacetylase inhibitors rescue newly synthesized transporter proteins and prevent aggresome targeting by disturbing TableÊf;1ߒߙMajor non-synonymous single-nucleotide polymorphisms found in the ABCG2 coding region Allele frequencies presented in this table do not reflect interethnic differences Mutation Position in BCRP Cellular effects of SNP Allele frequency % References 34G>A, V12M (rs2231137) N-terminus Lower expression, no impact on function 0-29.8 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 151G>T, G51C N-terminus Slightly overexpressed, decreased transport activity 0.1 Tamura et al. (2006), Yoshioka et al. (2007) 376C>T, Q126X (rs7255271) NBD No expression, no activity 0-1.7 Tamura et al. (2006), Mizuarai et al. (2004), Itoda et al. (2003), Imai et al. (2002), Kobayashi et al. (2005), Kondo et al. (2004) 421C>A, Q141K (rs2231142) NBD Lower expression, decreased transport activity, substrate specificity altered 0-35.7 Tamura et al. (2006), Bosch et al. (2005), Mizuarai et al. (2004), Imai et al. (2002), Kobayashi et al. (2005), Backstrom et al. (2003), Honjo et al. (2002), Kondo et al. (2004) 458C>T, T153 M NBD Slightly lower expression, no impact on function 3.3 Tamura et al. (2006), Mizuarai et al. (2004) 479G>A, R160Q NBD Not determined 0.5 Bosch et al. (2005), Tamura et al. (2006) 496C>G, Q166E (rs1061017) NBD Slightly lower expression, no impact on function 0-1.1 Tamura et al. (2006), Kondo et al. (2004), Yoshioka et al. (2007) 616A>C, I206L (rs12721643) NBD Well expressed, decreased transport activity 0-10.0 Tamura et al. (2006), Zamber et al. (2003), Vethanayagam et al. (2005), Ieiri (2012a) 623T>C, F208 (rs1061018) NBD No expression, no transport activity 0.9-3.9 Tamura et al. (2006) 742T>C, S248P (rs3116448) NBD Well expressed, no transport activity 0.5 Tamura et al. (2006), Yoshioka et al. (2007) 1000G>T, E334X (rs3201997) NBD No expression, no transport activity Not determined Tamura et al. (2006), Ishikawa et al. (2005) 1291T>C F431L ECL1 Lower expression, substrate specificity altered 0.6-0.8 Tamura et al. (2006), Itoda et al. (2003), Yoshioka et al. (2007) 1322G>A, S441 N ECL1 Slightly lower expression, no transport activity 0.5 Tamura et al. (2006), Kobayashi et al. (2005), Kondo et al. (2004) 1465T>C, F489L TM3 Slightly lower expression, no transport activity 0.5-0.8 Tamura et al. (2006), Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F506S TM4 Not determined 0.5 Itoda et al. (2003), Kobayashi et al. (2005) 1515delC, F507L 1515delC, V508L 1515delC, M509X 1711T>A, F571I (rs9282571) TM5 Well expressed, substrate specificity altered 0.5 Tamura et al. (2006) 1723C>T, R575X TM5 Not determined 0.5 Tamura et al. (2006) 1768A>T, N590Y (rs34264773) ECL3 Slightly overexpressed, substrate specificity altered 0-9.7 Tamura et al. (2006), Mizuarai et al. (2004), Zamber et al. (2003), Vethanayagam et al. (2005) 1858G>A, D620 N (rs34783571) ECL3 Slightly overexpressed, substrate specificity altered 0-11.1 Tamura et al. (2006), Bosch et al. (2005), Honjo et al. (2002), Vethanayagam et al. (2005) the trafficking along microtubules (Basseville et al. 2012). Login to comment

PMID: 24857923 [PubMed] Zhou D et al: "Functional polymorphisms of the ABCG2 gene are associated with gout disease in the Chinese Han male population."

No. Sentence Comment

5 High-resolution melting analysis and Sanger sequencing were performed to identify the genetic polymorphisms V12M, Q141K and Q126X in the ABCG2 gene. Login to comment
10 The A allele frequency for V12M was lower (18.3%) in the gout patients than in the controls (29%) (OR 0.55, 95% CI 0.43-0.71, p = 2.55 &#d7; 10-6 ). Login to comment
11 In the order of V12M, Q126X and Q141K, the GCA and GTC haplotypes indicated increased disease risk (OR = 2.30 and 2.71, respectively). Login to comment
37 In the present study, we developed an HRM assay to detect three functional SNPs (Q141K, V12M and Q126X) and then assessed the genetic association of those SNPs in the ABCG2 gene with gout to investigate the association between ABCG2 dysfunction and gout risk in a Han Chinese male population. Login to comment
42 The results obtained from the DNA sequencing analysis confirmed the reliability of the HRM assay. The genotype and allelic frequencies of the three SNPs (Q141K, V12M and Q126X) among the cases and controls were in Hardy-Weinberg equilibrium for all of the polymorphisms analyzed. Login to comment
45 The results of the association study, shown in Table 1, demonstrate that 141K and 126X were significantly associated with an increased risk of gout, whereas the frequency of the A allele of V12M appeared to be significantly decreased in gout patients (18.3%) compared with controls (29%) (OR 0.55, 95% CI: 0.43-0.71). Login to comment
48 The three groups are well distinguished: (A) V12M; (B) Q126X; and (C) Q141K. Login to comment
54 SNP Genotype * Allele Frequency Mode Case Control p-Value p-Value OR 95% CI 1/1 1/2 2/2 MAF 1/1 1/2 2/2 MAF Q141K 84 181 87 0.496 33 150 167 0.309 1.18 &#d7; 10-11 8.99 &#d7; 10-13 2.20 1.77-2.74 Q126X 0 33 319 0.047 0 12 338 0.017 1.31 &#d7; 10-3 1.57 &#d7; 10-3 2.91 1.49-5.68 V12M 16 97 239 0.183 35 133 182 0.290 3.67 &#d7; 10-5 2.55 &#d7; 10-6 0.55 0.43-0.71 * The minor allele was referred to as allele 1, and the major allele was referred to as allele 2. Login to comment
56 Allele 1 is A and allele 2 is G in V12M. Login to comment
58 Haplotype Analysis We performed a 3-SNP haplotype analysis (in the order V12M, Q126X and Q141K). Login to comment
63 Haplotype frequency analysis of V12M, Q126X and Q141K. Allele Frequency p-Value OR 95% CI V12M Q126X Q141K Gout Control G C A 0.481 0.289 1.26 &#d7; 10-13 2.30 1.84-2.87 G T C 0.044 0.017 2.97 &#d7; 10-3 2.71 1.37-5.36 G C C 0.292 0.404 8.27 &#d7; 10-6 0.60 0.48-0.75 A C C 0.165 0.271 1.53 &#d7; 10-6 0.53 0.41-0.69 2.3. Login to comment
76 Discussion This study is the first to examine the possible role of ABCG2 variants, which have previously been found to be associated with gout, in terms of their genetic susceptibility to gout in the Han Chinese population. We found that the Q141K, Q126X and V12M alleles were strongly associated with gout in Chinese males. Login to comment
86 Consistent with the genetic susceptibility identified in gout patients in a cohort of Japanese individuals [18], we observed that the rare alleles of both the 141K and 126X SNPs of ABCG2 were associated with an increased risk for gout, whereas the minor A allele in V12M had a protective effect on susceptibility to gout. Login to comment
115 We selected three functional ABCG2 SNPs: V12M, Q126X and Q141K. Login to comment
124 SNP ID SNP Allele Sequence (5'-3') Size V12M A/G ATGGTATGGGCCATTCATTG 250 bp ATGCCTTCAGGTCATTGGAA Q141K A/C ATGTTGTGATGGGCACTCTG 158 bp CCACATTACCTTGGAGTCTG Q126X C/T GCTGCAAGGAAAGATCCAAG 163 bp CAGCCAAAGCACTTACCCAT 4.3. Login to comment

PMID: 25036722 [PubMed] Szafraniec MJ et al: "Determinants of the activity and substrate recognition of breast cancer resistance protein (ABCG2)."

No. Sentence Comment

201 To elucidate the significance of this polymorphism for porphyrin transport, a set of 18 variants of BCRP (Val12 Met, Gly51 Cys, Gln126 stop, Gln141 Lys, Thr153 Met, Gln166 Glu, Ile206 Leu, Phe208 Ser, Ser248 Pro, Glu334 stop, Phe431 Leu, Ser441 Asn, Arg482 Gly, Arg482 Thr, Phe489 Leu, Phe571 Ile, Asn590 Tyr and Asp620 Asn) have been expressed in insect cells. Login to comment

PMID: 25236865 [PubMed] Mao Q et al: "Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport--an update."

No. Sentence Comment

214 Of these SNPs, 34G>A (V12M) and 421C>A (Q141K) occur most frequently in East Asians (~30-60%) and with relatively low allele frequencies in Caucasians and African-American populations (~5-10%). Login to comment
218 V12M resulting from the 34G>A SNP and other variants (e.g., I206L, F208S, N590Y, and D620N) display expression levels and drug resistance profiles comparable to wild-type BCRP (100,101). Login to comment

PMID: 25468777 [PubMed] Grey Nee Cotte S et al: "Lack of efficacy of mitoxantrone in primary progressive Multiple Sclerosis irrespective of pharmacogenetic factors: a multi-center, retrospective analysis."

No. Sentence Comment

16 Patients, material and methods After approval by local ethics committees and informed consent, genotyping for ABCG2 V12M (reference SNP rs2231137) and Q141K (rs2231142) and ABCB1 3435CNT (rs1045642) and 2677GNT (rs2032582) was performed using TaqManࡊ polymerase chain reaction Journal of Neuroimmunology 278 (2015) 277-279 Ìe; Corresponding author at: Department of Neurology, St. Josef-Hospital, Ruhr University Bochum, Gudrunstr. Login to comment

PMID: 25469257 [PubMed] Sari FM et al: "Investigation of the functional single-nucleotide polymorphisms in the transporter and susceptibility to colorectal cancer."

No. Sentence Comment

20 The BCRP 34G>A variant (rs2231137), resulting in a Val12Met (V12M) substitution, results in apical plasma membrane dislocalization of BCRP and generates a protein with a significantly reduced ability to transport several drugs/xenobiotics. Login to comment

PMID: 25515134 [PubMed] Miura Y et al: "Sunitinib-induced severe toxicities in a Japanese patient with the ABCG2 421 AA genotype."

No. Sentence Comment

85 Another population pharmacokinetics study also identified ethnic background as a significant covariate for the Table 1 Genotypes of seven SNPs in CYP3A5, ABCB1 and ABCG2 Gene SNP Allele Amino acid Genotype CYP3A5 rs776746 6986A > G Splice Site AG ABCB1 rs1128503 1236C > T G412G CT ABCB1 rs2032582 2677G > T/A A893S/T GT ABCB1 rs1045642 3435C > T I1145I CT ABCG2 rs2231137 34G > A V12M GG ABCG2 rs72552713 376G > A Q126X GG ABCG2 rs2231142 421C > A Q141K AA prediction of oral clearance [16]. Login to comment

PMID: 26428519 [PubMed] Stiburkova B et al: "Novel dysfunctional variant in ABCG2 as a cause of severe tophaceous gout: biochemical, molecular genetics and functional analysis."

No. Sentence Comment

18 The analysis of ABCG2 revealed eight variants in intron regions, an unpublished heterozygous intron variant c.689+1G>A and two exon variants, synonymous rs35622453 and heterozygous non-synonymous rs22231137 (p.V12M), which had little effect on the expression and urate transport activity of ABCG2 [6]. Login to comment