ABCMdb

ABCG2 p.Gln126*

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Publications

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

No. Sentence Comment

105 The variant Q126stop (c.376C>T) was consistently observed in certain Japanese cohorts; however, it was absent in Caucasian and African American groups (Imai et al. 2002; Itoda et al. 2003; Kobayashi et al. 2005). 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
132 No MTX-transport activity was observed in the Q126stop and E334stop variants, as well as in acquired mutation variants (R482G and R482T). 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

213 Some of the above sequence variations showed an allele frequency of ~ 1% in distinct populations, Q126stop and F489L in the Japanese and N590Y in the Caucasian population [129-131,134,135], whereas most of the mutations were only detected in single individuals (e.g., I206L, F431L, S441N, D620N). Login to comment
238 The variant Q126stop (c.376C > T) was consistently observed in certain Japanese cohorts; however, it was absent in two different Caucasian and African-American groups [129,134,135]. 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
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
269 No MTX-transport activity was observed in the Q126stop and E334stop variants, as well as in acquired mutation variants (R482G and R482T). 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

64 C376T (Q126stop)-BCRP SNP Another of the BCRP gene SNPs, C376T, substitutes a stop codon for Gln-126 (Q126stop), and was found in 3/124 of our general Japanese samples as a heterozygosity [23]. 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
112 Some of the above sequence variations showed an allele frequency of about 1% in distinct populations (Q126X, F489L in the Japanese and N590Y in the Caucasian population [45-47,49,64]), while most of the mutations were only detected in single individuals (missense mutations: I206L, F431L, S441N, D620N, and a frameshift mutation: c.1515delC [44-46,49]). Login to comment
118 An interesting sequence variant Q126X (c.376CO T), affecting the coding region and leading to premature termination of protein synthesis, was consistently observed in certain Japanese cohorts, however, it was absent in two different Caucasian and African American groups [45,46,64]. 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
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

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
125 No MTX transport activity was observed in the variants Q126stop, E334stop, R482G, and R482T. Login to comment
233 Figure 13 shows the result of SNP array detection where nonsynonymous polymorphisms of ABCG2, that is, Q126stop and Q141K, were analyzed. Login to comment
249 Detection of nonsynonymous polymorphisms (Q126stop and Q141K) of ABCG2 with the SNP array. 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
4 We herein provide evidence that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in porphyrin transport, whereas F489L exhibited impaired transport, approximately 10% of the activity observed for the wild type. Login to comment
6 Thus, among those genetic polymorphisms of ABCG2, at least the hitherto validated alleles of Q126stop, S441N, and F489L are suggested to be of clinical importance related to the potential risk of porphyria. Login to comment
36 We herein provide evidence that the variants Q126stop, F208S, S248P, E334stop, S441N, and F489L are defective or impaired in the transport of porphyrins, suggesting that those genetic polymorphisms in the ABCG2 gene may be related to the risk of certain diseases resulting from disruption of porphyrin homeostasis. 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
148 For Q126stop and E334stop, however, that treatment created truncated proteins (Fig. 4A). Login to comment
164 It is important to note that the variants Q126stop, F208S, S248P, E334stop, and S441N substantially lack transport activity for both hematoporphyrin and methotrexate. 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
215 We provide evidence that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in the transport of hematoporphyrin (Fig. 5). 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
220 The variant Q126stop was consistently observed in certain Japanese cohorts; however, it was absent in two different Caucasian and African-American groups (Imai et al., 2002; Itoda et al., 2003; Mizuarai et al., 2004; Kobayashi et al., 2005; for a recent review, see Ishikawa et al., 2005) for recent review. 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
240 Therefore, at least, the validated alleles such as Q126stop, S441N, and F489L with a loss of porphyrin transport activity are at potential risk of diseases. 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

917 0.005 Exon 4 c. 376 C>T Q126stop 0.01 Lack of function 0.00a 0.00b Exon 5 c. 421 C>A Q141K 0.35 Reduced activity (Mizuarai et al., 2004; Kobayashi et al., 2005; Sparreboom et al., 2005) 0.11a 0.02b IVS 5-16 A>G ? 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

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
177 The variants Q126stop, F208S, S248P, E334stop, and S441N were found to be defective in the transport of hematoporphyrin (Tamura et al., 2006) (Table 2). 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

1002 1425AϾG) mutations, one nonsense (Q126X, c. Login to comment
1005 The sequence variant Q126X, leading to premature termination of protein synthesis, was consistently observed in certain Japanese cohorts, while absent in different Caucasian and African American groups (145, 148, 185). Login to comment

PMID: 17093005 [PubMed] Enokizono J et al: "Involvement of breast cancer resistance protein (BCRP/ABCG2) in the biliary excretion and intestinal efflux of troglitazone sulfate, the major metabolite of troglitazone with a cholestatic effect."

No. Sentence Comment

192 BCRP has some functional single nucleotide polymorphisms (SNP), such as C376T (Q126stop), C421A (Q141K), and G1322A (S441N). Login to comment

PMID: 17323126 [PubMed] Huang Y et al: "Pharmacogenetics/genomics of membrane transporters in cancer chemotherapy."

No. Sentence Comment

124 Moreover, Letourneau et al. examined 10 non-synonymous ABCC1 SNPs to determine Table 2 Summary of genetic variants in ABC transporters ABCB1, ABCC1, ABCC2 and ABCG2 involved in cancer chemotherapy Variants (location, effect) Phenotype Drug Sample Reference ABCB1 +103T>C (5'flanking, non-coding) Increased transcription Doxorubicin vincristine osteosarcoma Stein et al., 1994 [19] +8T>C (5'flanking, non-coding) Unknown Leukemia Rund et al., 1999 [21] 1236C>T (exon12, synonymous) Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Higher exposure Irinotecan, SN-38 Cancer patients Mathijssen et al., 2003 [45] 2677G>T/A (exon21, A893S/T) Lower expression placenta Tanabe et al., 2001 [42] Lower expression placenta Hitzl et al., 2004 [37] Higher expression AML blasts Illmer et al., 2002 [47] Allele specific expression Cell lines, lymphoma Mickley et al., 1998 [22] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Survival leukemia Illmer et al., 2002 [47] Survival leukemia van den Heuvel-Eibrink et al., 2001 [48] Worse survival AML blasts Kim et al., 2006 [10] Higher efficacy Paclitaxel Ovarian cancer Green et al., 2006 [50] 2995G>A (exon24, A999T) None Cell lines, lymphoma Mickley et al., 1998 [22] 3435C>T (exon26, synonymous) Lower expression Duodenal protein Hoffmeyer et al., 2000 [26] Lower expression placenta Hitzl et al., 2004 [37] Higher expression Intestine mRNA Nakamura et al., 2002 [32] Higher expression AML blasts Illmer et al., 2002 [47] Lower clearance Irinotecan Cancer patients Sai et al., 2003 [44] Lower efflux Digoxin CD56+ NK cells Hitzl et al., 2001 [27] Higher plasma level Digoxin Healthy volunteers Hoffmeyer et al., 2000 [26] Higher AUC Cyclosporin transplant patients Bonhomme-Faivre et al., 2004 [36] Lower CNS relapse Cancer patients Stanulla et al., 2005 [46] Better survival leukemia Illmer et al., 2002 [47] Higher efficacy Breast cancer Kafka et al., 2003 [49] Higher activity, worse survival AML Kim et al., 2006 [10] Better survival Platinums Esophageal cancer Wu et al., 2006 [43] No difference Docetaxel patients Puisset et al., 2004 [41] No difference Irinotecan Cancer patients Mathijssen et al., 2004 [39] No difference Vincristine patients Plasschaert et al., 2004 [40] No difference colon Taniguchi et al., 2003 [24] ABCC1 -260G>C (5'flanking, non-coding) Higher activity Transfected cell line Wang et al., 2005 [62] Table 2 (Continued) Variants (location, effect) Phenotype Drug Sample Reference 128G>C (exon2, C43S) Reduced resistance Vincristine, arsenite Transfected cell line Leslie et al., 2003 [60] 1299G>T (exon10, R433S) Reduced transport of LTC4, increased resistance to doxorubicin Leukotriene C4, doxorubicin Transfected cell line Conrad et al., 2002 [59] 2012G>T (exon16, G671V) No change in activityLeukotriene C4 Transfected cell line Conrad et al., 2001 [58] Heart toxicity Doxorubicin nLon-Hodgkin lymphoma Wojnowski et al., 2005 [63] 2965G>A (exon22, A989T) Reduced transport Estradiol 17β-glucuronide Transfected cell line Letourneau et al., 2005 [61] ABCC2 1271A>G (exon10, R421G) Reduced drug elimination, increased nephrotoxicity Methotrexate One lymphoma patient Hulot et al., 2005 [79] 3972C>T (exon28, nonsynonymous) Reduced drug clearance Irinotecan Cancer patients Innocenti et al., 2004 [80] ABCG2 376C>T (exon4, Q126stop) Reduced transport Porphyrin Trensfected cell Tamura et al., 2006 [104] 421C>A (exon5, Q141K) Lower expression Transfected cell lines Imai et al., 2002 [94] Lower expression Transfected cell lines Kondo et al., 2004 [95] Lower expression Placenta Kobayashi et al., 2005 [98] Reduced ATPase activity Trensfected cell lines Mizuarai et al., 2004 [97] Higher plasma levels Diflomotecan patients Sparreboom et al., 2004 [100] Increased bioavailability Topotecan patients Sparreboom et al., 2005 [101] Increased bioavailability 9-Aminocamptothecin patients Zamboni et al., 2006 [81] Increased drug accumulation Imatinib Transfected cell lines Gardner et al., 2006 [96] Increased drug accumulation Topotecan Trensfected cell lines Imai et al., 2002 [94] No difference Imatinib patients Gardner et al., 2006 [96] No difference intestine Zamber et al., 2003 [99] No difference MTX Trensfected cell lines Kondo et al., 2004 [95] the effects on expression and function of this transporter in transfected HEK293T cells [61]. Login to comment
187 Another polymorphism, 376C>T, substitutes a stop codon for Gln (Q126stop) and causes the absence of active ABCG2 protein from the T allele [95, 99]. Login to comment
189 It was recently demonstrated that in vitro the Q126stop protein was defective in porphyrin transport [104]. 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
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

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
368 A recent study characterized the activity of 18 ABCG2 variants, and concluded that Q126stop, F208S, S248P, E334stop, S441N and F489L are defective in hematoporphyrin transport [170], which may increase the risk of disease in individuals carrying these polymorphisms. 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

22 By using plasma membrane vesicles and a high-speed screening system, we precisely evaluated functional changes associated with genetic polymorphisms in vitro.24) Since porphyrins are considered to be endogenous substrates for ABCG2, we have investigated the transport of porphyrins with a total of 18 variant forms of human ABCG2 in the plasma membrane vesicle system.4) As a result, we found that the variants Q126stop, F208S, S248P, E334stop, S441N, and F489L are defective or impaired in the transport of porphyrins. Login to comment
199 Indeed, we reported that the variants Q126stop, F208S, S248P, E334stop, and S441N are defective in the transport of hematoporphyrin.4) The F489L variant showed impaired transport activity. 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

26 The ABCG2 non-synonymous SNP variants Q126stop, F208S, S248P, E334stop, S441N and F489L were defective in the active transport of methotrexate and haematoporphyrin [18]. 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: 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
246 The variants Q126stop, F208S, S248P, E334stop, and S441N were defective in the transport of hematoporphyrin (Figure 9). 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: 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
232 S. Koshiba et al. variants Q126stop, F208S, S248P, E334stop, and S441N substantially lack transport activity for both haematoporphyrin and methotrexate. Login to comment

PMID: 18958403 [PubMed] Furukawa T et al: "Major SNP (Q141K) variant of human ABC transporter ABCG2 undergoes lysosomal and proteasomal degradations."

No. Sentence Comment

174 The nonsynonymous SNP variants of Q126stop, F208S, S248P, E334stop, S441N, and F489L were defective in the active transport of methotrexate and hematoporphyrin (42). Login to comment

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

No. Sentence Comment

228 C376T (Q126stop)-BCRP SNP . Login to comment
865 C376T (Q126stop)-BCRP SNP We have identified another SNP within the BCRP gene, C376T, which substitutes a stop codon for Gln-126 (Q126stop) and is present at a low frequency in samples from healthy Japanese individuals as a heterozygote (reported frequencies of 3/124 and 2/120 in two studies, respectively) [54,60]. 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

PMID: 19111842 [PubMed] Wakabayashi-Nakao K et al: "Quality control of human ABCG2 protein in the endoplasmic reticulum: ubiquitination and proteasomal degradation."

No. Sentence Comment

950 The non-synonymous SNP variants Q126stop, F208S, S248P, E334stop, S441N, and F489L were defective in the active transport of methotrexate and hematoporphyrin [54]. Login to comment

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

107 These variations include an amino acid substitution leading to reduced in vitro activity, ABCG2 1465T[C (F489L) [36], and the stop codons, ABCG2 376C[T (Q126X) and 1723C[T (R575X) [28]. Login to comment
118 It was noted that the additive effect of g1 [ABCG2 376C[T (Q126X)] was not observed in the heterozygotes (g1/-), but was evident in the compound heterozygotes with another ABCG2 genetic polymorphism, # IIB, (G/g1) (Fig. 2a, b). Login to comment
124 patients who experienced grade 4 neutropenia ID Gene Genetic variation Nucleotide change (amino acid substitution) Haplotypea b1 ABCB1 304G[C (G102R) Block 1 *3 b2(B)b 1804G[A (D602N) Block 2 *12 b3(B)b 1342G[A (E448K) Block 2 *14 b4 3043A[G (T1015A) Block 2 *16 b5 3751G[A (V1251I) Block 3 *2 c1 ABCC2 1177C[T (R393W) *7 g1 ABCG2 376C[T (Q126X) Block 1 *4 g2 1465T[C (F489L) Block 2 *2 g3 1723C[T (R575X) Block 2 *5 s1(S)c SLCO1B1 1007C[G (P336R) s2 311T[A (M104K) u1 UGT1A1 -3279T[G, 1941C[G # 60-# IB (?/?) 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
227 The non-synonymous SNP variants Q126stop, F208S, S248P, E334stop, S441N, and F489L were defective in the active transport of methotrexate and hematoporphyrin (Tamura et al., 2006) (Fig. 7C). 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

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

No. Sentence Comment

242 0.005 c. 376 C>T Q126stop 0.01 0.00a 0.00b Lack of function c. 421 C>A Q141K 0.35 0.11a 0.02b Reduced activity [120, 124, 137] IVS 5 -16 A>G ? Login to comment

PMID: 20090896 [PubMed] Ichida K et al: "What lies behind serum urate concentration? Insights from genetic and genomic studies."

No. Sentence Comment

91 Q126X shows stronger effects on gout development than Q141K, conferring an odds ratio of 5.97 [44]. Login to comment

PMID: 20421215 [PubMed] Yamagishi K et al: "The rs2231142 variant of the ABCG2 gene is associated with uric acid levels and gout among Japanese people."

No. Sentence Comment

86 A recent functional and association study of Japanese people [8] has identified another causal SNP of ABCG2, Q126X, with less frequency of minor allele (1.8% among control), but stronger effect on gout/hyperuricaemia than presently analysed ABCG2 (Q141K). Login to comment

PMID: 20613716 [PubMed] Wright AF et al: "A 'complexity' of urate transporters."

No. Sentence Comment

36 Other loss-of-function variants have been identified in the Japanese population (for example, Q126X in 5% of Japanese) so that variants at the ABCG2 locus have been estimated to account for about 10% of gout cases in both Caucasian and Japanese populations.21,22 The equivalent 'population attributable risk`-the proportional reduction in disease incidence if the associated variants could be removed from the population- for SLC2A9 is 55% of gout cases, because a very common SLC2A9 allele (frequency B77%) is associated with raised serum urate and the odds ratio for gout is similar to ABCG2, at 1.4 per allele.8 Population attributable risk figures are multiplicative, so that the combined reduction in gout due to these two loci would be 41% (0.9 Â 0.45). Login to comment

PMID: 20812902 [PubMed] Ni Z et al: "Structure and function of the human breast cancer resistance protein (BCRP/ABCG2)."

No. Sentence Comment

249 A systematic study of 18 natural variants of BCRP expressed in insect cells showed that the variants Q126stop, F208S, S248P, E334stop, and S441N were defective in porphyrin transport, whereas F489L displayed approximately 10% of the transport activity of wild-type BCRP [120]. Login to comment

PMID: 20858603 [PubMed] Phipps-Green AJ et al: "A strong role for the ABCG2 gene in susceptibility to gout in New Zealand Pacific Island and Caucasian, but not Maori, case and control sample sets."

No. Sentence Comment

108 However, this needs to be confirmed by re-sequencing ABCG2 in this population group and genotyping all variants in gout cases and controls, in a fashion analogous to that done previously in a Japanese sample set (9), in which a genetically independent variant (Q126X; rs72552713) also confers risk to gout (OR ¼ 4.25). Login to comment

PMID: 21103975 [PubMed] Meyer zu Schwabedissen HE et al: "In vitro and in vivo evidence for the importance of breast cancer resistance protein transporters (BCRP/MXR/ABCP/ABCG2)."

No. Sentence Comment

251 To date there are 26 nonsynonymous, five synonymous (c.114T>C, c.369C>T, c.474C>T, c.1098G>A, and c.1425A>G) polymorphisms, three nonsense mutations (Q126X, E334X, and R575X), and one frameshift mutation (c.1515delC) described in healthy individuals or patients (compare Table 3). 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
168 The variants Q126stop, F208S, S248P, E334stop, and S441N are defective in the transport of hematoporphyrin (Figure 4(b)). 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: 21511506 [PubMed] Hamajima N et al: "Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population."

No. Sentence Comment

0 Significant association of serum uric acid levels with SLC2A9 rs11722228 among a Japanese population Nobuyuki Hamajima a, ⁎, Rieko Okada a , Sayo Kawai a , Asahi Hishida a , Emi Morita a , Guang Yin a , Kenji Wakai a , Hirotaka Matsuo b , Hiroki Inoue b , Yuzo Takada c , Yatami Asai d , Atsuyoshi Mori d , Mariko Naito a a Department of Preventive Medicine, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan b Department of Integrative Physiology and Bio-Nano Medicine, National Defense Medical College, Saitama 359-8513, Japan c Laboratory for Biofunctions, the Central Research Institute, National Defense Medical College, Saitama 359-8513, Japan d Seirei Social Welfare Community, Hamamatsu 433-8558, Japan a b s t r a c ta r t i c l e i n f o Article history: Received 8 March 2011 Received in revised form 3 April 2011 Accepted 3 April 2011 Available online xxxx Keywords: Serum uric acid SLC2A9 rs11722228 ABCG2 Q126X SLC22A12 W258X Polymerase chain reaction with confronting two-pair primers Hypouricemia Genome-wide association studies identified that SLC2A9 (GLUT9) gene polymorphisms were associated with serum uric acid (SUA) levels. Login to comment
13 ATP-binding cassette subfamily G member 2 (ABCG2) gene in chromosome 4q22, coding a uric acid transporter, has a functional polymorphism, Q126X (rs72552713), which was reported to reduce transportation activity, resulting in hyperuricemia [1-3]. Login to comment
52 ABCG2 Q126X and SLC22A12 W258X were genotyped as described in the previous papers [2,18]. Login to comment
65 Among them, examinees with SLC22A12 258X (230 individuals), ABCG2 126X (250 individuals), and/or not genotyped (one for SLC22A12 W258X and thirteen for ABCG2 Q126X) were excluded from the analysis, and 4535 subjects (3082 males and 1453 females) with SLC22A12 258WW and ABCG2 126QQ remained. Login to comment
49 ABCG2 Q126X and SLC22A12 W258X were genotyped as described in the previous papers [2,18]. Login to comment
62 Among them, examinees with SLC22A12 258X (230 individuals), ABCG2 126X (250 individuals), and/or not genotyped (one for SLC22A12 W258X and thirteen for ABCG2 Q126X) were excluded from the analysis, and 4535 subjects (3082 males and 1453 females) with SLC22A12 258WW and ABCG2 126QQ remained. 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: 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: 22945592 [PubMed] Reginato AM et al: "The genetics of hyperuricaemia and gout."

No. Sentence Comment

58 In the liver, GCKR regulates glucokinase75,85 by mediating the phosphorylation of glucose to glucose‑6-phosphate, a precursor of liver glycogen synthesis and of de novo purine synthesis.75,85 A deficiency in the activity of glucose‑6-phosphatase causes glycogen storage disease type 1 (also known as von Gierke disease), which is characterized by hypertriglyceridaemia and hyperuricaemia.75,85 The GCKR SNP rs780094 might affect both serum uric acid and triglyceride levels (which are associated with insulin resistance) via a common mediator.75 Interestingly, GCKR is associated with insulin resistance,32 glucose level, triglyceride level, and C‑reactive protein,86 which are components of metabolic syndrome.75 Table 2 | SLC2A9, ABCG2 and SLC22A12 variants associated with serum uric acid levels, FeUA and gout Variant Location Phenotype Populations SLC2A9 (chromosome 4) rs1014290 Intron 3 SUA, FeUA, gout European ancestry34 rs6449213 Intron 4 SUA, FeUA, gout White,34-37,43 African American51,72 rs16890979 Exon 6 SUA, gout White,37,42,44 African American,72 Amish55 rs734553 Intron 6 SUA, gout White,32,39,44 Icelandic,13 African American72 rs7442295 Intron 6 SUA, gout White 35,38,39,44 rs737267 Intron 7 SUA, FeUA, gout European ancestry34,44 rs6855911 Intron 7 SUA, gout White,35,38,39,44 African American72 rs13129697 Intron 7 SUA, gout White,33,44 African American72 rs2241480 Intron 8 SUA, gout European ancestry72 rs7663032 Intron 9 SUA, gout African American,72 Croatian44 rs3775948 Intron 9 SUA Croatian,44 African American51 rs16890979 Intergenic SUA, gout White,37 Amish,55 Croatian,44 Pacific Islander,42 New Zealander42 rs717615 Intergenic SUA Croatian44 rs6856396 Intergenic SUA African American51 rs10489070 Intergenic Gout Amish55 ABCG2 (chromosome 4) rs2231137 Exon 2 SUA Japanese63 rs72552713 (Q126X) Exon 4 SUA, gout Japanese63 rs2231142 (Q141K) Exon 5 FeUA, SUA, gout White,32,37,39,44,62 African,37,72 Chinese,60 Icelandic,13 Japanese,59,63 Pacific Islander,61 New Zealander31,61 rs2199936 Intergenic SUA White 32,33,44 SLC22A12 (chromosome 11) rs11231825 Exon 1 FeUA, SUA Chinese,70 White,32,68 African American72 rs3825016 Exon 2 FeUA German68 rs12800450 Exon 2 SUA African American72 rs161109885 Intron 3 SUA Chinese73 rs893006 Intron 4 SUA Japanese,67 Chinese71 rs1529909 Intron 4 FeUA, SUA Korean74 rs475688 Intron 4 Gout Chinese,70 Solomon Islander70 rs17300741 Intron 4 SUA European32,75 rs7932775 Exon 8 SUA, FeUA, gout German,68 Chinese,70,73 Solomon Islander70 rs505802 Intergenic SUA European,32,44 African American72 rs11602903 Intergenic FeUA, SUA German,68 Chinese73 Abbreviations: FeUA, fractional excretion of urate; SUA, serum uric acid. Login to comment

PMID: 22565184 [PubMed] Hamajima N et al: "Significant interaction between LRP2 rs2544390 in intron 1 and alcohol drinking for serum uric acid levels among a Japanese population."

No. Sentence Comment

31 This study aimed to confirm the association of SUA with LRP2 rs2544390 at intron 1 and rs3755166 at the promoter region in a Japanese population, after eliminating the effects of SLC22A12 W258X SLC2A9 rs11722228 at intron 8, ABCG2 Q126X, and ABCG2 Q141K on SUA (Hamajima et al., 2011a, 2011b; Matsuo et al., 2009; Tabara et al., 2010). Login to comment
110 The difference in the mean SUA between CC and TT was 0.08 mg/dL among males with creatinineb2 mg/dL (G1 in Table 3), which was smaller than those among SLC22A12 W258X, SLC2A9 rs11722228, ABCG2 Q126X, and Q141K. Login to comment

PMID: 22473008 [PubMed] Ichida K et al: "Decreased extra-renal urate excretion is a common cause of hyperuricemia."

No. Sentence Comment

21 We also showed that common dysfunctional genotype combinations of ABCG2 gene (Q126X (rs72552713) and Q141K) are a major cause of gout21. Login to comment
28 The risk allele frequency of Q126X (risk allele, X) and Q141K (risk allele, K), among 644 male outpatients with hyperuricemia including 575 gout cases, was 4.1 and 45.9%, respectively. Login to comment
29 Those who had Q126X and Q141K variants were 8.1 and 71.9%, respectively, of all patients (Supplementary Table S2). Login to comment
30 Subsequent haplotype frequency analysis revealed that the minor alleles of Q126X and Q141K were in different haplotypes (Supplementary Table S3), which indicated that these variants were independent risks, as reported previously21. Login to comment
31 Therefore, we could estimate urate export function of ABCG2 by the combination of two common variants, non-functional Q126X and half-functional Q141K (Supplementary Fig. S1). Login to comment
82 Estimated transport activity Genotype N Frequency of OP hyperuricemia RR 95% CI P Adjusted RR† Adjusted 95% CI† Adjusted PȂ0; Q126X (rs72552713) Q141K (rs2231142) OP hyperuricemia* Non-OP hyperuricemia* ≤1/4 Function X/X Q/Q 26 3 0.897 2.35 1.86-2.97 3.32×10 - 7 2.30 1.31-3.90 2.65×10 - 3 Q/X Q/K 1/2 Function Q/X Q/Q 96 55 0.636 1.66 1.32-2.10 8.58×10 - 6 1.79 1.25-2.59 1.55×10 - 3 Q/Q K/K 3/4 Function Q/Q Q/K 160 147 0.521 1.36 1.09-1.71 4.55×10 - 3 1.42 1.03-2.00 0.035 Full function Q/Q Q/Q 60 97 0.382 1.00 Abbreviations: CI, confidence interval; OP, overproduction; RR, risk ratio. Login to comment
143 The export function of ABCG2 was then estimated from the combinations of ABCG2 variants, rs72552713 (Q126X) and rs2231142 (Q141K), and divided into four functional groups21; that is, full function, 3/4 function (mild dysfunction), 1/2 function (moderate dysfunction) and ≤1/4 function (severe dysfunction). Login to comment
146 The wild-type human ABCG2 cDNA (GenBank accession number NM_004827) or mutated (Q126X and Q141K) ABCG2 cDNA was inserted into the Nhe I and Apa I sites of pcDNA3.1( + ) vector plasmid, with a myc-tag sequence attached at the 5'-end21. 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: 22132966 [PubMed] Matsuo H et al: "ABCG2/BCRP dysfunction as a major cause of gout."

No. Sentence Comment

11 Two relatively frequent dysfunctional variants, Q126X and Q141K, were Received 29 May 2011; accepted 17 October 2011. Login to comment
19 Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Login to comment
20 Becuase Q126X and Q141K are assigned to nonfunctional and half-functional haplotypes, respectively, their genotype combinations are divided into four functional groups. Login to 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
79 Among six mutants, ATP-dependent urate transport was reduced by approximately half (46.7%) in one mutant, Q141K, and was nearly eliminated in four mutants, Q126X, G268R, S441N, and F506SfsX4 (Figure 2B). Login to comment
85 ABCG2 Dysfunction Increases Gout Risk Additional genotyping of ABCG2 SNPs for 228 Japanese men with hyperuricemia (including 161 men with gout) served to identify Q126X homozygous (n = 2) and heterozygous (n = 24) mutations. Login to comment
86 Two patients with Q126X homozygous mutations showed very high SUA (> 10 mg/dl) before they were treated for hyperuricemia/gout. Login to comment
88 Through the association study, Q126X was revealed to increase the risk of hyperuricemia (odds ratio [OR], 3.61; 95% confidence interval [CI], 2.14-6.08; p = 2.91 × 10-7 ). Login to comment
89 Among the 161 gout patients, Q126X homozygous (n = 1) and heterozygous (n = 21) mutations were found, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; p = 3.04 × 10-8 ). Login to comment
91 Haplotype frequency analysis revealed no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype. Login to comment
92 The haplotype with Q126X markedly increased gout risk (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) compared with nonrisk haplotypes. Login to comment
94 Our data also revealed enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment
95 Thus, the Q126X mutation of the ABCG2 gene is identified as a major cause of primary gout. Login to comment
96 Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
98 Because Q126X and Q141K are assigned to different risk haplotypes, nonfunctional and half-functional, respectively, their genotype combinations are divided into four functional groups on the basis of the estimated ABCG2 transport functions, i.e., full function, 3/4 function, 1/2 function, and ≤1/4 function. Login to comment
106 We also demonstrated that nonfunctional ABCG2 variant Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. Login to comment
110 Together with P-glycoprotein 21.4% 45.3% 23.3% 10.1% 50.8% 35.6% 12.7% 0.9% other gout risks gout no function Q126X T/T Q141K C/C Full function C/C C/C 3/4 function 1/2 function C/C C/C T/C A/C A/A C/C Gout patients Normal control SUA ≤ 7.0 mg/dl 1/4 function T/C A/C 25.8-fold gout risk ≥3.02-fold gout risk (n = 865) (n = 161) FIGURE 3 ABCG2 transport dysfunction as a major gout risk. Login to comment
111 Genotype combinations of Q126X and Q141K are divided into several groups based on estimated ABCG2 transport functions. Login to comment
125 [14] Our approach (Figure 1) revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
126 Different from the rare Mendelian disorders described above, the disease haplotype carrying the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) is present in up to 13.5% of primary gout patients in our population, suggesting that Q126X is a major mutation causing gout. Login to comment
135 A meta-analysis of GWAS of European descent also showed that the nine loci, including GLUT9 and ABCG2, influence SUA,[11] which confirms the findings of Dehghan et al.[10] In this study, we identified several nonfunctional ABCG2 mutations, including Q126X, which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0). Login to comment

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

No. Sentence Comment

16 Among the variants, ATP-dependent urate transport was reduced or eliminated in five variants, and two out of the five variants (Q126X and Q141K) were frequently detected in patients. Login to comment
17 Haplotype frequency analysis revealed that there is no simultaneous presence of Q126X and Q141K in one haplotype. Login to comment
18 As Q126X and Q141K are a nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four estimated functional groups. Login to 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
52 The ATP-dependent transport of urate was reduced by approximately half (46.7%) in Q141K and was nearly eliminated in Q126X, G268R, S441N, and F506SfsX4 mutants (Figure 1B). Login to comment
54 Additional genotyping of ABCG2 SNPs was performed for 228 Japanese men with hyperuricemia (including 161 men with gout) and identified Q126X homozygous (N = 2) and heterozygous (N = 24) mutations. Login to comment
55 Two patients with Q126X homozygous mutations showed very high SUA (>10 mg/dl) before they were treated for hyperuricemia. Login to comment
56 A total of 871 TABLE 1 Association analysis of ABCG2 genotype combination in gout patients Genotype Number Estimated transport Q126X Q141K Gout Control p value OR* 95% CI* ≤1/4 function T/T C/C 16 8 3.39 × 10-21 25.8 10.3-64.6 T/C A/C - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 1/2 function T/C C/C 37 110 2.23 × 10-9 4.34 2.61-7.24 C/C A/A - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - 3/4 function C/C A/C 72 308 2.29 × 10-7 3.02 1.96-4.65 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Full function C/C C/C 34 439 1.00 *OR = odds ratio; 95% CI = 95% confidence interval. Login to comment
57 OR is obtained by comparing the non-risk genotype combination C/C (Q126X) and C/C (Q141K). Login to comment
58 Risk alleles for Q126X and Q141K are underlined. Login to comment
60 The association study showed that the risk of hyperuricemia was increased by Q126X (odds ratio [OR], 3.61; 95% confidence interval [CI], 2.14-6.08; p = 2.91 × 10-7 ). Login to comment
61 There were Q126X homozygous (N = 1) and heterozygous (N = 21) mutations among the 161 patients with gout, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; p = 3.04 × 10-8 ). Login to comment
63 The haplotype frequency analysis revealed no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype. Login to comment
64 The haplotype with Q126X was present in up to 13.5% of gout patients, and markedly increased gout risk (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) compared with non-risk haplotypes. Login to comment
65 Our data also revealed enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment
66 Thus, the Q126X mutation of the ABCG2 gene is identified as a major contributing factor in Japanese gout patients. Login to comment
67 Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
70 Because the nonfunctional variant Q126X and half-functional variant Q141K are assigned to different risk haplotypes, their genotype combinations are divided into four functional groups on the basis of the estimated ABCG2 transport functions, i.e., full function, 3/4 function, 1/2 function, and ≤1/4 function (Table 1). Login to comment
79 We also demonstrated that the nonfunctional ABCG2 variant Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. Login to comment
83 Our approach reported here revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
84 The disease haplotype with the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; p = 4.10 × 10-12 ) is present in up to 13.5% of primary gout patients in our population, suggesting that Q126X may well be a major causative mutation for gout. Login to comment
93 In our study, we also identified several nonfunctional ABCG2 mutations including Q126X which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0). Login to comment
94 [3] There is a possibility that these dysfunctional mutations, including Q126X, are specific to the Japanese or Asian population, or alternatively, there may be nonfunctional mutations in the ABCG2 gene that increase the incidence of gout in Caucasians and other groups. 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
50 [8] To clarify how ABCG2 SNPs affect function, the urate transport capacity of these variants was examined in comparison with that of wild-type ABCG2. ATP-dependent transport of urate was reduced by approximately half (46.7%) in Q141K and was nearly eliminated in Q126X (Figure 2A). Login to comment

PMID: 21816982 [PubMed] Shimizu T et al: "PDZK1 regulates breast cancer resistance protein in small intestine."

No. Sentence Comment

214 The genotype combination of two dysfunctional variants Q126X and Q141K results in increased serum uric acid concentration and increased risk of gout (Matsuo et al., 2009). 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
108 In addition to Q141K, Q126X was identified as a novel loss-of-function variant. Login to comment
109 Q126X was assigned to a different haplotype than Q141K and shown to increase gout risk (odds ratio 5.97) to an even greater extent than the Q141K variant. Login to comment
110 In addition, 10% of the gout patients studied had genotype combinations of the Q141K and Q126X variants that resulted in more than a 75% reduction of ABCG2 function compared with patients that were homozygous for the non-risk allele at both variants (odds ratio 25.8, 95% confidence interval 10.3-64.6). Login to comment

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

No. Sentence Comment

530 (2010) 6(11) 1383 Q126X, known functional variants in vitro, on the disposition of lamivudine. 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

1 Because this gene is responsible for giving rise to a protein namely the Q126X nonfunctional mutation, confers an even higher risk associated with an increase in uric acid ,ABCG2Now, a team led by Hirotaka Matsuo report that in a Japanese population, another risk variant in high-risk variant in nearly 10% of gout cases in Caucasians. Login to comment
12 Sequencing of the ABCG2 gene in 90 hyperuricemia patients revealed several nonfunctional ABCG2 mutations, including Q126X. Login to comment
14 Q126X is assigned to the different disease haplotype from Q141K and increases gout risk, conferring an odds ratio of 5.97. Login to 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
52 ATP-dependent transport of urate was reduced by approximately half (46.7%) in Q141K and was nearly eliminated in Q126X, G268R, S441N, and F506SfsX4 mutants (Fig. 2B). Login to comment
53 Western blot analysis showed that ABCG2 protein expression levels in the Q141K variant decreased by half (47.2%), whereas Q126X resulted in no protein on membrane vesicles (fig. S4). Login to comment
71 Additional genotyping and association analysis of gout Through additional genotyping of ABCG2 SNPs for 228 Japanese men with hyperuricemia (including 161 men with gout), Q126X homozygous (n = 2) and heterozygous (n = 24) mutations were identified (Table 2). Login to comment
72 Two patients with Q126X homozygous mutations showed very high SUA (>10 mg/dl)before they were treated for hyperuricemia. Login to comment
74 The association study showed that Q126X increased the risk of hyperuricemia [odds ratio (OR), 3.61; 95% confidence interval (CI), 2.14-6.08; P = 2.91 × 10-7 ]. Login to comment
75 Among the 161 patients with gout, Q126X homozygous (n = 1) and heterozygous (n = 21) mutations were found, which revealed that Q126X dramatically increased gout risk (OR, 4.25; 95% CI, 2.44-7.38; P = 3.04 × 10-8 ). 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
91 Haplotype frequency analysis revealed that there is no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype (Table 3). Login to comment
92 The haplotype with Q126X is present in up to 13.5% of gout patients, and it markedly increases gout risk (OR, 5.97; 95% CI, 3.39-10.51; P = 4.10 × 10-12 ) compared with nonrisk haplotypes. Login to comment
94 Our data also show enrichment of the Q126X minor allele in gout or hyperuricemia patients relative to normouricemic subjects (SUA ≤ 7.0 mg/dl). Login to comment
95 Thus, the Q126X mutation of the ABCG2 gene is identified as a major cause of primary gout. Login to comment
96 Together, these findings suggest that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
99 Because Q126X and Q141K are assigned to different risk haplotypes, nonfunctional and half-functional haplotype, respectively, their genotype combinations are divided into four groups on the basis of the estimated ABCG2 transport functions, that is, full function, ¾ function, ½ function, and ≤¼ function (Table 4). Login to comment
106 We also demonstrated that nonfunctional ABCG2 mutation Q126X is assigned to the identical haplotype, which increases gout risk, conferring an OR of 5.97. 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
116 Allele 1 is T and allele 2 is C in Q126X. Login to comment
120 Haplotype frequency analysis of V12M, Q126X, and Q141K. Login to comment
122 Risk alleles for Q126X and Q141K are underlined. 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
137 The approach reported here (fig. S1) revealed that nonfunctional variants of ABCG2, such as Q126X, essentially block urate excretion and cause gout. Login to comment
138 In contrast to the rare Mendelian disorders described above, the disease haplotype carrying the ABCG2 Q126X mutation (OR, 5.97; 95% CI, 3.39-10.51; P = 4.10 × 10-12 ) is present in as many as 13.5% of primary gout patients in our population, suggesting that Q126X is a major causative mutation for gout. Login to comment
144 OR is obtained by comparing with nonrisk genotype combination C/C(Q126X) and C/C(Q141K). Login to comment
145 Risk alleles for Q126X and Q141K are underlined. Login to comment
146 Estimated transport Genotype Number P value OR 95% CI Q126X Q141K Gout Control ≤¼ function T/T C/C 16 8 3.39 × 10-21 25.8 10.3-64.6 T/C A/C ½ function T/C C/C 37 110 2.23 × 10-9 4.34 2.61-7.24 C/C A/A ¾ function C/C A/C 72 308 2.29 × 10-7 3.02 1.96-4.65 Full function C/C C/C 34 439 Normal control UA ABCG2 transport Gout <UA 7.0 mg/dl 23.3% 10.1% 35.6% 12.7% 0.9% patients Gout no function Q126X T/T Q141K C/C 25% function 50% function =< T/C A/C 45.3% 50.8% 100% function 75% function 50% function C/C C/C T/C A/C A/A C/C 21.4%s 100% function C/C C/C Other gout risk G G G G G N G Fig. 3. Login to comment
148 The genotype combinations of Q126X and Q141K are divided into several groups based on estimated ABCG2 transport functions. Login to comment
149 The Q126X homozygous and heterozygous mutations were identified in up to 13.5% of total gout patients (n = 161). Login to comment
156 In this study, we identified several nonfunctional ABCG2 mutations, including Q126X, in Japanese gout patients, which shows stronger effects on gout development than Q141K did in a previous study (OR < 2.0) (22). Login to comment
157 There is a possibility that these nonfunctional mutations, including Q126X, are specific to a Japanese or Asian population, or alternatively, there may be nonfunctional mutations in the ABCG2 gene that cause gout in Caucasians and other groups. 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: 23307580 [PubMed] George RL et al: "Genetics of hyperuricemia and gout: implications for the present and future."

No. Sentence Comment

129 The investigators found that common dysfunctional genotype combinations of ABCG2 gene (variants, Q126X and Q141K) are a major cause of gout [48]. Login to comment
135 The relationship between overproduction, hyperuricemia, and ABCG2 dysfunction led the authors to propose a new, testable model of hyperuricemia that takes into account population genotypes such as Q126X and Q141K affecting ABCG2 function. Login to comment

PMID: 23544272 [PubMed] Hinohara Y et al: "No association between MTHFR C677T and serum uric acid levels among Japanese with ABCG2 126QQ and SLC22A12 258WW."

No. Sentence Comment

5 This study examined the association with the polymorphism, taking into account the genotypes of ABCG2 Q126X and SLC22A12 W258X. Login to comment
11 The present study indicated no association between SUA and MTHFR C677T genotype, after the influences of ABCG2 Q126X and SLC22A12 W258X were removed. Login to comment
12 Key Words: Serum uric acid, Urate transporter polymorphisms, MTHFR C677T INTRODUCTION It is well known that serum uric acid (SUA) levels are associated with various factors such as sex, age, body mass index (BMI), dietary habit and drinking habit.1-3) In addition, there is evidence that genetic traits influence SUA concentrations; the heritability was estimated to be up to 73%.4) A recent genome-wide association study performed in Japan showed strong associations of SUA with genetic polymorphisms of SLC22A12 coding uric acid transporter 1 (URAT1), Received: January 13, 2013; accepted: January 24, 2013 Corresponding author: Yukako Hinohara MD, MPH Department of Preventive Medicine, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan Phone: +81 52 744 2132, Fax: +81 52 744 2971, E-mail address: y.hinohara@soumu.go.jp SLC2A9 coding glucose transporter 9 (GLUT9), and ABCG2 coding ATP-binding cassette subfamily G member 2 (ABCG2),5) which were also reported to have associations in European ancestry.6) Among the polymorphisms, SLC22A12 W258X,7,8) SLC2A9 R380W and R198C,9) and ABCG2 Q126X and Q141K10,11) were confirmed to have associations with SUA, although the association of ABCG2 Q141K was relatively weak. Login to comment
14 Although not detected in the genome-wide association study, methylenetetrahydrofolate reductase (MTHFR) C677T was reported to have associations with SUA.12-14) A recent meta-analysis on the association with six studies (two from Iran, two from China, one from Korea, and one from Japan) demonstrated that the summary odds ratio (OR) was 1.879 (95% confidence interval (CI), 1.596-2.213).15) The present study investigated the association of MTHFR C677T with SUA levels among Japanese health checkup examinees, after taking into account the genotypes of SLC22A12 W258X and ABCG2 Q126X. Login to comment
62 A systematic review showed that the ethnicity may affect the relationship between the MTHFR mutation and SUA levels.33) In conclusion, though some limitations remain, the present study indicated no association between SUA and MTHFR C677T genotype among Japanese, after the influences of ABCG2 Q126X and SLC22A12 W258X were removed. 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: 23774753 [PubMed] Matsuo H et al: "Common dysfunctional variants in ABCG2 are a major cause of early-onset gout."

No. Sentence Comment

17 We also showed that genotyping of only two dysfunctional variants, Q126X (rs72552713) and Q141K (rs2231142), is sufficient to estimate the severity of ABCG2 dysfunction; i.e. full function, 3/4 function (mild dysfunction), 1/2 function (moderate dysfunction), and # 1/4 function (severe dysfunction). Login to comment
39 Table 1 | ABCG2 functions of participants Estimated Function Genotype Combination Number (%) Q126X* (rs72552713) Q141K* (rs2231142) Gout Control #1/4 function T/T C/C 37 (5.2) 22 (1.2) T/C C/A 1/2 function T/C C/C 169 (24.0) 219 (11.6) C/C A/A 3/4 function C/C C/A 331 (47.0) 699 (37.0) Full function C/C C/C 168 (23.8) 947 (50.2) Total 705 (100.0) 1,887 (100.0) * Risk alleles (T for Q126X, A for Q141K) are indicated in bold type at four locations, respectively. Login to comment
73 Genotyping of Q126X (rs72552713) and Q141K (rs2231142) in ABCG2 gene by high-resolution melting (HRM) analysis was performed with a LightCycler 480 (Roche Diagnostics)41 . Login to comment

PMID: 24441388 [PubMed] Matsuo H et al: "ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload."

No. Sentence Comment

17 Their functional ABCG2 activities were estimated from their genotype combinations of its two dysfunctional missense variants, Q126X (rs72552713) and Q141K (rs2231142). Login to comment
18 Because there is no simultaneous presence of the minor alleles of non-functional variant Q126X and half-functional variant Q141K in one hap- lotype5,7 , we defined three haplotype IDs as *1, *2, and *3, as shown in Figure 1a. Login to comment
24 Furthermore, Q126X homozygote signifying complete deficiency of ABCG2 was identified in one case with gout in the ROL hyperuricemia group. Login to comment
26 When hyperuricemia was divided into three distinct types (i.e., RUE type, combined type, and ROL type as shown in Supplementary Fig. S1), severe ABCG2 dysfunction (#1/4 function) significantly raised the risk of combined and ROL types but not that of RUE type Figure 1 | Estimation of ABCG2 function from diplotype of Q126X and Q141K alleles. Login to comment
27 (a) ABCG2*2 or *3 represents a haplotype with Q141K or Q126X variant, respectively. Login to comment
28 ABCG2*1 indicates a haplotype with neither Q141K nor Q126X variant. Login to comment
29 Since Q141K is a half-functional variant and Q126X is a nonfunctional variant, relative function of ABCG2*1, *2, and *3 is 1, 1/2, and 0, respectively, which is visualized by black-indicated areas. Login to comment
32 Table 1 | ABCG2 functions of participants Estimated transport activity Diplotype of Q126X (rs72552713) and Q141K (rs2231142) alleles** Case{ Control N % N % #1/4 function *3/*3 or *2/*3 29 (26) 4.5 (4.7) 22 1.3 1/2 function *1/*3 or *2/*2 151 (135) 23.4 (23.5) 190 11.7 3/4 function *1/*2 307 (277) 47.7 (48.2) 600 37.0 Full function *1/*1 157 (136) 24.4 (23.7) 811 50.0 Total 644 (575) 100.0 (100.0) 1,887 100.0 **Haplotypes ''Q-Q``, ''Q-K``, and ''X-Q`` of two SNPs (Q126X and Q141K) are referred to as *1, *2, and *3, respectively. Login to comment
33 Risk alleles are X for Q126X, and K for Q141K. Login to comment
67 Genotyping of ABCG2 Q126X (rs72552713) and Q141K (rs2231142) was performed by high-resolution melting analysis with a LightCycler 480 (Roche Diagnostics)19 . Login to comment
68 From the haplotype analyses reported in the previous studies5,7 , there is no simultaneous presence of the minor alleles (risk alleles) of non-functional variant Q126X and half-functional variant Q141K in one haplotype. Login to comment
69 In this study, their haplotype IDs, *1, *2, and *3, were defined as Figure 1a; the combination of wild-type Q126X and Q141K alleles (''Q-Q``) was designated as ABCG2*1, which corresponds to the cDNA sequence of GenBank (accession number NM_004827). Login to comment
71 Based on the diplotype of Q126X and Q141K alleles (Fig. 1b)5,7 , ABCG2 function was estimated and divided into four groups5-7 ; i.e., full function, 3/4 function, 1/2 function, and #1/4 function (Table 1). Login to comment

PMID: 24476385 [PubMed] Dalbeth N et al: "Influence of the ABCG2 gout risk 141 K allele on urate metabolism during a fructose challenge."

No. Sentence Comment

54 The Q126X SNP rs72552713 was also genotyped using the Taqman assay as described above (the context sequence for rs72552713 (assay ID C__98388180_20) is [VIC/ FAM] AATGCAAACCCACTAATACTTACTT[G/A]TAC CACGTAACCTGAATTACATTTG). 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

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
7 A prediction model for gout risk using ABCG2 protein function was established based on the genotype combination of Q126X and Q141K. Login to comment
9 Regarding Q126X, the T allele frequency was 4.7% in the gout patients and 1.7% in the controls (OR 2.91, 95% CI: 1.49-5.68, p = 1.57 &#d7; 10-3 ). 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
33 Furthermore, the SNPs Q141K and Q126X in the human ABCG2 gene have recently been recognized as clinical biomarkers to assess hyperuricemia and gout. 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
44 Regarding Q126X, the T allele was found on 4.7% of the chromosomes from the gout patients compared with 1.7% of the chromosomes from the controls (OR 2.91, 95% CI: 1.49-5.68, p = 1.57 &#d7; 10-3 ). 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
55 Allele 1 is A and allele 2 is C in Q141K. Allele 1 is T and allele 2 is C in Q126X. 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
74 Estimated Function Genotype Combination Number (%) p-Value OR 95% CI Q141K Q126X Gout Control ࣘ1/4 function C/A T/C 22 (6.2) 8 (2.3) 8.47 &#d7; 10-6 5.90 2.56-13.58 1/2 function C/C T/C 95 (27.0) 37 (10.5) 1.12 &#d7; 10-13 5.51 3.46-8.77 A/A C/C 3/4 function C/A C/C 159 (45.2) 142 (40.6) 1.00 &#d7; 10-6 2.40 1.69-3.42 Full function C/C C/C 76 (21.6) 163 (46.6) ߟ ߟ p-Value, OR and 95% CI for each ABCG2 dysfunction were obtained via comparisons with full function. 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
91 The other nonfunctional variant, Q126X, is consistently observed in certain Japanese and Korean cohorts [18,32]. Login to comment
93 These findings reflect the diversity of the Q126X and Q141K distributions in different ethnic populations, which may explain the different prevalence of gout in Chinese and Caucasian populations. Login to comment
94 Among the 352 patients with gout, Q126X heterozygous (n = 33) mutations were found that revealed that non-functional 126X dramatically increased gout risk (OR 2.91). Login to comment
96 Matsuo et al. [16,18] reported that the genotype combination of Q126X and Q141K is a clinically important biomarker for predicting gout risk in the Japanese population. We analyzed the relationship between ABCG2 transport dysfunction and gout and found that dysfunctional ABCG2 is responsible for approximately 78.4% of gout cases. 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
137 The recent findings on the roles of the ABCG2 Q141K and Q126X polymorphism in gout may pave the way for pharmacological chaperones targeting ABCG2 as a potential new therapeutic target for gout. Login to comment

PMID: 24909660 [PubMed] Nakayama A et al: "Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors."

No. Sentence Comment

18 Based on the previous studies8,11 , all of the participants were divided into four groups by the combination of common dysfunctional variants of ABCG2, non-functional Q126X (rs72552713) and half-functional Q141K (rs2231142), as follows: full function (normal function), 3/ 4 function (mild dysfunction), 1/2 function (moderate dysfunction) and #1/4 function (severe dysfunction) (see Supplementary Figure S1 and Table S2). Login to comment
36 We also found that ABCG2 has two common dysfunctional variants: a nonsense variant Q126X and a missense variant Q141K8 . Login to comment
37 Functional analyses revealed that Q126X is a nonfunctional variant and Q141K is a half-functional variant due to the halved ABCG2 expression on the membrane8 . Login to comment
38 Since haplotype frequency analyses demonstrated no simultaneous presence of the minor alleles of Q126X and Q141K in one haplotype, the combination of nonfunctional variant Q126X and half-functional variant Q141K makes it possible to estimate dysfunctional levels of ABCG28,10 (Supplementary Figure S1 and Table S2). Login to comment
46 Ours is the first report to show the PAR% of ABCG2 dysfunction using the combination of Q126X and Q141K for functional evaluation. Login to comment
49 In the present study, we defined hyperuricemia as SUA .7.0 mg/dl17 and obtained the PAR% of Q141K and Q126X as 23.5% and 2.6%, respectively. Login to comment
52 Subsequent regression analysis revealed that ABCG2 dysfunction defined by the combination of Q126X and Q141K significantly increased SUA, while previous studies showed the association of SUA and only Q141K7,8 . Login to comment
76 Genotyping of the two variants in ABCG2 gene, Q126X and Q141K, was performed with a LightCycler 480 (Roche Diagnostics) by high resolution melting (HRM) analysis22 . Login to comment
79 The MAFs of Q126X and Q141K were 0.025 and 0.294, respectively, and both variants were in Hardy-Weinberg equilibrium (P . 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: 25741042 [PubMed] Suma S et al: "ASSOCIATIONS BETWEEN BODY MASS INDEX AND SERUM URIC ACID LEVELS IN A JAPANESE POPULATION WERE SIGNIFICANTLY MODIFIED BY LRP2 rs2544390."

No. Sentence Comment

17 Polymorphisms ABCG2 Q126X (rs72552713) and Q141K (rs2231142) have been shown to influence the risk of hyperuricemia through reduction of the uric acid transportation activity.16-18) Our previous studies have confirmed the associations with these polymorphisms,16,19,20) and we observed an interaction with alcohol consumption on SUA in our investigation of the LRP2 intron 1 polymorphism rs2544390.21) Because obesity is an important factor that determines SUA,6) the present study aimed to investigate the interaction between LRP2 rs2544390 and BMI on SUA levels using the same dataset as our previous work. Login to comment

PMID: 26119820 [PubMed] Ogura J et al: "Reactive oxygen species derived from xanthine oxidase interrupt dimerization of breast cancer resistance protein, resulting in suppression of uric acid excretion to the intestinal lumen."

No. Sentence Comment

254 BCRP mutations, such as partially functional mutation Q126K and nonfunctional mutation Q126X, markedly increase gout risk [12,13], indicating that BCRP dysfunction affects serum uric acid level. Login to comment

PMID: 26136557 [PubMed] Woodward OM et al: "ABCG2: the molecular mechanisms of urate secretion and gout."

No. Sentence Comment

42 Matsuo et al. compared gouty and normal cohorts of Japanese males and found two ABCG2 mutations, Q141K (50% function) and Q126X (no function), and used these to correlate ABCG2 function with age of gout onset. Login to comment

PMID: 26506822 [PubMed] Jiri M et al: "Genetic variation in the ABCG2 gene is associated with gout risk in the Chinese Han population."

No. Sentence Comment

74 ABCG2 is a high-capacity urate transporter which physiologically excretes urate Fig. 1 Haplotype block map for ABCG2 SNPs Table 3 ABCG2 haplotype frequencies and their association with gout (adjust by age and sex) Gene(s) Haplotype Frequency OR (95 % CI) p value ABCG2 GCCTAGT 0.2868 1 - GGCTCTC 0.2092 0.46 (0.28-0.75) 0.0019 AGACCTC 0.2014 0.71 (0.45-1.12) 0.14 GCCTCTC 0.0735 1.10 (0.57-2.13) 0.78 GGACCTC 0.0669 0.57 (0.27-1.18) 0.13 GCCTATC 0.0582 1.53 (0.75-3.14) 0.24 GGCTAGT 0.0378 0.37 (0.12-1.16) 0.09 GCCTAGC 0.0124 0.80 (0.19-3.46) 0.77 GCCTAGT 0.0538 0.47 (0.19-.13) 0.092 p value<0.05 indicates statistical significance OR odds ratio, CI confidence interval for the regulation of SUA. ABCG2 has the following two common dysfunctional variants: a non-sense variant Q126X and a missense variant Q141K [19, 22]. Login to comment

PMID: 26617691 [PubMed] Li R et al: "A meta-analysis of the associations between the Q141K and Q126X ABCG2 gene variants and gout risk."

No. Sentence Comment

3 ABCG2 is a urate transporter, and the Q141K and Q126X variants of ABCG2 have been associated with a risk of developing gout, though previous studies of these associations have been inconsistent. Login to comment
5 In total, 9 eligible articles on the associations between the Q141K (rs2231142) and Q126X (rs72552713) variants and gout risk, including 11 case-control studies were selected. Login to comment
9 The Q126X variant also significantly increased the risk of gout in Asians (dominant model: OR=3.87, 95% CI=2.07-7.24, P=0.06 for heterogeneity). Login to comment
12 Keywords: Gout, Q141K, Q126X, single nucleotide polymorphism, meta-analysis Introduction Gout is a recurrent relapsing inflammatory disease, caused by the precipitation of monosodium urate (MSU) crystals in the joints and soft tissues. Login to comment
26 Among these, Q141K and Q126X are the most commonly studied. Login to comment
29 SNP rs72552713, also referred to as C376T or Q126X in ABCG2, has also been shown to play a role in gout. Login to comment
33 The literature search was performed in English and Chinese using the following primary key words: gout, ABCG2, C421A, Q141K, rs2231142, C376T, Q126X, and rs72552713. Login to comment
38 Characteristics of the included studies (Q126X) First author (Ref.) Year Ethnicity/ country Diagnostic standard Study design Sample size (case/control) HWE p-value Genotype distribution (case/control) Genotype frequency (case/control) CC CT TT CC (%) CT (%) TT (%) Zhang Xin-Lei [28] 2014 Asians China ACR preliminary diagnostic criteria for acute gout (1977) Case-control 136/321 Yes 127/320 9/1 0/0 93.4/99.7 6.6/0.3 0/0 Danqiu Zhou [36] 2014 Asians China ACR preliminary diagnostic criteria for acute gout (1977) Case-control 352/350 Yes 319/338 33/12 0/0 90.6/96.6 9.4/3.4 0/0 The following index terms were used: gout and ABCG2, gout and C421A, gout and Q141K, gout and rs2231142, gout and C376T, gout and Q126X, and gout and rs72552713. Login to comment
53 Each relationship was assessed in a dominant model (Q141K: CC compared to AC+AA; Q126X: CC compared to CT+TT), a recessive model (Q141K: AA compared to CC+AC), and a co-dominant model (Q141K: AC compared to CC+AA). Login to comment
66 All of these 9 studies involved the Q141K variant, and only 2 studies referred to the Q126X variant. Login to comment
72 We extracted the characteristics of these studies, which are summarized in Tables 1, 2 of Article 9 on the Q126X variant. Login to comment
75 Subgroup analysis by ethnicity also revealed significant associations for both Asians (dominant model: OR=2.64, 95% CI=2.043.43, P=0.02 for heterogeneity; recessive model: OR=3.19, 95% CI=2.56-3.97, P=0.28 for heterogeneity; co-dominant model: OR=1.37, 95% CI=1.181.59, P=0.09 for heterogeneity) and other populations (dominant model: OR=1.85, Figure 6. Forest plot for the association between the Q126X variant and gout risk using the dominant model (CT+TT compared to CC). Login to comment
87 Among the ABCG2 polymorphisms, Q141K and Q126X are the most commonly studied. Login to comment
88 Nevertheless, the role of the Q141K variant in gout risk and the potential for the Q126X variant to increase gout risk are controversial. Login to comment
92 Until now, there has been no meta-analysis demonstrating the role of Q126X in gout. Login to comment
95 Our results suggested that the Q141K variant results in increased gout risk in dominant, recessive, and co-dominant models, and in subgroup analyses, Q126X also increased gout risk in a dominant model. Login to comment
118 Our evidence revealed that Q141K and Q126X are risk factors for the development of gout. Login to comment