ABCMdb

ABCB1 p.Asn21Asp

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Publications

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

No. Sentence Comment

90 A detailed analysis of the potential functional consequences of different ABCB1 variants has not yet been performed, except for the five most common non-synonymous coding SNPs (i.e., Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser/Thr, and Ala998Thr) as assessed by a vaccinia virus-based transient expression system [74]. Login to comment
106 Nonetheless, the association of the C3435T polymorphism with Table 2. Summary of common genetic variants in the ABCB1 gene cDNA position* Region‡ Wild-type allele Variant allele Amino acid Change§ -274 Intron -1 G A -223 Intron -1 C T -146 Intron -1 T C -60 Intron -1 A T -41 Intron -1 A G Non-coding -241 Exon 1 G A Non-coding -145 Exon 1 C G Non-coding -129 Exon 1 T C Non-coding -43 Exon 1 A G Non-coding +140 Intron 1 C A +237 Intron 1 G A -4 Exon 2 C T Non-coding -1 Exon 2 G A Non-coding 61 Exon 2 A G 21 Asn to Asp -8 Intron 3 C G 266 Exon 4 T C 89 Met to Thr 307 Exon 5 T C 103 Phe to Leu -25 Intron 4 G T +139 Intron 6 C T +145 Intron 6 C T 548 Exon 7 A G 183 Asn to Ser 729 Exon 8 A G 243 Syn 781 Exon 8 A G 261 Ile to Val -44 Intron 9 A G -41 Intron 10 T G 1199 Exon 11 G A 400 Ser to Asn -4 Intron 11 G A 1236¶ Exon 12 C T 412 Syn 1308 Exon 12 A G 436 Syn +17 Intron 12 G A +44 Intron 12 C T 1474 Exon 13 C T 492 Arg to Cys +24 Intron 13 C T 1617 Exon 14 C T 539 Syn +38 Intron 14 A G +38 Intron 15 G A 1985 Exon 16 T G 662 Leu to Arg 2005 Exon 16 C T 669 Arg to Cys -27 Intron 17 A G +8 Intron 20 C G *cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number M14758 with an A as the reference at position 43. 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

94 Kimchi-Sarfaty et al. [73] assessed the five most common coding SNPs (i.e., N21D, F103L, S400N, A893S and A999T) by using a vaccinia virus-based transient expression system. Login to comment
106 Position Allele Amino acid Allele frequency in Caucasian populations Allele frequency in Japanese populatins Allele frequency in African populations n % n % n % 61 A G 21 Asn 21 Asp 799 89.7 10.3 193 100 0 100 97.5 2.5 266 T C 89 Met 89 Thr 100 99.5 0.5 145 100 0 100 100 0 307 T C 103 Phe 103 Leu 546 99.9 0.1 48 100 0 ND ND ND 325 G A 108 Glu 108 Lys ND ND ND 37 95.9 4.1 ND ND ND 781 A G 261 Ile 261 Val 100 100 0 145 100 0 100 98.5 1.5 1199 G A 400 Ser 400 Asn 696 95.0 5.0 193 100 0 100 99 1 1985 T G 662 Leu 662 Arg 100 99.5 0.5 145 100 0 100 100 0 2005 C T 669 Arg 669 Cys 100 100 0 145 100 0 100 99 1 2485 A G 829 Ile 829 Val 185 99.2 0.8 ND ND ND ND ND ND 2547 A G 849 Ile 849 Met 100 99.5 0.5 145 100 0 100 100 0 2677 G T A 893 Ala 893 Ser 893 Thr 611 55.1 42.1 2.8 241 40.0 41.1 18.9 100 90 10 0.5 2956 A G 986 Met 986 Val ND ND ND 100 99.5 0.5 ND ND ND 3151 C G 1051 Pro 1051 Ala 100 100 0 145 100 0 100 99.5 0.5 3320 A C 1107 Gln 1107 Pro 461 99.8 0.2 ND ND ND ND ND ND 3322 T C 1108 Trp 1108 Arg 100 100 0 145 100 0 100 99.5 0.5 3421 T A 1141 Ser 1141 Thr 100 100 0 145 100 0 100 88.9 11.1 3751 G A 1251 Val 1251 Ile 100 100 0 145 99 1 100 100 0 3767 C A 1256 Thr 1256 Lys 100 99.5 0.5 145 100 0 100 100 0 Data from [31-38, 203]. Login to comment
129 N21D M89T N44S H2N F103L E108K N183S G185V I261V S400N R492C A599T L662R R669C V801M A893S/T I829V I849M M986V A999T G1063A P1051A Q1107P W1108R I1145M S1141T V1251I T1256K COOH ATP-binding site ATP-binding site EXTRACELLULAR INTRACELLULAR A80E Figure 2. 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

761 0.09d c. 61 A>G N21D 0.11d IVS 5-35 G>C intronic 0.006c IVS 5-25 G>T intronic 0.16c IVS 6+139 C>T intronic 0.37d c. 548 A>G N183S 0.01e c. 1199 G>A S400N 0.05d c. 1236 C>T synonymous 0.41d IVS 12+44 C>T intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17-76 T>A intronic 0.46d IVS 17+137 A>G intronic 0.006c c. 2650 C>T synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T synonymous 0.54e c. 4030 G >C synonymous 0.005b c. 4036 A>G synonymous 0.30b a Taniguchi et al. (2003). Login to comment

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

No. Sentence Comment

487 Exon 2 contains a polymorphism that changes Asn21 to Asp, and the mutation at exon 5 changes Phe103 to Leu. Login to comment
532 Nucleotide change rs number Amino acid change 49T>C rs28381804 F17L 61A>G rs61615398; rs9282564 N21D 131A>G rs1202183 N44S 178A>C rs41315618 I60L 239C>A rs9282565 A80E 266T>C Rs35810889 M89T 431T>C rs61607171 I144T 502G>A rs61122623 V168I 548A>G rs60419673 N183S 554G>T rs1128501 G185V 781A>G rs36008564 I261V 1199G>A rs2229109 S400N 1696G>A rs28381902 E566K 1777C>T rs28381914 R593C 1778G>A rs56107566 R593H 1795G>A rs2235036 A599T 1837G>T rs57001392 D613Y 1985T>G rs61762047 L662R 2005C>T rs35023033 R669C 2207A>T rs41316450 I736K 2398G>A rs41305517 D800N 2401G>A rs2235039 V801M 2485A>G rs2032581 I829V 2506A>G rs28381967 I836V 2547A>G rs36105130 I849M 2677T>A/G rs2032582 S893A/T 2975G>A rs56849127 S992N 3151C>G rs28401798 P1051A 3188G>C rs2707944 G1063A 3262G>A rs57521326 D1088N 3295A>G rs41309225 K1099E 3320A>C rs55852620 Q1107P 3322T>C rs35730308 W1108R 3410G>T rs41309228 S1137I 3421T>A rs2229107 S1141T 3502A>G rs59241388 K1168E 3669A>T rs41309231 E1223D 3751G>A rs28364274 V1251I 3767C>A r35721439 T1256K Data are from NCBI dbSNP (access date: 2 August 2008). Login to comment

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

No. Sentence Comment

229 [113], who showed that HeLa cells transfected with either the wild-type or the ABCB1 polymorphisms A61G (N21D), T307C (F103L), G1199A (S400N), G2677T (A893S) and G2995A (A998T) expressed the transporter at the cell surface. Login to comment
230 Additionally, cells transfected with double mutants (N21D-S400N, N21D-A893S, and S400N-A893S) revealed similar ABCB1 cell surface expression [113]. Login to comment

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

No. Sentence Comment

52 Functional Significance of ABCB1 SNPs Table6.3 Frequency of ABCB1 genetic variants in Caucasians, position on DNA, putative effect, and frequencies (134) Position Amino acid or effect Frequency of the variant allele 5'-Flanking -2903 T>C 0.02a 5'-Flanking -2410 T>C 0.10a 5'-Flanking -2352 G>A 0.28a 5'-Flanking -1910 T>C 0.10a 5'-Flanking -1717 T>C 0.02a 5'-Flanking -1325 A>G 0.02a 5'-Flanking -934 A>G 0.10a 5'-Flanking -692 T>C 0.10a 5'-Flanking -41 A>G 0.09b IVS 1a -145 C>G 0.02b IVS 1b -129 T>C 0.06b IVS 1b 12 T>C 0.06c IVS 2 -1 G>A 0.09d c. 61 A>G N21D 0.11d IVS 5 -35 G>C Intronic 0.006c IVS 5 -25 G>T Intronic 0.16c IVS 6 +139 C>T Intronic 0.37d c. 548 A>G N183S 0.01e c. 1199 G>A S400N 0.05d c. 1236 C>T Synonymous 0.41d IVS 12 +44 C>T Intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17 -76 T>A Intronic 0.46d IVS 17 +137 A>G Intronic 0.006c c. 2650 C>T Synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T Synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T Synonymous 0.54d c. 4030 Synonymous 0.005b c. 4036 Synonymous 0.30b References: a [42], b [26], c [25], d [28], e [23] with lower activity or expression in Caucasians. Login to comment

PMID: 11258197 [PubMed] Kerb R et al: "ABC drug transporters: hereditary polymorphisms and pharmacological impact in MDR1, MRP1 and MRP2."

No. Sentence Comment

97 SNP Region N Frequency of SNPs (%) Effect Heterozygous Homozygous Observed Estimated T-12C E1 85 11.8 0 0.4 Non-coding G-1A E2 188 11.2 0 0.4 TL initiation A61G E2 188 17.6 0.5 0.81 Asn21Asp G-25T I4 85 26 3.5 2.3 G-35C I4 85 1.2 0 0.01 # T307C E5 85 1.2 0 0.01 Phe103Leu C+139T I5 85 48.2 16.5 16.8 C+145T I5 85 2.4 0 0.01 G1199A E11 85 12.9 0 0.4 Ser400Asn C1236T E12 188 48.9 13.3 14.4 Gly412Gly # C+44T I12 188 11.7 0 0.4 T-76A I16 85 45.9 22.4 20.3 A+137G I17 85 1.2 0 0.01 G2677T E21 83b 43.4 42.2 38.4 Ala893Ser G2995A E24 36b 11.1 38.4 Ala999Thr C3435T E26 537 47.7 26.4 24.1 Ile1145Ile C3396T E26 188 0.53 0 0.01 Wobble § MDR1 sequences gb:AC002457 and AC005068 are defined as 'wild type`. Login to comment
106 A61G leads to the replacement of Asn by Asp at position 21 resulting in a net charge change (basic to acidic) close to the N-terminus of PGP. Login to comment

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

No. Sentence Comment

101 or Ref sequence; locus Frequencies Fold-increase of nelfinavir AUCintracell Significance AA Aa aa Aa2 AA Aa aa Aa2 chi-squared P-value ABCB1 IVS 1 - 80delG rs3214119 27 1 1 1.0 0.03 0.85 c.61A > G (N21D) rs9282564 26 2 1 2.5 3.85 0.05 TAG1 rs3789243 7 17 3 1 0.8 0.6 1.23 0.54 c.1199G > A (S400N) rs2229109 24 2 1 0.9 0.62 0.43 TAG5 rs1128503 4 18 5 1 0.8 1.3 3.33 0.19 TAG6 rs2235046 6 18 3 1 0.6 0.7 4.43 0.11 c.2677G > T (A893S) rs2032582 4 17 5 1 1 1.0 1.7 1.2 6.42 0.09 IVS 21 + 49T > C rs2032583 19 8 1 0.6 3.45 0.06 TAG8, 3435C > T rs1045642 4 18 6 1 1.4 2.1 6.35 0.04 IVS 26 + 59T > G rs2235047 24 2 1 1.0 0.02 0.89 IVS 26 + 80T > C rs2235048 3 17 6 1 1.3 2.4 7.09 0.03 TAG11 rs1186746 16 10 1 1 1.1 0.3 2.46 0.29 TAG12 rs1186745 17 9 1 1 0.7 1.0 0.33 0.85 ABCC1 c.816G > A NM_004996; c.1012G > A 27 1 1 1.5 1.05 0.30 c.825T > C rs246221 13 11 3 1 1.5 0.7 3.99 0.14 c.1062T > C rs35587 13 11 3 1 1.5 0.7 3.02 0.22 IVS 9 + 8A > G rs35588 13 11 3 1 1.5 0.7 3.02 0.22 IVS 10 + 64C > T NC_000016; g.98791C > T 23 3 1 0.4 1.97 0.16 ABCC2 g. Login to comment
69 - 4 C > T exon 2 (50 UTR) Epidauros md-v-177 c.61A > G exon 2 p.N21D Hoffmeyer et al., 2000 md-v-017 rs9282564 IVS 2 + 23 T > C intron 2 Epidauros md-v-057 Tag 1 intron 3 Soranzo et al., 2004 rs3789243 IVS 11 - 40 T > G intron 10 Epidauros md-v-078 rs2235029 c.1137 C > G exon 11 p.P373A Epidauros md-v-079 c.1149 C > T exon 11 synonymous (p.H383H) Epidauros md-v-080 c.1199G > A exon 11 p.S400N Hoffmeyer et al., 2000 md-v-025 rs2229109 IVS11 + 48 T > A intron 11 Epidauros md-v-081 Tag 5 exon 12 Soranzo et al., 2004 rs1128503 Tag 6 intron 16 Soranzo et al., 2004 rs2235046 IVS 21 - 78 G > A intron 20 Epidauros md-v-228 IVS 21 - 43 A > T intron 20 Epidauros md-v-160 c.2547A > G exon 21 p.I849M Kroetz et al., 2003 md-v-222 c. Login to comment
94 We detected an association with phenotype for three loci: ABCB1_61A > G (N21D) (w2 = 3.85, 1 d.f., P = 0.05), median cellular AUCAG > AUCAA (ratio 2.5, 1), ABCB1_3435C > T (w2 = 6.34, 2 d.f., Kruskal-Wallis P = 0.04, Spearman rank test Ptrend = 0.01); median cellular AUCTT > AUCCT > AUCCC (ratio 2.1, 1.4, 1), and ABCB1_ IVS26 + 80T > C (w2 = 7.09, 2 d.f., P = 0.03, Ptrend = 0.006); median cellular AUCCC >AUCCT >AUCTT (ratio 2.4, 1.3, 1). Login to comment
114 Since the only change differentiating haplotype 16 from 20 is at 61A > G (N21D), this may also suggest an effect, separate from the main effect observed at 3435C > T, for 61A > G (N21D). Login to comment
115 We pursued further the apparent association between the ABCB1_61A > G (N21D), ABCB1 3435C > T and IVS26 + 80T > C variant and drug AUC phenotype by testing this association also in a larger number of individuals (n = 129) receiving nelfinavir, and for which plasma AUC phenotypes were available. Login to comment
138 A second variant, ABCB1_61A > G, resulting in a N21D substitution reported to modify the kinetic parameters of P-glycoprotein in vitro [13], was associated with increased cellular nelfinavir exposure in the present study. Login to comment

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

No. Sentence Comment

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

PMID: 11240981 [PubMed] Cascorbi I et al: "Frequency of single nucleotide polymorphisms in the P-glycoprotein drug transporter MDR1 gene in white subjects."

No. Sentence Comment

5 Results: Five amino acid exchanges were found with allelic frequencies of 11.2% for Asn21Asp and 5.5% for Ser400Asn. Login to comment
53 A61G in exon 2,14 which resulted in an Asn21Asp exchange, occurred with an allele frequency of 11.2%; therefore only 4 individuals were homozygous carriers. Login to comment

PMID: 12011154 [PubMed] Potocnik U et al: "Naturally occurring mutations and functional polymorphisms in multidrug resistance 1 gene: correlation with microsatellite instability and lymphoid infiltration in colorectal cancers."

No. Sentence Comment

264 To the best of our knowledge, this Table 2 Correlation between MDR1 polymorphisms and increased lymphoid infiltration in tumours Exon Genotype (polymorphism) Amino acid change No (%) of tumours with specific genotype (polymorphism)/No of tumours analysed No (%) of tumours with specific genotype (polymorphism) and lymphoid infiltration p* Promoter †Promoter +8 T/T 313/327 (96%) 152/313 (49%) Promoter Promoter +8 T/C Non-coding 14/327 (4%) 9/14 (64%) 0.036 Intron 1b IVS1-81 (G)4 311/327 (95%) 149/311 (48%) Intron 1b IVS1-81 (G)4/(G)3 Non-coding 16/327 (5%) 12/16 (75%) 0.010 Intron 1b ‡IVS-1 G/G 271/317 (85%) 127/271 (47%) Intron 1b IVS-1 G/A 45/317 (14%) 27/45(60%) NS Intron 1b IVS-1 A/A Non-coding 1/317 (<1%) 1/1 (100%) NS 2 ‡61 A/A 266/321 (83%) 125/266 (47%) 2 61 A/G Asn21Asp 51/321 (16%) 29/51 (57%) NS 2 61 G/G 4/321 (1%) 2/4 (50%) NS Intron 4 ‡IVS4-25 G/G 44/63 (70%) 19/44 (43%) Intron 4 IVS4-25 G/T Non-coding 15/63 (24%) 7/15 (47%) NS Intron 4 IVS4-25 T/T 4/63 (6%) 2/4 (50%) NS 11 1199 G/G 307/327 (94%) 152/307 (50%) 11 1199 G/A Ser400Asn 20/327 (6%) 11/20 (55%) NS 12 ‡1236 C/C 81/327 (25%) 39/81 (48%) 12 1236 C/T No change 163/327 (50%) 80/163 (49%) NS 12 1236 T/T 83/327 (25%) 42/83 (51%) NS Intron 16 IVS16+158 G/G 82/87 (94%) 41/82 (50%) Intron 16 IVS16+158 G/A Non-coding 5/87 (6%) 3/5 (60%) NS 21 §2677 G/G 14/41 (34%) 7/14 (50%) 21 2677 G/T Ala893Ser 17/41 (41%) 7/17 (41%) NS 21 2677 T/T 10/41 (24%) 4 /10 (40%) NS 26 ‡3435 C/C 44/159 (28%) 18/44 (41%) 26 3435 C/T No change 85/159 (53%) 46/85 (54%) NS 26 3435 T/T 30/159 (19%) 15/30 (50%) NS NS=not significant. Login to comment

PMID: 12065748 [PubMed] Kimchi-Sarfaty C et al: "Functional characterization of coding polymorphisms in the human MDR1 gene using a vaccinia virus expression system."

No. Sentence Comment

2 To determine whether common polymorphic forms of P-gp are likely to alter function of P-gp, we characterized five known MDR1 coding polymorphisms (N21D, F103L, S400N, A893S, and A998T) using a vaccinia virus-based transient expression system. Login to comment
7 Cell surface expression and function of double mutants including the more common polymorphisms (N21D-S400N, N21D-A893S, and S400N-A893S) showed no differences from wild-type. Login to comment
20 In this study, we examined the five most common P-gp coding polymorphisms previously reported in the literature (N21D, F103L, S400N, A893S, and A998T). Login to comment
30 Using the technique described by Kunkel et al. (1987), five different mutated sites were introduced into the MDR1 gene with the following primers: for the N21D (A3G) polymorphism, 5Ј TTT TTC ACT TTT ATC GTT CAG TTT AA 3Ј; for the F103L (C3T) polymorphism, 5Ј CAG ATT CAT GAA GAG CCC TGT ATC A 3Ј; for the S400N (G3T) polymorphism, 5Ј TCG AGA TGG GTA ATT GAA GTG AAC AT 3Ј; for the A893S (G3T) polymorphism, 5Ј AGC GAT CTT CCC AGA ACC TTC TAG TT 3Ј; and for the A998T (G3A) polymorphism, 5Ј TAT TTT GGC TTT GGT ATA GTC AGG AGC 3Ј. Login to comment
31 Double mutant MDR1s were generated using the NdeI and XhoI restriction enzymes on single mutant templates (N21D-S400N, N21D-A893S, and S400N-A893S). Login to comment
48 We have chosen HeLa cells for these studies because of their low level of endogenous P-gp expression, their ability to express high TABLE 1 Common MDR1 polymorphisms that change amino acids Location Polymorphic Variant Heterozygous Frequency Reference Exon Nucleotide % 2 61 N21D 17.6 Hoffmeyer et al. (2000) 11.2 Cascorbi et al. (2001) 5.7 Decleves et al. (2000) 5 307 F103L 1.2 Hoffmeyer et al. (2000) 10 1107 G369P 0.2 Cascorbi et al. (2001) 11 1199 S400N 12.9 Hoffmeyer et al. (2000) 5.5 Cascorbi et al. (2001) A893S 43.0 Mickley et al. (1998) A893T 41.6 Cascorbi et al. (2001) 21 2677 A893S 62.0a , 13.0b Kim et al. (2001) A893G 56.4 Cascorbi et al. (2001) 24 2995 A998T 11.0 Mickley et al. (1998) a European Americans. b African Americans. levels of wild-type and mutant P-gp after vaccinia infection/ transfection, and their relative ease of transfection (Hrycyna et al., 1998; Ramachandra et al., 1998; Gribar et al., 2000). Login to comment
63 HeLa cells were infected/transfected with the pTM1-MDR1 vector harboring the MDR1 polymorphisms N21D, F103L, S400N, A893S, and A998T (described in Table 1). Login to comment
70 All cells infected/ transfected with double mutants (N21D-S400N, N21D-A893S, and S400N-A893S) revealed results similar to those of the single mutants (data not shown). Login to comment
71 Discussion In this study a transient vaccinia expression system was used to determine the effect of five known coding human MDR1 polymorphisms on P-gp function: N21D, F103L, S400N, A893S, and A998T. Login to comment
113 Infected/transfected HeLa cells with wild-type pTM1-MDR1 (--), pTM1-MDR1-N21D (- -⅐- -⅐), pTM1-MDR1-F103L (⅐⅐⅐⅐), pTM1-MDR1-S400N (-⅐-⅐-), pTM1-MDR1-A998T (- - - -), and pTM1-MDR1-A893S (⅐⅐⅐-⅐⅐⅐) were incubated and analyzed by FACS as described under Materials and Methods, with MRK-16 or control IGg2a␬ monoclonal antibodies (-⅐-⅐-⅐) 13.5 h after infection/transfection. Login to comment
117 Cells were transfected with pTM1 (control), pTM1-MDR1, (wild-type P-gp), pTM1-MDR1- N21D, pTM1-MDR1-F103L, pTM1-MDR1-S400N, pTM1-MDR1-A893S, and pTM1-MDR1-A998T. Login to comment
119 with A, 0.5 ␮M Calcein-AM: wild-type (--), N21D (- -⅐- -⅐), and S400N (-⅐-⅐-), in the presence of an inhibitor, 5 ␮M cyclosporin A (- - -); B, 0.5 ␮M bodipy-FL-forskolin: wild-type (--), N21D (- -⅐- -⅐), F103L (⅐⅐⅐⅐), and S400N (-⅐-⅐-), in the presence of an inhibitor, 5 ␮M cyclosporin A (- - -); C, 0.5 ␮M bodipy-FL-verapamil: wild-type (--), N21D (- -⅐- -⅐), F103L (⅐⅐⅐⅐), and S400N (-⅐- ⅐-), in the presence of an inhibitor, 5 ␮M cyclosporin A (- - -); D, 0.1 ␮M bodipy-FL-paclitaxel: wild-type (--), A893S (- -⅐- -⅐), in the presence of an inhibitor, 5 ␮M cyclosporin A for the wild-type (- -), and for A893S (- - -). Login to comment

PMID: 12172212 [PubMed] Tang K et al: "Distinct haplotype profiles and strong linkage disequilibrium at the MDR1 multidrug transporter gene locus in three ethnic Asian populations."

No. Sentence Comment

101 The previously reported exon 2 61A.G polymorphism, which changes the codon from Asn to Asp at amino acid position 21 in the MDR1 protein, has a minor G allele frequency of 11.2% in German Caucasians [11]. Login to comment

PMID: 12172213 [PubMed] Goto M et al: "C3435T polymorphism in the MDR1 gene affects the enterocyte expression level of CYP3A4 rather than Pgp in recipients of living-donor liver transplantation."

No. Sentence Comment

42 In the present study, the variants in exon 2 G-1A, A61G (Asn21 Asp) in exon 2, T307C (Phe103 Leu) in exon 5, G1199A (Ser400 Asn) in exon 11 and C+44T in intron 12 were not observed. Login to comment

PMID: 12357145 [PubMed] Lotsch J et al: "Does the A118G polymorphism at the mu-opioid receptor gene protect against morphine-6-glucuronide toxicity?"

No. Sentence Comment

106 33 T/T T/T MDR1 2 A61G Asn21Asp 11.2 20.6 9 A/G A/G Forward: 5Ј-AGG AGC AAA GAA GAA GAA CTT TTT TAA ACT GAT C-3Ј 9.3 17.6 8 Reverse: 5Ј-GAT TCC AAA GGC TAG CTT GC-3Ј 5 T307C Phe103Leu 0.6 1.2 9 T/T T/T Forward: 5Ј-GTG GTT GCA CAC AGT CAG CA-3Ј Reverse: 5Ј-GGA GGA TGT CTA ATT ACC TGG TCA-3Ј 11 G1199A Ser400Asn 5.5 11.1 9 G/G G/G Forward: 5Ј-CAG CTA TTC GAA GAG TGG GC-3Ј 6.5 12.9 8 Reverse: 5Ј-CCG TGA GAA AAA AAC TTC AAG G-3Ј 21 G2677T Ala893Ser 41.6 49.2 9 T/T T/T Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј 63.9 43.4 8 Reverse: 5Ј-GTT TGA CTC ACC TTC CCA G-3Ј 21 G2677A Ala893Thr 0.9 2 9 NA NA Forward: 5Ј-TGC AGG CTA TAG GTT CCA GG-3Ј Reverse: 5Ј-TTT AGT TTG ACT CAC CTT CCC G-3Ј 26 A3320C Gln1107Pro 0.2 0.4 9 A/A A/A 26 C3396T Ala1132Ala 0.3 0.5 8 C/C C/C Forward: 5Ј-ATC TGT GAA CTC TTG TTT TCA GC-3Ј 26 C3435T Ile1145Ile 50.3 47.7 8 T/T T/T Reverse: 5Ј-TCG ATG AAG GCA TGT ATG TTG-3Ј 53.9 50.5 9 - - MRP2 10 G1249A Val417Ile 12.5 20.8 34 G/G G/G Forward: 5Ј-GGG TCC TAA TTT CAA TCC TTA-3Ј Reverse: 5Ј-TAT TCT TCT GGG TGA CTT TTT-3Ј 18 C2302T Arg768Trp 1 2.1 34 C/C C/C Forward: 5Ј-GGA GTA GTG CTT AAT ATG AAT-3Ј 18 C2366T Ser789Phe 1 2.1 34 C/C C/C Reverse: 5Ј-CCC ACC CCA CCT TTA TAT CTT-3Ј 28 C3972T Ile132Ile 21.9 35.4 34 C/T C/T Forward: 5Ј-TGC TAC CCT TCT CCT GTT CTA-3Ј Reverse: 5Ј-ATC CAG GCC TTC CTT CAC TCC-3Ј 31 G4348A Ala1450Thr 1 2.1 34 G/G G/G Forward: 5Ј-AGG AGC TAA CAC ATG GTT GCT-3Ј Reverse: 5Ј-GGG TTA AGC CAT CCG TGT CAA-3Ј † Sequence is not translated. Login to comment

PMID: 12359865 [PubMed] Schwab M et al: "Genetic polymorphisms of the human MDR1 drug transporter."

No. Sentence Comment

50 Of the 15 identified SNPs, three polymorphisms resulted in protein alterations, one in exon 2 (Asn21Asp), in exon 5 (Phe103Leu), and in exon 11 (Ser400Asn). Login to comment
52 The SNPs at positions A61G (Asn21Asp), C1236T, and C3435T had been reported previously (23, 26). Login to comment
60 In a Northern Italian population, the extent of linkage disequilibrium TABLE 2 Summary of MDR1 genetic variants in different ethnic groups Location Position Allele Effect Reference promotor 5 flanking/-41a A (28) G exon 1a exon 1a/-145 C (28) G exon 1b exon 1b/-129 T (25, 33) C intron 1 exon 2/-4 C (29) T intron 1 exon 2/-1 G initiation of translation (25, 27, 29) A exon 2 exon 2/61 A Asn21Asp (25-27, 29) G intron 4 exon 5/-35 G (25) C intron 4 exon 5/-25 G (25) T exon 5 exon 5/307 T Phe103Leu (25) C intron 6 exon 6/+139 C (25, 27) T intron 6 exon 6/+145 C (25) T exon 7 exon 7/548 A Asn183Ser (29) G exon 11 exon 11/1199 G Ser400Asn (25, 27, 29) A exon 12 exon 12/1236 C wobble (23, 25, 27, 29) T (Gly412Gly) intron 12 exon 12/+44 C (25, 27) T exon 13 exon 13/1474 C Arg492Cys (29) T intron 16 exon 17/-76 T (25, 27) A intron 17 exon 17/137 A (25) G exon 21 exon 21/2650 C wobble (29) T (Leu884Leu) (Continued ) TABLE 2 (Continued) Location Position Allele Effect Reference exon 21 exon 21/2677 G (22, 23, 27, 29) T Ala893Ser A Ala893Thr exon 24 exon 24/2956 A Met986Val (33) G exon 24 exon 24/2995 G Ala999Thr (22) A exon 26 exon 26/3320 A Gln1107Pro (27) C exon 26 exon 26/3396 C wobble (25) T exon 26 exon 26/3421 T Ser1141Thr (29, 30) A exon 26 exon 26/3435 C wobble (23, 25, 29) T (Ile1145Ile) exon 28 exon 28/4030 G (33) C exon 28 exon 28/4036 A (23, 33) G The positions of the polymorphisms correspond to positions of MDR1 cDNA with the first base of the ATG start codon set to 1 (GenBank accession # M14758). Login to comment
68 The A61G mutation (Asn21Asp) results in a net charge change (basic to acidic) close to the N-terminus of P-glycoprotein, which appears to be of minor functional importance if recombinant mutational analyses of P-glycoprotein are considered (6). Login to comment
86 However, a recent publication characterized the functional consequences of five coding SNPs (Asn21Asp, Phe103Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system (40a). Login to comment
312 A new polymorphism (N21D) in the exon 2 of the human MDR1 gene encoding the P-glycoprotein. Login to comment

PMID: 12419946 [PubMed] Sakaeda T et al: "MDR1 genotype-related pharmacokinetics and pharmacodynamics."

No. Sentence Comment

52 Kim et al. defined 15 alleles based on the frequencies of 11 polymorphisms of C-4T (noncoding), G-1A (noncoding), A61G (Asn21Asp), A548G (Asn183Ser), G1199A (Ser400Asn), C1236T (silent), C1474T (Arg492Cys), C2650T (silent), G2677T (Ala893Ser), T3421A (Ser1141Thr) and C3435T (silent).54) Six of 11 accompanied an amino acid change, and the others were conservative mutations. Login to comment
56 In 2001, Hitzl et al. also indicated that healthy Caucasian subjects with T/T3435 had a more decreased efflux of rhodamine from CD56ϩ NK cells and a lower MDR1 mRNA expression in leukocytes than those with C/C3435 .65) In renal tissues, the C3435T polymorphism is reported to be associated with reduced MDR1 expression.31) However, Tanabe et al. suggested that C3435T had no effect on the placental MDR1 expression based on 89 subjects and Western blotting.53) We determined MDR1 mRNA levels in biopsy specimens of the duodenum obtained from 13 healthy Japanese subjects by real time quantitative RT-PCR and found that MDR1 mRNA expression was higher in T/T3435 than C/C3435 or C/T3435 (Fig. 1).66) The discrepancies between the reports might be ex- November 2002 1393 Table 2. Summary of Genetic Polymorphisms in MDR1 Position Location Effect A1a/-41G Intron Noncoding C-145G Exon 1a Noncoding T-129C (T12C) Exon 1b Noncoding C-4T Exon 2 Noncoding G-1A Exon 2 Noncoding A61G Exon 2 Asn21Asp G5/-25T Intron G5/-35C Intron T307C Exon 5 Phe103Leu C6/ϩ139T Intron A548G Exon 7 Asn183Ser G1199A Exon 11 Ser400Asn C1236T Exon 12 Silent C12/ϩ44T Intron C1474T Exon 13 Arg492Cys T17/-76A Intron A17/ϩ137G Intron C2650T Exon 21 Silent G2677(A,T) Exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G Exon 24 Met986Val G2995A Exon 24 Ala999Thr A3320C Exon 26 Gln1107Pro C3396T Exon 26 Silent T3421A Exon 26 Ser1141Thr C3435T Exon 26 Silent G4030C Exon 28 Silent A4036G Exon 28 Silent This list was based on the literature (refs. 49-54). Login to comment
61 Kim et al. indicated that cells transduced with a variant MDR1 containing Ser893 showed a reduced intracellular accumulation of [3 H]-digoxin compared with cells with the wild-type Ala893 , suggesting enhanced efflux by the polymorphism of Ala893Ser (G2677T).54) On the other hand, very recently, Kimchi-Sarfaty et al. indicated that the cell surface expression and function of double mutants including the more common polymorphisms (A61G (Asn21Asp) and G1199A (Ser400Asn), A61G (Asn21Asp) and G2677T (Ala893Ser), G1199A (Ser400Asn) and G2677T (Ala893Ser)) showed no differences from the wild-type.67) MDR1 Genotype-Related Pharmacokinetics The aim of the clinical study by Greiner et al.64) was to elucidate the role of intestinal MDR1 expression in the interaction of digoxin with rifampin, and plasma concentration-time profiles were monitored after oral and intravenous administration of digoxin at 1 mg before and after oral administration of rifampin once daily for 16 d. Using the digoxin plasma concentration data after MDR1 induction by rifampin, Hoffmeyer et al.50) suggested that intestinal absorption of digoxin was greater in the subjects with the T-allele at position 3435. Login to comment

PMID: 12426521 [PubMed] Siegmund W et al: "The effects of the human MDR1 genotype on the expression of duodenal P-glycoprotein and disposition of the probe drug talinolol."

No. Sentence Comment

32 The following 10 most frequent or putatively functional SNPs of the MDR1 gene were identified, as recently described19 : intron 1 (exon 2 -1) G/A, exon 2 A61G (amino acid exchange Asn21Asp), intron 6 (exon 6 ϩ139) C/T, exon 11 G1199A (Ser400Asn), exon 12 C1236T, intron 12 (exon 12 ϩ44) C/T, intron 16 (exon 17 -76) T/A, exon 21 G2677T (Ala893Ser), G2677A (Ala893Thr), and exon 26 C3435T. Login to comment
112 Other authors, however, did not observe any significant correlation between the MDR1 genotype and fexofenadine disposition35 ; furthermore, a study in human placenta trophoblasts obtained from 100 Japanese women revealed less placental P-glycoprotein (Western blotting) in individuals having the G2677A/T allele.20 The nonanonymous variants A61G (Asn21Asp) in exon 2 and G1199A (Ser400Asn) in exon 11 were also expected to have a functional impact on human P-glycoprotein. Login to comment
113 The Asn21Asp exchange is located close to the N-terminus and the Ser400Asn variant just preceding the first adenosine triphosphate-binding domain.22 However, both mutations in our study did not influence P-glycoprotein expression and talinolol disposition. Login to comment

PMID: 12831320 [PubMed] Sakaeda T et al: "Pharmacogenetics of MDR1 and its impact on the pharmacokinetics and pharmacodynamics of drugs."

No. Sentence Comment

75 Position Location Effect A1a/-41G Intron Non-coding C-145G Exon 1a Non-coding T-129C (T12C) Exon 1b Non-coding C-4T Exon 2 Non-coding G-1A Exon 2 Non-coding A61G Exon 2 Asn21Asp G5/-25T Intron G5/-35C Intron T307C Exon 5 Phe103Leu C6/+139T Intron A548G Exon 7 Asn183Ser G1199A Exon 11 Ser400Asn C1236T Exon 12 Silent C12/+44T Intron C1474T Exon 13 Arg492Cys T17/-76A Intron A17/+137G Intron C2650T Exon 21 Silent G2677(A,T) Exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G Exon 24 Met986Val G2995A Exon 24 Ala999Thr A3320C Exon 26 Gln1107Pro C3396T Exon 26 Silent T3421A Exon 26 Ser1141Thr C3435T Exon 26 Silent G4030C Exon 28 Silent A4036G Exon 28 Silent See references [34-39]. Login to comment

PMID: 12893986 [PubMed] Kroetz DL et al: "Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene."

No. Sentence Comment

141 Unauthorized reproduction of this article is prohibited. Table 1 Genetic variation in ABCB1 Allele frequencyd Variant cDNA NT DNA/AA AA Total CA AA AS ME PA No.a positionb changec position change (n ¼ 494) (n ¼ 200) (n ¼ 200) (n ¼ 60) (n ¼ 20) (n ¼ 14) 1.1Ã (À274) G to A Intron À1 0.006 0 0.016 0 0 0 1.2Ã (À223) C to T Intron À1 0.002 0.005 0 0 0 0 1.3Ã (À146) T to C Intron À1 0.002 0 0.005 0 0 0 1.4Ã (À60) A to T Intron À1 0.004 0 0.010 0 0 0 1.5 (À41) A to G Intron À1 0.002 0 0 0.017 0 0 1.6Ã À241 G to A Non-coding 0.002 0 0 0.017 0 0 1.7 À145 C to G Non-coding 0.002 0 0 0.017 0 0 1.8 À129 T to C Non-coding 0.060 0.051 0.071 0.036 0.100 0.071 1.9 À43 A to G Non-coding 0.012 0 0.020 0.036 0 0 1.10Ã (+140) C to A Intron 1 0.013 0.005 0.021 0 0 0.071 1.11Ã (+237) G to A Intron 1 0.004 0 0.010 0 0 0 2.1 À4 C to T Non-coding 0.004 0 0.010 0 0 0 2.2 À1 G to A Non-coding 0.036 0.080 0.005 0 0.050 0 2.3 61 A to G 21 Asn to Asp 0.045 0.080 0.025 0.017 0 0 4.1Ã (À8) C to G Intron 3 0.002 0.005 0 0 0 0 4.2Ã 266 T to C 89 Met to Thr 0.002 0.005 0 0 0 0 5.1 (À25) G to T Intron 4 0.210 0.158 0.300 0.067 0.200 0.286 8.1 729 A to G 243 Syn 0.002 0.005 0 0 0 0 8.2Ã 781 A to G 261 Ile to Val 0.006 0 0.015 0 0 0 10.1Ã (À44) A to G Intron 9 0.400 0.450 0.255 0.685 0.450 0.571 11.1Ã (À41) T to G Intron 10 0.002 0 0 0.017 0 0 11.2 1199 G to A 400 Ser to Asn 0.014 0.025 0.010 0 0 0 12.1Ã (À4) G to A Intron 11 0.002 0 0.005 0 0 0 12.2 1236 C to T 412 Syn 0.385 0.459 0.209 0.685 0.450 0.571 12.3Ã 1308 A to G 436 Syn 0.002 0 0.005 0 0 0 12.4Ã (+17) G to A Intron 12 0.008 0 0.020 0 0 0 12.5 (+44) C to T Intron 12 0.088 0.046 0.168 0 0 0 13.1 (+24) C to T Intron 13 0.530 0.521 0.542 0.540 0.450 0.571 14.1 1617 C to T 539 Syn 0.002 0.005 0 0 0 0 14.2 (+38) A to G Intron 14 0.540 0.505 0.540 0.683 0.450 0.500 15.1 (+38) G to A Intron 15 0.004 0.005 0.005 0 0 0 16.1Ã 1985 T to G 662 Leu to Arg 0.002 0.005 0 0 0 0 16.2Ã 2005 C to T 669 Arg to Cys 0.004 0 0.010 0 0 0 18.1Ã (À27) A to G Intron 17 0.008 0.010 0.005 0 0.050 0 20.1Ã (+8) C to G Intron 20 0.002 0 0.005 0 0 0 20.2 (+24) G to A Intron 20 0.126 0.121 0.150 0.067 0.200 0 20.3Ã (+40) C to T Intron 20 0.014 0 0.035 0 0 0 21.1Ã 2547 A to G 849 Ile to Met 0.002 0.005 0 0 0 0 21.2 2650 C to T 884 Syn 0.004 0.005 0.005 0 0 0 21.3a 2677 G to T 893 Ala to Ser 0.308 0.464 0.100 0.450 0.400 0.357 21.3b 2677 G to A 893 Ala to Thr 0.035 0.036 0.005 0.067 0 0.357 22.1 (+31) G to A Intron 22 0.002 0 0.005 0 0 0 25.1Ã 3151 C to G 1051 Pro to Ala 0.002 0 0.005 0 0 0 26.1Ã 3322 T to C 1108 Trp to Arg 0.002 0 0.005 0 0 0 26.2 3421 T to A 1141 Ser toThr 0.047 0 0.111 0 0.050 0 26.3 3435 C to T 1145 Syn 0.392 0.561 0.202 0.400 0.500 0.500 28.1 3751 G to A 1251 Val to Ile 0.002 0 0 0 0.050 0 28.2 3767 C to A 1256 Thr to Lys 0.002 0.005 0 0 0 0 28.3 (+21) T to C Intron 28 0.031 0 0.077 0 0 0 a Variants are numbered sequentially by exon. Login to comment
156 Only two haplotypes (ABCB1Ã14 and ABCB1Ã14A) contain two non-synonymous changes (Asn21Asp and Ala893Ser). Login to comment
164 M89T I849M V1251I T1256K S1141TW1108R P1052AR669C A893S/T L662R Cytoplasm S400N I261V N21D Extracellular Fig. 1. Login to comment
301 Other non-synonymous variants (Asn21Asp, Phe103Leu, Ser400Asn, and Ala998Thr) have also been shown not to affect P-glycoprotein function [43]. Login to comment

PMID: 14576852 [PubMed] Ambudkar SV et al: "P-glycoprotein: from genomics to mechanism."

No. Sentence Comment

85 Kioka et al. (1989) showed a slight increase in resistance to doxorubicin, but no effect on colchicine or vinblastine Table 2 Common MDR1 exonic polymorphisms Exon number Polymorphic nucleotide variant Change in amino acid References 1 À145 - Ito et al. (2001) 1 À129 - Hoffmeyer et al. (2000); Tanabe et al. (2001) 2 61 N21D Cascorbi et al. (2001); Decleves et al. (2000); Hoffmeyer et al. (2000); Kim et al. (2001) 5 307 F103L Hoffmeyer et al. (2000) 7 548 N183S Kim et al. (2001) 10 1107 G369P Hoffmeyer et al. (2000) 11 1199 S400N Cascorbi et al. (2001); Hoffmeyer et al. (2000); Kim et al. (2001) 12 1236 Wobble Cascorbi et al. (2001); Hoffmeyer et al. (2000); Kim et al. (2001); Kioka et al. (1989) 13 1474 R492C Kim et al. (2001) 21 2650 Wobble Kim et al. (2001) 21 2677 893A, S, or T Cascorbi et al. (2001); Kim et al. (2001); Kioka et al. (1989); Mickley et al. (1998) 24 2956 M986V Tanabe et al. (2001) 24 2995 A999T Mickley et al. (1998) 26 3320 Q1107P Cascorbi et al. (2001) 26 3396 Wobble Hoffmeyer et al. (2000) 26 3421 S1141T Kim et al. (2001) 26a 3435 Wobble Hoffmeyer et al. (2000); Kim et al. (2001); Kioka et al. (1989) 28 4030 - Tanabe et al. (2001) 28 4036 - Kioka et al. (1989); Tanabe et al. (2001) a The only polymorphism that correlates with changes in drug delivery and disposition P-glycoprotein SV Ambudkar et al resistance in the SNP located on exon 21, position 2677, Ser893 (Kioka et al., 1989). Login to comment
110 HeLa cells were infected/transfected with empty vector (pTM1), wild-type pTM1-MDR1, pTM1-MDR1-S400N, pTM1-MDR1-N21D, pTM1-MDR1-F103L, pTM1-MDR1-A998T, and pTM1-MDR1-A893S, and were analysed by FACS as described previously (Kimchi-Sarfaty et al., 2002) Table 3 Selected substrates and modulators of P-glycoprotein Substrates Modulators Vinca alkaloids Calcium channel blockers Vinblastine Verapamil Vincristine Dihydropyridines Anthracyclines Antiarrhythmics Daunorubicin Quinine Doxorubicin Antihypertensives Antibiotics Reserpine Dactinomycin Antibiotics Actinomycin D Cephalosporins Other cytotoxic agents Immunosuppressants Mitomycin Cyclosporin A Taxol Steroid hormones Colchicine Progesterone Puromycin HIV protease inhibitors Digoxin Saquinavir Alcoholism treatment drug Disulfiram Phytochemical Curcumin Moreover, most of these studies correlated the manifestation of this polymorphism with a change in drug delivery or disposition. Login to comment

PMID: 14586389 [PubMed] Pauli-Magnus C et al: "No effect of MDR1 C3435T variant on loperamide disposition and central nervous system effects."

No. Sentence Comment

118 One individual was homozygous for MDR1*14, which contains the G2677T variation, leading to the Ser893 coding change plus an additional A61G variant resulting in an Asn21Asp change in P-glycoprotein. Login to comment
168 In the MDR1 3435CC group, 2 individuals had haplotypes encoding P-glycoprotein variants (Ala893Thr and Asn21Asp), and all subjects in the MDR1 3435TT group were at least heterozygous for a haplotype encoding for the P-glycoprotein Ala893Ser variant. Login to comment

PMID: 14646693 [PubMed] Sai K et al: "Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan."

No. Sentence Comment

103 746Pharmacogenetics2003,Vol13No12 Copyright(c)LippincottWilliams&Wilkins.Unauthorizedreproductionofthisarticleisprohibited. Table 3 Classification of major ABCB1 haplotypes Site Exon 2 Exon 5 Exon 7 Exon 11 Exon 12 Exon 13 Exon 21 Exon 21 Exon 21 Exon 26 Exon 26 Exon 27 Exon 28 PositionÃ Exon 1 Exon 1 61A.G 325G.A 548A.G 1199G.A 1236C.T 1474C.T 2650C.T 2677G.T 2677G.A 3421T.A 3435C.T 3587T.G 3751G.A Effect on protein À4C.T À1G.A N21D E109K N183S S400N G412G R492C L884L A893S A893T S1141T I1145I I1196S V1251I Classification by Kim et al. [12] Ã1 - - - - - - - - - - - Ã1A - - - - A - - - - - - Ã1B T - - - - - - - - - - Ã1C - - - - - - - - - A - Ã1D - - - G - - - - - - - Ã2 - - - - - T - - T - T Ã2A - - G - - T - - T - T Ã2B - - - - - T - T T - T Ã2C - - - - - T T - T - T Ã3 - - - - - - - - T - T Ã4 - - - - - T - - - - T Ã5 - A - - - - - - - - T Ã6 - - - - - - - - - - T Ã7 - - - - - - - - T - - Ã8 - - - - - T - - - - - Classification of haplotype group detected in this paperÃÃ Block 1 Ã1 - - - - Ã2 - - G - Block 2 Ã1 - - - - - - - - - Ã2 - - T - - T - - T Ã4 - - T - - - - - T Ã6 - - - - - - - - T Ã8 - - T - - - - - - Ã9 - - - - - - - - - Ã10 - - - - - - A - - Ã11 - - T - - - A - - Block 3 Ã1 - - Ã2 - A Ã3 G - ÃAdenine of the initiation codon ATG in exon 2 was numbered +1. Login to comment

PMID: 14749689 [PubMed] Marzolini C et al: "Polymorphisms in human MDR1 (P-glycoprotein): recent advances and clinical relevance."

No. Sentence Comment

75 Summary of genetic polymorphisms in MDR1 Location Position Mutation Effect Mutant allele frequency (%) Hoffmeyer et al89 : C Cascorbi et al90 : C Siegmund et al91 : C Promotor 5' flanking/-41 A/G Noncoding Exon 1a Exon 1a/-145 C/G Noncoding Exon 1b Exon 1b/-129 T/C Noncoding 5.9 Intron 1 Exon 2/-4 C/T Noncoding Intron 1 Exon 2/-1 G/A Initial translation 5.6 9 3.7 Exon 2 Exon 2/61 A/G Asn21Asp 9.3 11.2 8.9 Intron 4 Exon 5/-35 G/C 0.6 Intron 4 Exon 5/-25 G/T 16.5 Exon 5 Exon 5/307 T/C Phe103Leu 0.6 0 Intron 6 Exon 6/ϩ139 C/T 40.6 37.2 35.8 Intron 6 Exon 6/ϩ145 C/T 1.2 Exon 7 Exon 7/548 A/G Asn183Ser Exon 11 Exon 11/1199 G/A Ser400Asn 6.5 5.5 2.9 Exon 12 Exon 12/1236 C/T Silent 37.8 41 34.3 Intron 12 Exon 12/ϩ44 C/T 5.9 4.9 7.5 Exon 13 Exon 13/1474 C/T Arg492Cys Intron 16 Exon 17/-76 T/A 45.3 46.2 49.3 Intron 17 Exon 17/ϩ137 A/G 0.6 Exon 21 Exon 21/2650 C/T Silent Exon 21 Exon 21/2677 G/T Ala893Ser 41.6 40.3 G/A Ala893Thr 1.9 3.7 Exon 24 Exon 24/2956 A/G Met986Val Exon 24 Exon 24/2995 G/A Ala999Thr Exon 26 Exon 26/3320 A/C Gln1107Pro 0.2 Exon 26 Exon 26/3396 C/T Silent 0.3 Exon 26 Exon 26/3421 T/A Ser1141Thr Exon 26 Exon 26/3435 C/T Silent 48.1 53.9 50.7 Exon 28 Exon 28/4030 G/C Exon 28 Exon 28/4036 A/G The positions of the polymorphisms were established with the first base of the ATG start codon set to 1. Login to comment

PMID: 15212152 [PubMed] Pauli-Magnus C et al: "Functional implications of genetic polymorphisms in the multidrug resistance gene MDR1 (ABCB1)."

No. Sentence Comment

28 6, June 2004 ((c) 2004) 9040724-8741/04/0600-0904/0 (c) 2004 Plenum Publishing Corporation Table I. MDR1 Coding Variants cDNA positiona NT change DNA/AA position AA change Allele frequencyb Total (n ‫ס‬ 494) CA (n ‫ס‬ 200) AA (n ‫ס‬ 200) AS (n ‫ס‬ 60) ME (n ‫ס‬ 20) PA (n ‫ס‬ 14) 61 A to G 21 Asn to Asp 0.045 0.080 0.025 0.017 0 0 266 T to C 89 Met to Thr 0.002 0.005 0 0 0 0 729 A to G 243 Syn 0.002 0.005 0 0 0 0 781 A to G 261 Ile to Val 0.006 0 0.015 0 0 0 1199 G to A 400 Ser to Asn 0.014 0.025 0.010 0 0 0 1236 C to T 412 Syn 0.385 0.459 0.209 0.685 0.450 0.571 1308 A to G 436 Syn 0.002 0 0.005 0 0 0 1617 C to T 539 Syn 0.002 0.005 0 0 0 0 1985 T to G 662 Leu to Arg 0.002 0.005 0 0 0 0 2005 C to T 669 Arg to Cys 0.004 0 0.010 0 0 0 2547 A to G 849 Ile to Met 0.002 0.005 0 0 0 0 2650 C to T 884 Syn 0.004 0.005 0.005 0 0 0 2677 G to T 893 Ala to Ser 0.308 0.464 0.100 0.450 0.400 0.357 2677 G to A 893 Ala to Thr 0.035 0.036 0.005 0.067 0 0.357 3151 C to G 1051 Pro to Ala 0.002 0 0.005 0 0 0 3322 T to C 1108 Trp to Arg 0.002 0 0.005 0 0 0 3421 T to A 1141 Ser to Thr 0.047 0 0.111 0 0.050 0 3435 C to T 1145 Syn 0.392 0.561 0.202 0.400 0.500 0.500 3751 G to A 1251 Val to Ile 0.002 0 0 0 0.050 0 3767 C to A 1256 Thr to Lys 0.002 0.005 0 0 0 0 a cDNA numbers are relative to the ATG site and based on the cDNA sequence from GenBank accession number M14758. Login to comment
94 A vaccinia virus expression system was used to examine the Asn21Asp, Phe103Leu, Ser400Ala, Ala893Ser, and Ala893Thr P-glycoprotein variants. Login to comment
118 Functional Impact in vitro of MDR1 Variants Amino acid change Functional effect of the variant allele Reference Val185Ser Increased colchicine resistance [30] ⌬Phe335 Decreased resistance to vinca alkaloids; no resistance to dactinomycin [31] Lys536Gln, Gly534Asp, Lys536Arg, Ser532Arg, ⌬Tyr490 Defective RNA processing [33] Ala893Ser Acquired overexpression of one allele in drug-resistant cells [20] Ala893Ser Decreased digoxin efflux [19] Asn21Asp, Phe103Leu, Ser400Ala, Ala893Ser, Ala893Thr No effect on P-glycoprotein cell surface expression and substrate specificity [69] Ala893Ser No difference in calcein-AM transport [27] Ala893Ser/Thr No difference in transport of verapamil, digoxin, viblastine and cyclosporine A [35] 3435 polymorphisms were analyzed separately, with AUC values being highest for individuals carrying the reference alleles. Login to comment

PMID: 15256718 [PubMed] Ishikawa T et al: "Pharmacogenomics of drug transporters: a new approach to functional analysis of the genetic polymorphisms of ABCB1 (P-glycoprotein/MDR1)."

No. Sentence Comment

79 For this purpose, the cDNA of ABCB1 was cloned from the human liver cDNA library, and several variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) were prepared by site-directed mutagenesis (see Fig. 4A for primers). Login to comment
94 The variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) exhibited the verapamil-enhanced ATPase activity, as did the wild type of ABCB1. Login to comment
97 The variant G185V (acquired mutation) was found to have the highest Vmax value, which was followed by N21D (Table 1). Login to comment
118 Kinetic Parameters of the Wild Type and SNP Variants of ABCB1 Variant Km Vmax (mM) (nmol/min/mg protein) Wild type 2.190Ϯ0.150 13.14Ϯ1.95 N21D 0.502Ϯ0.126 45.26Ϯ11.33 N44S 0.580Ϯ0.148 31.03Ϯ4.65 F103L 1.100Ϯ0.078 36.34Ϯ8.33 G185V 0.831Ϯ0.102 56.76Ϯ6.76 S400N 0.327Ϯ0.025 13.74Ϯ2.08 A893S 0.441Ϯ0.042 17.24Ϯ6.72 A893T 0.904Ϯ0.244 10.77Ϯ1.35 M986V 0.419Ϯ0.062 22.69Ϯ6.84 The wild type and variants of ABCB1 were then expressed it in Sf9 cells using the pFASTBAC1 vector and recombinant baculoviruses. Login to comment

PMID: 15379652 [PubMed] Sakaeda T et al: "Pharmacogenetics of drug transporters and its impact on the pharmacotherapy."

No. Sentence Comment

127 Position Location Effect A1a/-41G intron noncoding C-145G exon 1a noncoding T-129C (T12C) exon 1b noncoding C-4T exon 2 noncoding G-1A exon 2 noncoding A61G G5/-25T G5/-35C exon 2 intron intron Asn21Asp T307C C6/+139T exon 5 intron Phe103Leu A548G exon 7 Asn183Ser G1199A exon 11 Ser400Asn C1236T C12/+44T exon 12 intron silent C1474T T17/-76A A17/+137G exon 13 intron intron Arg492Cys C2650T exon 21 silent G2677(A,T) exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G exon 24 Met986Val G2995A exon 24 Ala999Thr A3320C exon 26 Gln1107Pro C3396T exon 26 silent T3421A exon 26 Ser1141Thr C3435T exon 26 silent G4030C exon 28 silent A4036G exon 28 silent The list was based on the reports [67,68,71-74]. Login to comment

PMID: 15499164 [PubMed] Ishikawa T et al: "Functional evaluation of ABCB1 (P-glycoprotein) polymorphisms: high-speed screening and structure-activity relationship analyses."

No. Sentence Comment

78 For this purpose, the cDNA of ABCB1 was cloned from the human liver cDNA library, and several variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) were prepared by site-directed mutagenesis (see Fig. 2A for primers). Login to comment
86 The variant forms (i.e., N21D, N44S, F103L, G185V, S400N, A893S, A893T, M986V) exhibited the verapamil-enhanced ATPase activity, as did the wild type of ABCB1. Login to comment
89 The variant G185V (acquired mutation) was found to have the highest Vmax value, which was followed by N21D (Table 2). Login to comment
105 Kinetic parameters of the wild type and SNP variants of ABCB1 Variant Km Vmax (mM) (nmolWminWmg protein) Wild type 2.190±0.150 13.14±1.95 N21D 0.502±0.126 45.26±11.33 N44S 0.580±0.148 31.03±4.65 F103L 1.100±0.078 36.34±8.33 G185V 0.831±0.102 56.76±6.76 S400N 0.327±0.025 13.74±2.08 A893S 0.441±0.042 17.24±6.72 A893T 0.904±0.244 10.77±1.35 M986V 0.419±0.062 22.69±6.84 The wild type and variants of ABCB1 were then expressed it in Sf9 cells using the pFASTBAC1 vector and recombinant baculoviruses. Login to comment

PMID: 15499174 [PubMed] Ozawa S et al: "Ethnic differences in genetic polymorphisms of CYP2D6, CYP2C19, CYP3As and MDR1/ABCB1."

No. Sentence Comment

85 Ethnic dierences in nonsynonymous SNPs of ABCB1W MDR1 cDNA positiona Position and amino acid change C AA AS J 61AÀG N21D 0.080 0.025 0.017 0 266TÀC M89T 0.005 0 0 0 781AÀG I261V 0 0.015 0 0 1199GÀA S400N 0.025 0.010 0 0 1985TÀG L662R 0.005 0 0 0 2005CÀT R669C 0 0.010 0 0 2547AÀG I849M 0.005 0 0 0 2677GÀT A893S 0.464 0.100 0.450 0.403 2677GÀA A893T 0.036 0.005 0.067 0.200 3151CÀG P1051A 0 0.005 0 0 3322TÀC W1108R 0 0.005 0 0 3421TÀA S1141T 0 0.111 0 0 3751GÀA V1251I 0 0 0 0.010 3767CÀA T1256K 0.005 0 0 0 C, 100 Caucasians; AA, 100 African-Americans; AS, 30 Asians; J, 145 Japanese (our study 116) ). Login to comment

PMID: 15618700 [PubMed] Honda T et al: "Polymorphism of MDR1 gene in healthy japanese subjects: a novel SNP with an amino acid substitution (Glu108Lys)."

No. Sentence Comment

13 To date, the following SNPs in the MDR1 gene leading to amino acid substitutions have been identiˆed: A61G (Asn21Asp) in exon 2, T307C (Phe103Leu) in exon 5, G1199A (Ser400Asn) in exon 11, G2677T (Ala893Ser) in exon 21, G2677A (Ala893Thr) in exon 21 and A2956G (Met986Val) in exon 24. Login to comment

PMID: 15618713 [PubMed] Itoda M et al: "Twelve novel single nucleotide polymorphisms in ABCB1/MDR1 among Japanese patients with ventricular tachycardia who were administered amiodarone."

No. Sentence Comment

18 Much eort has been taken to uncover polymorphisms in the ABCB1WMDR1 gene since a synonymous SNP, which correlated with diminished MDR1 expression levels in the human duodenum, was reported by Homeyer et al.7) To date, information on 19 single nucleotide polymorphisms (SNPs) including 7 nonsynonymous ones (N21D, F103L, S400N, A893S, A893T, A999T and Q1107P) for ABCB1WMDR1 have been reported in Caucasians.8,9) ABCB1WMDR1 gene SNPs including intronic10) and 2 nonsynonymous SNPs (E108K, M986V)11,12) were also reported in Japanese population. Login to comment
78 Moreover, the reported nonsynonymous polymorphisms, N21D, F103L, S400N, A893S and A999T have been shown not to substantially aect the activity of P-glycoprotein14) . Login to comment

PMID: 15692830 [PubMed] Allabi AC et al: "Single nucleotide polymorphisms of ABCB1 (MDR1) gene and distinct haplotype profile in a West Black African population."

No. Sentence Comment

66 AA amino acid, n number of chromosomes examined, ND not detected Variant no.a cDNA positionb NT changec DNA/AA position AA change Allele frequencyd (n=222) 2.1 À4 C to T Non-coding 0.0045 2.2 À1 G to A Non-coding 0 2.3 61 A to G 21 Asn to Asp 0 6.1 139 C to T Intron 6 0.17 9.0* À57 del A Intron 9 0.009 10.1 À44 A to G Intron 9 0.18 10.0* À8 T to A Intron 9 0.0045 11.1 À41 T to G Intron 10 0 11.2 1199 G to A 400 Ser to Asn 0 12.2 1236 C to T 412 Syn 0.15 14.1 1617 C to T 539 Syn 0 14.0* 1662 G to C 554 Syn 0.009 14.2 38 A to G Intron 14 0.49 17.1 À76 T to A Intron 16 0.347 21.2 2650 C to T 884 Syn 0 21.3a 2677 G to T 893 Ala to Ser 0.009 21.3b 2677 G to A 893 Ala to Thr 0 26.2 3421 T to A 1141 Ser to Thr 0.054 26.3 3435 C to T 1145 Syn 0.14 a Variants are numbered sequentially by exon. Login to comment

PMID: 15778422 [PubMed] Putnam WS et al: "Effect of the MDR1 C3435T variant and P-glycoprotein induction on dicloxacillin pharmacokinetics."

No. Sentence Comment

121 These results are consistent with the linkage reported between the 6 variant sites in the MDR1*13 haplotype.17 Three of the subjects in the 3435TT group also had a MDR1 variant leading to an Asn21Asp change in P-glycoprotein. Login to comment

PMID: 16004559 [PubMed] Hung CC et al: "Complex haplotypic effects of the ABCB1 gene on epilepsy treatment response."

No. Sentence Comment

40 The following 10 SNPs of the ABCB1 gene were identified by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) [15]: intron 1 (exon 2 -1) G/A, exon 2 A61G (amino acid exchange Asn21Asp), intron 6 (exon 6 +139) C/T, exon 11 G1199A (Ser400Asn), exon 12 C1236T, intron 12 (exon 12 +44) C/T, intron 16 (exon 17 -76) T/A, exon 21 G2677T (Ala893Ser), G2677A (Ala893Thr), and exon 26 C3435T. Login to comment

PMID: 16370938 [PubMed] Dey S et al: "Single nucleotide polymorphisms in human P-glycoprotein: its impact on drug delivery and disposition."

No. Sentence Comment

123 Location Position Mutation Effect Promoter 5`/-41 A→G Noncoding Exon 1a Exon 1a/-145 C→G Noncoding Exon 1b Exon 1b/-129 T→C Noncoding Intron 1 Exon 2/-4 C→T Noncoding Intron 1 Exon 2/-1 G→A Initiation of translation Exon 2 Exon 2/61 A→G Asn21Asp Intron 4 Exon 5/-35 G→C Intron 4 Exon 5/-25 G→T Exon 5 Exon 5/307 T→C Phe103Leu Intron 6 Exon 6/+139 C→T Intron 6 Exon 6/+145 C→T Exon 7 Exon 7/548 A→G Asn183Ser Exon 11 Exon 11/1119 G→A Ser400Asn Exon 12 Exon 12/1236 C→T Silent base change Intron 12 Exon 12/+44 C→T Exon 13 Exon 13/1474 C→T Arg492Cys Intron 16 Exon 17/-76 T→A Intron 17 Exon 17/+137 A→G Exon 21 Exon 21/2650 C→T Silent base change Exon 21 Exon 21/2677 G→T G→A Ala893Ser Ala893Thr Exon 24 Exon 24/2956 A→G Met986Val Exon 24 Exon 24/2995 G→A Ala999Thr Exon 26 Exon 26/3320 A→C Gln1107Pro Exon 26 Exon 26/3396 C→T Silent base change Exon 26 Exon 26/3421 T→A Ser1141Thr Exon 26 Exon 26/3435 C→T Silent base change Exon 28 Exon 28/4030 G→C Exon 28 Exon 28/4036 A→G The positions of the polymorphism are from the first base of the ATG start codon set to 1. Login to comment

PMID: 16374256 [PubMed] Urcelay E et al: "MDR1 gene: susceptibility in Spanish Crohn's disease and ulcerative colitis patients."

No. Sentence Comment

24 However, the C3435T variant together with another missense mutation, Asn21Asp, did not show association with any IBD in the latter study. Login to comment

PMID: 16415525 [PubMed] Sakaeda T et al: "MDR1 genotype-related pharmacokinetics: fact or fiction?"

No. Sentence Comment

29 Representative genetic polymorphisms in MDR1 Position Location EŠect A1aW-41G intron noncoding C-145G exon 1a noncoding T-129C (T12C) exon 1b noncoding C-4T exon 2 noncoding G-1A exon 2 noncoding A61G exon 2 Asn21Asp G5W-25T intron G5W-35C intron T307C exon 5 Phe103Leu C6W＋139T intron C6W＋145T intron A548G exon 7 Asn183Ser G1199A exon 11 Ser400Asn C1236T exon 12 silent C12W＋44T intron C1474T exon 13 Arg492Cys T17W-76A intron A17W＋137G intron C2650T exon 21 silent G2677A,T exon 21 Ala893Thr (G2677A) Ala893Ser (G2677T) A2956G exon 24 Met986Val G2995A exon 24 Ala999Thr A3320C exon 26 Gln1107Pro C3396T exon 26 silent T3421A exon 26 Ser1141Thr C3435T exon 26 silent G4030C exon 28 silent A4036G exon 28 silent See references 27, 32-36. Login to comment

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

No. Sentence Comment

171 Pharmacogenetics of HIV therapy Owen et al. 699 Table 1 Polymorphisms that have been studied within the context of metabolism, transport and toxicity (but not progression and response) along with the reference ID (where available), the genotypic consequence and the observed phenotype for antiretroviral drugs Gene SNP (haplotype) Reference SNP Genotypic consequence Phenotypic consequence Confirmation CYP3A4 A - 392G (CYP3A4*1B) rs2740574 Promoter; altered expression No effect on nelfinavir or efavirenz Yes for nelfinavir; controversial for efavirenz T878C (CYP3A4*18) rs4986909 L293P; altered activity No effect on efavirenz No CYP3A5 A6986G (CYP3A5*3) rs776746 Splice defect No effect on nelfinavir, saquinavir or efavirenz AUC but altered urinary metabolic ratio of saquinavir Yes for efavirenz G14690A (CYP3A5*6) rs10264272 Splice defect No effect on nelfinavir or efavirenz Yes CYP2C19 G681A (CYP2C19*2) rs4244285 Truncated protein Higher nelfinavir AUC and trend toward decreased virological failure; no effect on efavirenz Yes for efavirenz; controversial for nelfinavir CYP2D6 A2549del (CYP2D6*3) NT21914757 Frameshift Trend to higher plasma levels of nelfinavir and efavirenz No G1846A (CYP2D6*4) rs3892097 Splice defect Trend to higher plasma levels of nelfinavir and efavirenz No T1707del (CYP2D6*6) rs5030655 Frameshift Higher plasma nelfinavir concentrations No CYP2B6 G516 T (CYP2B6*6, *7, *9, *13, *19 and *20) rs3745274 Q172H Higher plasma and intracellular efavirenz AUCs and increased neurotoxicity Yes, numerous studies C1459T (CYP2B6*5 and *7) rs3211371 R487C No effect on nelfinavir or efavirenz No ABCB1 IVS1 - 80delG rs3214119 N/A No influence on cellular nelfinavir No A61G rs9282564 N21D No influence on cellular nelfinavir No TAG1 rs3789243 N/A No influence on cellular nelfinavir No G1199A rs2229109 S400N No influence on cellular nelfinavir No TAG5 rs1128503 N/A No influence on cellular nelfinavir No TAG6 rs2235046 N/A No influence on cellular nelfinavir No IVS21 + T49C rs2032583 N/A No influence on cellular nelfinavir No C3435T rs1045642 Synonymous Some evidence of an influence on plasma and intracellular nelfinavir; decreased efavirenz plasma concentrations; currently under debate; increase in HDL cholesterol with efavirenz Controversial G2677T rs2032582 Ala893Ser No effect on efavirenz, ritonavir, nelfinavir, indinavir or viral decay and CD4 count Yes IVS26 + T59G rs2235047 N/A No influence on cellular nelfinavir No IVS26 + T80C rs2235048 N/A Increased intracellular nelfinavir concentrations No TAG11 rs1186746 N/A No influence on cellular nelfinavir No TAG12 rs1186745 N/A No influence on cellular nelfinavir No ABCC1 G816A P272P No influence on cellular nelfinavir No T825C rs246221 V275V No influence on cellular nelfinavir No T1062C rs35587 Synonymous No influence on cellular nelfinavir No IVS9 + A8G rs35588 N/A No influence on cellular nelfinavir No IVS10 + C64T N/A No influence on cellular nelfinavir No ABCC2 C - 24T rs717620 N/A No influence on cellular nelfinavir No G1249A rs2273697 V417I No influence on cellular nelfinavir No C1436G Synonymous No influence on cellular nelfinavir No IVS16 - G47A N/A No influence on cellular nelfinavir No T3563A rs8187694 V1188E No influence on cellular nelfinavir No C4488T rs8187707 Synonymous No influence on cellular nelfinavir No IVS31 + G12A rs8187708 N/A No influence on cellular nelfinavir No IVS31 + C74T N/A No influence on cellular nelfinavir No G4544A rs8187710 C1515Y No influence on cellular nelfinavir No G + 259T N/A No influence on cellular nelfinavir No ABCG2 - 19571_ - 19568delT- CAC rs4148162 Deletion No influence on cellular nelfinavir No A-19541G N/A No influence on cellular nelfinavir No G34A rs2231137 V12M No influence on cellular nelfinavir No IVS2 + 35G rs4148152 N/A No influence on cellular nelfinavir No C421A rs2231142 Q141K No influence on cellular nelfinavir No APOCIII C-482T Pending Promoter Hyperlipidaemia in presence of ritonavir Yes T-455C Pending Promoter Hyperlipidaemia in presence of ritonavir Yes C3238G rs5128 30 UTR variant Hyperlipidaemia in presence of ritonavir Yes APOE 2060T/2198T (APOEe2) rs429358 R112C/R158C Hyperlipidaemia in presence of ritonavir Yes 2060T/2198C (APOEe3) rs7412 R112C/R158R Hyperlipidaemia in presence of ritonavir Yes TNFa G - 238A rs361525 Promoter Rapid development of lipoatrophy Controversial SPINK-1 C112T rs17107315 N34S Associated with risk of pancreatitis Yes, in general population CFTR G1717 - 1A Splice defect Associated with risk of pancreatitis Yes, in general population IVS8 5T Splice defect Associated with risk of pancreatitis Yes, in general population HLA-B HLA-B*57.1 N/A Abacavir hypersensitivity Yes, but not in all populations HLA-DR HLA-DRB1*0101 N/A Nevirapine hypersensitivity No HSPA1L C2437T rs2227956 M493T Abacavir hypersensitivity No UGT1A1 A(TA)7TAA, - 43_ - 42in- sTA (UGT1A1*28) rs8175347 Promoter; insertion at TATA box Gilberts syndrome, hyperbilirubinaemia in presence of atazanavir and indinavir but not saquinavir Yes MT-CO1 C7028T Synonymous Haplogroup T associated with greater incidence of peripheral neuropathy No 700 Pharmacogenetics and Genomics 2006, Vol 16 No The NNRTI nevirapine can also cause a hypersensitivity syndrome characterized by a rash with systemic symptoms; occasionally liver injury may be part of the clinical picture, or alternatively, may actually be the only manifestation. 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PMID: 17178267 [PubMed] Crettol S et al: "ABCB1 and cytochrome P450 genotypes and phenotypes: influence on methadone plasma levels and response to treatment."

No. Sentence Comment

24 P-gp is expressed in various human tissues, including the intestine, liver, kidneys, testes, lymphocytes, and blood-brain barrier.21 P-gp actively transports xenobiotics from the intracellular to the extracellular domain, resulting in a protective role against their potentially toxic accumulation, by enhancement of their elimination and limitation of their distribution in the body.22 The important role of P-gp in the limitation of access of xenobiotics to the brain has been demonstrated in vivo by studies on P-gp-deficient mice.23 The synonymous 3435CϾT single-nucleotide polymorphism (SNP) of the ABCB1 gene has been associated with lower P-gp expression.24 Since this first report by Hoffmeyer et al,24 contradictory results have been published on the impact of various ABCB1 SNPs (mostly 3435CϾT and 2677GϾT) on P-gp expression and function and on the kinetics of different P-gp substrates.21,25 Interestingly, it has recently been shown that the 3435TT genotype, in linkage disequilibrium with the 2677TT genotype, is associated with reduced P-gp expression resulting from a decrease in messenger ribonucleic acid stability.26 Another interesting SNP, ABCB1 61AϾG (N21D), is a nonsynonymous polymorphism. Login to comment

PMID: 17352537 [PubMed] Jeong H et al: "Function-altering SNPs in the human multidrug transporter gene ABCB1 identified using a Saccharomyces-based assay."

No. Sentence Comment

207 Third, only a few coding SNPs have been functionally tested, such as A893S and N21D, which our analysis predicted would have a weak functional impact [26]. Login to comment

PMID: 18183034 [PubMed] Wyen C et al: "Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients."

No. Sentence Comment

127 Genotyping for the CYP3A5*3 allele was done as described using a melting curve analysis technique.45,46 Genotyping for P-glycoprotein was done by direct sequencing of the MDR1 exons 2, 12, 21, and 26, including the single nucleotide polymorphisms C-4T, G-1A, A61G (Asn21Asp), C1236T (synonymous), G2677T (Ala893Ser), G2677A (Ala893Thr), and C3435T (synonymous). Login to comment

PMID: 18287207 [PubMed] Gow JM et al: "Substrate-dependent effects of human ABCB1 coding polymorphisms."

No. Sentence Comment

4 The A893S, A893T, and V1251I variants and the N21D/ 1236CϾT/A893S/3435CϾT haplotype altered intracellular accumulation compared with reference P-gp in a substrate-dependent manner. Login to comment
55 The following variants were created from the reference ABCB1 plasmid in pCIneo: 61AϾG (N21D), 1199GϾA (S400T), 1596TϾG [a nonfunctional nucleotide-binding domain (NBD) mutant], 2005CϾT (R669C), 2677GϾA (A893T), 3421TϾA (S1141T), and 3751GϾA (V1251I). Login to comment
103 There are six polymorphic residues that meet these criteria: N21D, S400T, R669C, A893S/T, S1141T, and V1251I. Login to comment
104 Residue 893 is interesting because it is triallelic and occurs naturally in haplotypes, with the two common synonymous SNPs, 1236CϾT and 3435CϾT as well as N21D (Kroetz et al., 2003). Login to comment
111 Intra-and interexperimental replicates (n ϭ 3) for reference, NBD, and variant P-gp samples have TABLE 2 Allele frequencies, evolutionary conservation, and Grantham values for selected ABCB1 nonsynonymous polymorphisms and haplotypes Variant or Haplotype Allele Frequenciesa Amino Acid Conservationc Grantham Valued Nucleotide Change Amino Acid Change AA (n ϭ 200) CA (n ϭ 200) Reference Variant % 61AϾG N21D 2.5 8 23 1199GϾA S400T 1 2.5 d, ha, mk ms, r 46 2005CϾT R669C 1 0 d, ha, mk, r, s 180 2677GϾT A893S 10 46.4 ha, ms, r d, mk, s 99 2677GϾA A893T 0.5 3.6 ha, ms, r 58 3421TϾA S1141T 11.1 0 d, ha, mk, ms, r, s 58 3751GϾA V1251I 0b 0 d, ha, mk, ms, r s 29 1236CϾT/2677GϾT/3435CϾT A893S 6 34 N.A. N.A. N.A. 61AϾG/1236CϾT/2677GϾT/3435CϾT N21D/A893S 2.5 8 N.A. N.A. N.A. N.A., not applicable. Login to comment
135 The representative histogram of APC fluorescence for empty vector (gray, dotted), NBD mutant (gray), reference (black), and variant-transfected cells (N21D, yellow; S400N, cyan; R669C, purple; A893S, green; A893T, orange; S1141T, pink; V1251I, blue; 1236CϾT/A893S/3435CϾT, brown; and N21D/1236CϾT/A893S/3435CϾT, red) shows P-gp expression based on the intensity of APC fluorescence, as indicated on the x-axis. Login to comment
141 The effects of cyclosporin A on calcein-AM accumulation are displayed in a representative histogram for P-gp reference (black, shaded), N21D (yellow), R669C (purple), and A893S (green). Login to comment
151 It is interesting that the N21D, R669C, and A893S variants are more sensitive to cyclosporin A (136 Ϯ 28, 139 Ϯ 43, and 130 Ϯ 22%, respectively; p Ͻ 0.05) compared to reference (Fig. 2c). Login to comment
156 The N21D, S400N, R669C, and A893T variants and the 1236CϾT/A893S/3435CϾT haplotype were within 5% of the reference (Fig. 3c). Login to comment
157 In contrast, the A893S and V1251I P-gp variants and the N21D/1236CϾT/A893S/ 3435CϾT haplotype showed intracellular paclitaxel levels that were 114 Ϯ 13, 118 Ϯ 12, and 124 Ϯ 13% of reference, respectively (p Ͻ 0.01), indicating decreased P-gp function. Login to comment
160 The haplotype containing N21D/1236CϾT/A893S/3435CϾT was 53 Ϯ 8% less sensitive to cyclosporin A inhibition than reference (p Ͻ 0.01). Login to comment
163 Six of 13 previously described nonsynonymous variants were chosen for study based on an allele frequency Ͼ2%: N21D, S400N, A893S, A893T, S1141T, and V1251I. Login to comment
170 The data collected in the absence of cyclosporin A for empty vector (gray, dotted), P-gp reference (black), NBD mutant (gray), A893S (green), V1251I (blue), and haplotype N21D/1236CϾT/A893S/3534CϾT (red) are shown in a representative fluorescence histogram (a). Login to comment
171 The effects of cyclosporin A on BODIPY-FL-paclitaxel accumulation are displayed in a representative histogram in b for P-gp reference (black, shaded), A893S (green), A893T (orange), S1141T (pink), V1251I (blue), and haplotype N21D/1236CϾT/A893S/3534CϾT (red). Login to comment
177 These haplotypes contained A893S, 1236CϾT, and 3435CϾT either with or without N21D. Login to comment
193 Previous work consistent with the current findings has shown that N21D, S400N, and A893S do not change calcein-AM transport (Kimchi-Sarfaty et al., 2002; Kroetz et al., 2003). Login to comment
206 In one study, the N21D, F103L, S400N, A893S, and A998T SNPs and three double mutants (N21N/S400N, N21D/A893S, and S400N/ A893S) were investigated using a vaccinia virus expression system with BODIPY-FL-paclitaxel, and no differences in function were noted among the variant and reference P-gps (Kimchi-Sarfaty et al., 2002). Login to comment
207 Our results are similar for N21D and S400N, but we found that A893S and N21D/A893S have decreased transport of BODIPY-FL-paclitaxel (Table 3). Login to comment
214 There was increased function for A893S and S1141T depending on the substrate, TABLE 3 Substrateand inhibitor-dependent effects of P-gp variants on transport function Variant or Haplotype Calcein-AM BODIPY-FL-Paclitaxel -CsAa ϩCsAb -CsA ϩCsA N21D 1 S400T R669C 1 A893S 1 2 2 A893T 1 2 S1141T 2 V1251I 1 2 2 1236CϾT/A893S/3435CϾT N21D/1236CϾT/A893S/3435CϾT 2 2 a Arrows indicate statistically significant changes in P-gp function relative to reference in the absence of cyclosporin A (-CsA). Login to comment
224 The N21D, R669C, and A893S P-gp variants show increased inhibition of calcein-AM transport by cyclosporin A. Login to comment
225 In contrast, the A893S, A893T, and S1141T variants and the N21D/1236CϾT/A893S/3435CϾT haplotype are less sensitive to cyclosporin A inhibition of BODIPY-FL-paclitaxel transport. Login to comment
229 Intracellular accumulation of calcein-AM and/or BODIPY-FL-paclitaxel was altered by A893S, A893T, V1251I, and N21D/1236CϾT/A893S/3435CϾT. Login to comment

PMID: 18300948 [PubMed] Vaclavikova R et al: "Single nucleotide polymorphisms in the multidrug resistance gene 1 (ABCB1): effects on its expression and clinicopathological characteristics in breast cancer patients."

No. Sentence Comment

79 Six SNPs in ABCB1 [( - 1)G > A, rs2214102; 61A > G, Asn21Asp, rs9282564; 1199G> A, Ser400Asn, rs2229109; 1236C> T, Gly412Gly, rs1128503; ( + 44)C > T, rs2032588 and 3435C > T, Ile1145Ile, rs1045642] were detected on the NanoChip Molecular Biology Workstation (Nanogen Inc.). Login to comment
154 Age, menopausal status, staging, tumor size, nodal status and histological type and grade of tumor did not significantly associate either with frequencies of Table 3 Distribution of ABCB1 genotypes and allele frequencies in breast cancer patients ABCB1 genotypea Nb Allele frequency ( - 1)G > A, rs2214102 G/G 77 (88.5) G (93.1) G/A 8 (9.2) A (6.9) A/A 2 (2.3) Total 87 61A > G, Asn21Asp, rs9282564 Asn/Asn 75 (84.3) Asn (91.6) Asn/Asp 13 (14.6) Asp (8.4) Asp/Asp 1 (1.1) Total 89 1199G > A, Ser400Asn, rs2229109 Ser/Ser 86 (95.6 Ser (97.8) Ser/Asn 4 (4.4) Asn (2.2) Asn/Asn 0 (0) Total 90 1236C > T, Gly412Gly, rs1128503 C/C 32 (35.6) C (61.7) C/T 47 (52.2) T (38.3) T/T 11 (12.2) Total 90 12( + 44)C > T, rs2032588 C/C 79 (89.8) C (93.8) C/T 7 (8.0) T (6.2) T/T 2 (2.2) Total 88 3435C > T, Ile1145Ile, rs1045642 C/C 17 (19.5) C (46.0) T/C 46 (52.9) T (54.0) T/T 24 (27.6) Total 87 a Protein positions are displayed for nonsynonymous single nucleotide polymorphisms (SNPs) in exons. Login to comment

PMID: 18334915 [PubMed] Crettol S et al: "Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients."

No. Sentence Comment

135 In this study, ABCB1 61A > G (N21D), 1236C > Tand 2677G > T (A893S) SNPs did not influence cyclosporine intracellular and blood concentrations. Login to comment

PMID: 18444945 [PubMed] Grinyo J et al: "Association of four DNA polymorphisms with acute rejection after kidney transplantation."

No. Sentence Comment

74 A417G (exon 28)a,b (0.87) rs3842 (0.86)g A61Gc (N21D) (0.91) rs9282564 (0.91)e C1236Ta (0.6) rs1128503 (0.61)e G2677T/Ac (0.58) rs2032582 (0.46)e Multi-drug resistance associated protein 2/adenosine triphosphate-binding cassette, subfamily c, member 2 (MRP2/ABCC2) T3972Cc Exon 28 (0.64) rs3740066 (0.66)e MRP2 is involved in the biliary excretion of mycophenolic acid glucuronide. Login to comment
121 Gene position and genotypes BPAR at 12 months No. patients BPAR incidence (%) Odds ratio P-value* CYP3A4 A-392G GG or AG 20 25.0 0.960 0.942 AAà 195 28.7 - CYP3A5 A6986G AA or AG 37 24.3 0.790 0.587 GGà 186 28.5 - ABCB1 A61G (N21D) GG or AG 37 32.4 1.46 0.362 AAà 180 26.7 - C3435T TT 53 37.7 4.19 0.0099 CT 117 29.9 2.6 CCà 56 16.1 - A417G GG or AG 53 18.9 0.519 0.099 AAà 167 29.9 - C1236T TT 41 43.9 3.9 0.009 CT 103 27.2 1.64 CC 87 20.7 - G2677T/A TT 39 43.6 4.93 0.003 GT 103 29.1 2.37 GA or TA 10 10 0.446 GG 73 17.8 - MRP2 G5`reg 6170A GG 40 27.5 1.26 0.853 AG 104 28.8 1.18 AAà 76 26.3 - T3600A AA or AT 30 16.7 0.363 0.053 TTà 189 29.1 - T3972C TT 31 25.8 1.38 0.63 CT 96 30.2 1.37 CCà 94 24.5 - IMPDH1 G1320A AA 15 33.3 1.0 0.571 AG 67 23.9 0.687 GGà 134 29.1 - IMPDH2 T3757C CC or CT 28 46.4 3.39 0.006 TTà 193 24.9 - Table 3. continued Gene position and genotypes BPAR at 12 months No. patients BPAR incidence (%) Odds ratio P-value* IL-2 T-330G GG 24 25 0.892 0.919 GT 94 28.7 1.06 TTà 105 27.6 - G114T TT 18 44.4 3.1 0.107 GT 97 26.8 0.885 GGà 109 25.7 - IL-10 C-592A AA 18 55.6 4.55 0.024 AC 72 25 0.897 CCà 127 25.2 - A-1082G GG 46 28.3 0.940 0.550 AG 105 23.8 0.688 AAà 69 33.3 - C-819T TT 13 53.8 4.23 0.104 CT 68 26.5 1.06 CC 119 24.4 - C851T CT or TT 6 16.7 0.460 0.465 CC 190 26.8 - TGF-b1 C869T (P10L) CC 37 29.7 1.40 0.214 CT 103 33 1.86 TTà 84 21.4 - C915G (R25P) CC or CG 37 32.4 1.2 0.662 GGà 187 27.8 - TNF-a G308A GA or AA 52 38.5 2.18 0.030 GG 170 24.7 - *P-value for the association test derived from the logistic regression using recipient age, gender, treatment group and donor type as covariates (see Materials and methods). Login to comment

PMID: 18668431 [PubMed] Zhou SF et al: "Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition."

No. Sentence Comment

296 Exon 2 contains a polymorphism that changes Asn-21 to Asp, and the mutation at exon 5 changes Phe-103 to Leu. Login to comment

PMID: 19685447 [PubMed] Huebner C et al: "Genetic analysis of MDR1 and inflammatory bowel disease reveals protective effect of heterozygous variants for ulcerative colitis."

No. Sentence Comment

53 Published MDR1 Genotype Studies Study Participants Population Analyzed SNPs Results Brant et al 2003 IBD_NJ¼211 Jewish and non-Jewish American c.2677G>T/A Association between G2677 allele and IBDHC_NJ¼392 c.3435C>T IBD_J¼114 p.Asn21Asp HC_J¼219 Schwab et al 2003 IBD¼275 German c.3435C>T Association between T3435 allele and UCUC¼149 CD¼126 No genotype-phenotype association HC¼998 Croucher et al 2003 IBD¼949 German c.3435C>T No genotype association CD¼629 UC¼320 HC¼531 IBD¼251 British CD¼164 UC¼87 HC¼164 Glas et al 2004 IBD¼258 German c.3435C>T Association between T3435 allele and UC when using control group 2CD¼135 UC¼123 No genotype association when using control group 1 or pooled controlsHC1¼145 HC2¼145 Gazouli et al 2004 IBD¼205 Greece c.3435C>T No genotype association CD¼120 UC¼85 HC¼100 Potocnik et al 2004 CD¼163 Slovenian c.2677G>T/A T2677 allele associated with UC UC¼144 c.3435C>T T1236 allele associated with UC IBD¼307 c.1236C>T (rs1128503) Intron 13 SNP C allele associated with UCHC¼355 C>T (50 upstream promoter) Intron 16 SNP associated with UC 129T>C (Promotor) 50 upstream promoter SNP associated with refractory CD Intron 1b_-81 del G Intron 41 SNP associated with refractory CD Intron 41_Ex04þ3854 G>T (rs1202172) T1236 allele associated with refractory CD Intron 42_Ex05-1100A>G Intron 13 SNP associated with refractory CD and proctitis Intron 13_Ex13þ81C>T (rs2235035) Intron 16 SNP associated with refractory CD Intron16_Ex17-76T>A (intronic) rs1922242 3 risk haplotypes identified for UC (1236T/2677T/3435T and Intron13C/Intron16A/2677T and 1236T/Intron13C/Intron16A/ 2677T/3435T) One protective haplotype identified for UC Intron13T/Intron16T/2677G) Risk Haplotype 1236T/2677T/3435T associated with refractory CD Intron13T/Intron16T/2677G haplotype protective in proctitis TABLE 1. Login to comment

PMID: 20212519 [PubMed] Leskela S et al: "Polymorphisms in cytochromes P450 2C8 and 3A5 are associated with paclitaxel neurotoxicity."

No. Sentence Comment

65 However, its effect on enzyme activity remains unclear.26 On the other hand, CYP3A5 is very polymorphic, and its activity in Caucasians is determined by CYP3A5*3 allele through alternative splicing.37 For the uptake transporters OATP 1B3 and OATP 1B1 we selected missense polymorphisms with reported functional consequences.17 Finally, for ABCB1 we selected the three most studied variants (1236C4T, 2677G4T and 3435C4T)27 associated with altered transport and a missense (N21D) polymorphism described in public databases but not previously studied. Login to comment

PMID: 21063774 [PubMed] Parkman HP et al: "Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects."

No. Sentence Comment

89 Between-group comparisons were carried out using analysis of Table 1 SNPs evaluated in this study, corresponding genes, and functional consequences of polymorphisms SNP marker Gene/allele Description Effect of genetic polymorphism rs1045642 ABCB1/3435T[C Transporter Ile1145Ile Decreased function rs2032582 ABCB1/2677T[G/A Transporter Ala893Ser Decreased function rs2229109 ABCB1/1199G[A Transporter Asn400Ser Decreased function rs9282564 ABCB1/61A[G Transporter Asn21Asp Decreased function rs3892097 CYP2D6*4/1846G[A Metabolism SNP in intron Loss of function rs5030655 CYP2D6*6/544del Metabolism Frame shift Loss of function rs35742686 CYP2D6*3/865del Metabolism Frame shift Loss of function rs6275 DRD2/1174C[T Dopamine receptor His313His Phenotype-associated allele rs6277 DRD2/1192T[C Dopamine receptor Pro319Pro Phenotype-associated allele rs727957 KCNE1 G/T Potassium voltage-gated channel, Isk-related member 1 SNP in intron Phenotype-associated allele rs16991652 KCNE2/165C[G Potassium voltage-gated channel, Isk-related member 2 Gln9Glu Phenotype-associated allele rs1805123 KCNH2/2703A[C Potassium voltage-gated channel H (eag-related) member 2 K897T Phenotype-associated allele rs3815459 KCNH2 A/G Potassium voltage-gated channel H (eag-related) member 2 SNP in intron Phenotype-associated allele rs757092 KCNQ1 A/G Potassium voltage-gated channel, KQT-like member 1 SNP in intron Phenotype-associated allele rs6107461 ADRA1D C/T Adrenergic receptor a1D SNP upstream of the gene rs6084673 ADRA1D G/A Adrenergic receptor a1D SNP upstream of the gene rs6052462 ADRA1D A/G Adrenergic receptor a1D SNP upstream of the gene rs4813680 ADRA1D C/A Adrenergic receptor a1D SNP upstream of the gene variance (ANOVA) for continuous data and Fisher`s exact test for categorical data. Login to comment
163 This non-synonymous SNP results in amino acid change Asn21Asp in the intracellular domain of P-gp transporter protein, and was demonstrated to modulate inhibition of calcein-AM transport by cyclosporine A [32]. Login to comment

PMID: 21103972 [PubMed] Cascorbi I et al: "P-glycoprotein: tissue distribution, substrates, and functional consequences of genetic variations."

No. Sentence Comment

13 Absence of the gene, as being the case in double-knockout mice, is conformable N21D S400N A893S/T Q1107P 3435C>T1236T>C N183S R492C S1141T NBD1 NBD2 Intracellular (e.g. lymphocyte) Extracellular M986V Fig. 1 Two-dimensional structure of ABCB1 with locations of amino acid replacements and two frequent synonymous SNPs, NBD ¼ nucleotide binding domain [adapted from Cascorbi and Haenisch (2010)] Inducer intra cellular ABCB1 Transkription Translation ABCB1 (P-gp) luminal Fig. 2 Induction of ABCB1 via the nuclear PXR/RXR receptor leading to accelerated extrusion of P-glycoprotein substrates with life. Login to comment
81 Table 2 Frequency of ABCB1 genetic variants in Caucasians, position on DNA, putative effect, and frequencies [according to Cascorbi (2006) and Cascorbi and Haenisch (2010)] Position Amino acid or effect Frequency of the variant allele Association to expression, kinetics or drug response 50 -flanking À2903 T>C 0.02a 50 -flanking À2410 T>C 0.10a Decreased mRNAa 50 -flanking À2352 G>A 0.28a 50 -flanking À1910 T>C 0.10a 50 -flanking À1717 T>C 0.02a 50 -flanking À1325 A>G 0.02a 50 -flanking À934 A>G 0.10a 50 -flanking À692 T>C 0.10a Decreased mRNAa 50 -flanking À41 A>G 0.09b IVS 1a À145 C>G 0.02b IVS 1b À129 T>C 0.06b IVS 1b 12 T>C 0.06c IVS 2 À1 G>A 0.09d c. 61 A>G N21D 0.11d IVS 5 À35 G>C Intronic 0.006c IVS 5 À25 G>T Intronic 0.16c IVS 6 þ139 C>T Intronic 0.37d c. 548 A>G N183S 0.01e c. 571 G>A G191R 0.07f Reduced chemotherapy resistancef c. 1199 G>A S400N 0.05d c. 1199 C>T S400I 0.02g Elevated activityg c. 1236 C>T Synonymous 0.41d Increased imatinib disposition and therapy responseh IVS 12 þ44 C>T Intronic 0.05d c. 1474 C>T R492C 0.01e IVS 17 À76 T>A Intronic 0.46d IVS 17 þ137 A>G Intronic 0.006c c. 2650 C>T Synonymous 0.03e c. 2677 G>T/A A893S/T 0.42d /0.02d In vitro increased vmax,i increased imatinib response in CMLh c. 2956 A>G M986V 0.005b c. 3320 A>C Q1107P 0.002d c. 3396 C>T Synonymous 0.03c c. 3421 T>A S1141T 0.00c c. 3435 C>T Synonymous 0.54d Decreased mRNA and protein expression,e, k decreased in vitro transport,l no effect on expression and bioavailability of talinolol,m no effect on in vitro transport,n, o decreased digoxin (continued) 4.2.1 Digoxin The heart glycoside digoxin is widely accepted as typical P-glycoprotein substrate. Login to comment

PMID: 21490239 [PubMed] Rudolph A et al: "Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes."

No. Sentence Comment

119 Table 2 Genotype frequencies and colorectal cancer risk estimates of polymorphisms in genes related to sex steroid signaling, transport, and metabolism in the female postmenopausal DACHS study population Gene Variant Genotype Effect estimate dbSNP rs# Amino acid substitution and functional consequence MAF Genotype N Co/N Ca OR (95% CI)a P trend ABCB1 rs1045642 I1145I, T allele associated with lower protein expression (Hoffmeyer et al. 2000) 49% T/T 183/190 1.00 T/C 329/336 1.04 (0.77-1.40) C/C 167/156 0.98 (0.69-1.39) 0.914 ABCB1 rs2229109 S400N, functional consequences unknown 6% G/G 596/614 1.00 G/A 86/64 0.69 (0.47-1.03) A/A 1/1 1.00 (0.03-33.9) 0.078 ABCB1 rs1202168 Intronic, functional consequences unknown, in high LD interval (Soranzo et al. 2004) 40% C/C 249/218 1.00 C/T 312/337 1.08 (0.82-1.42) T/T 119/127 1.02 (0.71-1.46) 0.829 ABCB1 rs9282564 N21D, results in a net charge change of the protein (Brinkmann and Eichelbaum 2001) 10% A/A 545/544 1.00 A/G 117/124 1.05 (0.76-1.45) G/G 12/9 0.73 (0.23-2.27) 0.997 ABCB1 rs2214102 50 -UTR, located at a translation initiation site (Hoffmeyer et al. 2000) 7% G/G 593/580 1.00 G/A 81/97 1.33 (0.91-1.92) A/A 6/6 0.96 (0.26-3.51) 0.208 SHBG rs6259 D356N, A allele is associated with reduced clearance of SHBG (Cousin et al. 1998) 11% G/G 525/549 1.00 G/A 141/115 0.69 (0.50-0.95) A/A 6/10 1.13 (0.36-3.60) 0.061 ESR2 rs1255998 30 -UTR, functional consequences unknown, G allele associated with endometrial cancer risk (Ashton et al. 2009) 12% C/C 519/547 1.00 C/G 138/114 0.76 (0.55-1.04) G/G 14/5 0.33 (0.11-1.01) 0.015 ESR2 rs928554 30 -UTR, G allele might create new acceptor splice site (MARIE-GENICA-Consortium 2010a) 40% A/A 246/222 1.00 A/G 316/317 1.19 (0.90-1.56) G/G 111/133 1.48 (1.03-2.13) 0.032 ESR2 rs4986938 30 -UTR, potentially affects pre-mRNA splicing (Zheng et al. 2003) 38% G/G 260/264 1.00 G/A 310/306 0.97 (0.74-1.27) A/A 99/106 1.02 (0.70-1.48) 0.997 ESR2 rs1271572 50 -UTR, might modulate binding of transcription factors (MARIE-GENICA-Consortium 2010a) 42% G/G 231/208 1.00 G/T 329/330 1.29 (0.97-1.70) T/T 120/138 1.40 (0.98-2.00) 0.046 ESR1 rs851984 50 -UTR, functional consequences unknown, T allele associated with breast cancer risk (MARIE-GENICA-Consortium 2010a) 41% C/C 221/231 1.00 C/T 341/314 0.95 (0.72-1.25) T/T 103/122 1.07 (0.74-1.55) 0.833 ESR1 rs2881766 50 -UTR, functional consequences unknown, G allele associated with breast cancer risk (MARIE-GENICA-Consortium 2010a) 18% T/T 461/453 1.00 T/G 190/195 1.02 (0.77-1.35) G/G 25/22 0.95 (0.48-1.87) 0.989 ESR1 rs2071454 50 -UTR, functional consequences unknown 11% T/T 536/551 1.00 T/G 132/120 0.81 (0.59-1.12) G/G 5/8 1.75 (0.51-6.03) 0.467 ESR1 rs2077647 S10S, potentially affects mRNA structure (Tanaka et al. 2003) 47% A/A 183/187 1.00 A/G 347/349 0.97 (0.73-1.30) G/G 140/135 0.93 (0.65-1.33) 0.697 ESR1 rs827421 Intronic, functional consequences unknown 48% T/T 172/178 1.00 T/C 350/355 1.02 (0.76-1.37) C/C 151/143 0.91 (0.64-1.30) 0.620 ESR1 rs2234693 Intronic, C allele introduces a binding site for transcription factor B-myb, leading to altered transcription (Herrington et al. 2002) 46% T/T 188/209 1.00 T/C 348/341 0.93 (0.70-1.24) C/C 136/120 0.87 (0.61-1.24) 0.429 ESR1 rs9340799 Intronic, functional consequences unknown, may lead to altered transcription or splicing (Schuit et al. 2004) 36% A/A 274/287 1.00 A/G 319/317 1.01 (0.78-1.32) G/G 83/72 0.94 (0.63-1.42) 0.864 ESR1 rs3798577 30 -UTR, functional consequences unknown 45% T/T 203/189 1.00 T/C 328/330 1.14 (0.86-1.52) C/C 139/154 1.27 (0.89-1.80) 0.181 Table 2 continued Gene Variant Genotype Effect estimate dbSNP rs# Amino acid substitution and functional consequence MAF Genotype N Co/N Ca OR (95% CI)a P trend ESR1 rs910416 30 near gene, functional consequences unknown, modified estrogen monotherapy- associated breast cancer risk (MARIE-GENICA-Consortium 2010a) 48% T/T 178/188 1.00 T/C 338/314 0.81 (0.61-1.10) C/C 148/159 0.92 (0.65-1.31) 0.599 PGR rs1042838 V660L, SNP possibly affects receptor dimerization, nuclear localization, ligand binding, cofactor interaction (Agoulnik et al. 2004) 15% C/C 495/478 1.00 C/A 154/181 1.32 (0.99-1.76) A/A 24/16 0.91 (0.44-1.88) 0.202 PGR rs1379130 G393G, functional consequences unknown 36% G/G 272/298 1.00 G/A 311/268 0.74 (0.56-0.96) A/A 88/108 1.01 (0.69-1.47) 0.412 PGR rs10895068 50 -UTR, creates new transcription start site, increasing expression of PR-B isoform (De Vivo et al. 2002) 4% G/G 615/619 1.00 G/A 58/59 0.89 (0.58-1.38) A/A 1/1 1.94 (0.05-80.6) 0.670 PGR rs518162 50 -UTR, SNP is located between PR-B and PR-A transcription start sites, potentially affecting PR-A/B expression (De Vivo et al. 2002) 7% G/G 580/586 1.00 G/A 93/88 1.06 (0.74-1.53) A/A 3/4 1.23 (0.21-7.06) 0.710 NR1I2 rs1523127 50 -UTR, belongs to a haplotype incl. SNPs that introduce new transcription factor binding sites (Zhang et al. 2001) 39% A/A 245/258 1.00 A/C 326/317 0.89 (0.68-1.17) C/C 98/88 0.89 (0.61-1.32) 0.450 NR1I2 rs2276706 Intronic, belongs to a haplotype incl. SNPs that introduce new transcription factor binding sites (Zhang et al. 2001) 38% G/G 251/267 1.00 G/A 329/324 0.92 (0.70-1.20) A/A 95/83 0.89 (0.60-1.31) 0.474 NR1I2 rs1464603 Intronic, functional consequences unknown 32% T/T 303/307 1.00 T/C 310/291 1.05 (0.80-1.36) C/C 65/78 1.11 (0.73-1.69) 0.608 NR1I2 rs6785049 Intronic, G allele associated with increased induction of CYP3A (Zhang et al. 2001) 38% A/A 260/264 1.00 A/G 323/313 1.00 (0.77-1.31) G/G 94/101 1.10 (0.75-1.60) 0.698 NR1I2 rs2276707 Intronic, T allele associated with increased induction of CYP3A (Zhang et al. 2001) 17% C/C 446/439 1.00 C/T 180/190 1.00 (0.75-1.32) T/T 21/24 1.19 (0.58-2.44) 0.794 NR1I2 rs1054191 30 -UTR, A allele associated with decreased induction of CYP3A (Zhang et al. 2001) 14% G/G 499/518 1.00 G/A 161/143 0.95 (0.70-1.28) A/A 17/12 0.80 (0.35-1.87) 0.581 NR1I2 rs3814057 30 -UTR, C allele associated with decreased induction of P-glycoprotein (Zhang et al. 2001) 17% A/A 458/440 1.00 A/C 177/201 1.15 (0.87-1.52) C/C 22/24 1.20 (0.60-2.41) 0.307 COMT rs4680 V158M, A allele leads to thermo-labile protein and 2-3 fold lower catalytic activity (Dawling et al. 2001) 49% G/G 171/177 1.00 A/G 343/327 0.88 (0.66-1.19) A/A 162/175 1.05 (0.74-1.48) 0.802 HSD17B1 rs605059 G313S, functional consequences unknown, C allele has been associated with lower estradiol levels (Setiawan et al. 2004) 46% T/T 199/167 1.00 T/C 330/340 1.30 (0.97-1.75) C/C 144/170 1.41 (0.99-2.01) 0.051 CYP1B1 rs1800440 N453S, G allele leads to enzyme which catalyzes hydroxylation of estradiol more efficiently (Hanna et al. 2000) 19% A/A 452/467 1.00 A/G 202/187 0.89 (0.68-1.18) G/G 26/22 0.81 (0.40-1.62) 0.342 CYP1B1 rs1056836 L432V, G allele leads to enzyme with increased activity (Shimada et al. 1999) 41% C/C 224/220 1.00 C/G 339/320 1.00 (0.75-1.32) G/G 106/128 1.31 (0.91-1.88) 0.209 CYP1B1 rs1056827 A119S, T allele leads to enzyme which catalyzes hydroxylation of estradiol more efficiently (Hanna et al. 2000) 31% G/G 317/323 1.00 G/T 304/297 0.90 (0.70-1.17) T/T 57/55 0.85 (0.54-1.35) 0.362 continued gene ESR1 (interaction ORZ1.49, 95% CI 1.04-2.13, P interactionZ0.03). 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PMID: 21625253 [PubMed] Wolf SJ et al: "An update on ABCB1 pharmacogenetics: insights from a 3D model into the location and evolutionary conservation of residues corresponding to SNPs associated with drug pharmacokinetics."

No. Sentence Comment

131 These are E3/61A4G (N21D), E5/266C4T (M89T), E17/1985T4C (L662R), E17/2005C4T (R669C). Login to comment
132 When in haplotype with the intensely studied SNPs E13/1236C4T (#s6), E22/2677G4T/A (#ns22) and E27/3435C4T (#s20), SNP E3/61A4G (N21D), which cannot be mapped to the 3D crystal structure, was reported to increase BODIPY-FL-paclitaxel accumulation and modulate the effect of cyclosporine A on the intracellular accumulation of BODIPY-FL-paclitaxel transport.50 However, the N21D substitution was found not to influence cyclosporine A pharmacokinetics in another study.51 In yet another study, the N21D polymorphism was reported to influence the trough but not the peak plasma levels concentration of methadone.52 Using a yeast-based assay, SNP E27/3421T4A (S1141T) (#ns33) and several SNPs that cannot be mapped to the crystal structure (E5/266C4T (M89T), E17/1985T4C (L662R), E17/2005C4T (R669C)) were reported to increase drug resistance to two or more drugs whereas SNP E27/ 3322T4C (W1108R) (#ns31) decreased drug resistance.49 Curiously, in another study, the E17/2005C4T (R669C) SNP was reported to be associated with decreased resistance to paclitaxel and etoposide in transfected LLC-PK1 cells.53 The increased resistance by SNP E17/2005C4T (R669C) was found to be reversed by SNP E27/3322T4C (W1108R) (#ns31).49 In another study using HEK293T cells, SNP E27/3421T4A (S1141T) (#ns33) was reported to be less sensitive to cyclosporine A inhibition of BODIPY-FL-paclitaxel transport.50 It was suggested that as the resistance profiles of SNPs E27/3421T4A (S1141T) (#ns33), E27/3322T4C (W1108R) (#ns31) and diplotype E27/3322T4C (W1108R)- E17/ 2005C4T (R669C)) display the largest variation across substrates, the region where S1141T (#ns33) and W1108R (#ns31) reside might contribute to the substrate discrimination activity of P-gp.49 The 3D crystal structure reveals that both S1141T (#ns33) and W1108R (#ns31) reside at the C-terminal NBD of the P-gp protein with S1141T (#ns33) residing on the outer surface and W1108R (#ns31) residing in the interior of the NBD (Figures 2b, 4d and 4e and flash movie http:// pfs.nus.edu.sg/demo_src/abcb1.html). Login to comment

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

No. Sentence Comment

6832 Nucleotide Change Amino Acid Change In Vitro Function Protein Expression/ Localization ABCB1 MDR1 A61G N21D ↔ N.D. T307C F103L N.D. N.D. G1199A S400N 1↔ Normal C2005T R669C ↔ N.D. G2677T A893S 21↔ Normal G2677A A893T 1↔ Notmal T3421A S1141T 2↔ N.D. C3435T I1145I 2↔ N.D. G3751A V1251I 2 N.D. 2, reduced function; 1, increased function; ↔, no change in function; N.D. not determined. Login to comment

PMID: 22565165 [PubMed] Grover S et al: "Genetic association analysis of transporters identifies ABCC2 loci for seizure control in women with epilepsy on first-line antiepileptic drugs."

No. Sentence Comment

87 - 330-21247T > C Intron 1 0.005 6 rs4148731 chr7:87239329 c.-330 - 8935C > T Intron 1 0.000 7 rs9282564 chr7:87229440 c.61A > G Exon 3 (Asn21Asp) 0.000 8 rs9282565 chr7:87214875 c.239C > A Exon 5 (Ala80Glu) 0.000 9 rs28381826 chr7:87214531 c.286 + 297G > A Intron 5 0.000 10 rs1989830 chr7:87205663 c.287 - 6124C > T Intron 5 0.135 11 rs2520464 chr7:87201086 c.287 - 1547A > G Intron 5 0.409 12 rs2235023 chr7:87190452 c.827+ 127G > A Intron 9 0.000 13 rs10276036 chr7:87180198 c.1000 - 44C > T Intron 10 0.401 14 rs2229109 chr7:87179809 c.1199G > A Exon 12 (Ser400Asn) 0.000 15 rs1128503 chr7:87179601 c.1236T > C Exon 13 (Gly412Gly) 0.390 16 rs2235036 chr7:87175271 c.1795G > A Exon 16 (Ala599Thr) 0.000 17 rs2235039 chr7:87165854 c.2401G > A Exon 21 (Val801Met) 0.000 18 rs2235040 chr7:87165750 c.2481 + 24G > A Intron 21 0.155 19 rs2032581 chr7:87160810 c.2485A > G Exon 22 (Ile829Val) 0.000 20 rs2032582 chr7:87160618 c.2677T/A > G Exon 22 (Ser/Thr893Ala) 0.318 21 rs7779562 chr7:87144816 c.3085 -72G > C Intron 25 0.043 22 rs2707944 chr7:87144641 c.3188C > G Exon 26 (Ala1063Gly) 0.000 23 rs2229107 chr7:87138659 c.3421A > T Exon 27 (Thr1141Ser) 0.000 24 rs1045642 chr7:87138645 c.3435T > C Exon 27 (Ile1145Ile) m Expression and activity [28] m mRNA expression [29] Altered substrate specificity [30] 0.375 25 rs2235048 chr7:87138511 c.3489 + 80C > T Intron 27 0.381 26 rs17064 chr7:87133470 c.3932A > T 30 UTR 0.000 ABCC1 1 rs504348 chr16:16043174 rs50438C > G Near gene region k Promoter activity [31] 0.135 2 rs215106 chr16:16047542 c.48 + 3886A > G Intron 1 0.210 3 rs215049 chr16:16070768 c.48 + 27112G > C Intron 1 0.245 4 rs246220 chr16:16082128 c.49 - 19545C > G Intron 1 0.118 5 rs119774 chr16:16086833 c.49 - 14840G > A Intron 1 0.089 6 rs246217 chr16:16090354 c.49 - 11319C > A Intron 1 0.118 7 rs2014800 chr16:16099966 c.49 - 1707C > T Intron 1 0.398 8 rs41494447 chr16:16101842 c.218C > T Exon 2 (Thr73Ile) 0.000 9 rs4781712 chr16:16103232 c.226 - 401A > G Intron 2 0.355 10 rs246240 chr16:16119024 c.616 -7942A > G Intron 5 0.114 11 rs924135 chr16:16123459 c.616 - 3507A > T Intron 5 0.412 12 rs903880 chr16:16130514 c.809 + 54C > A Intron 7 0.147 13 rs8187852 chr16:16139709 c.1057G > A Exon 9 (Met353Val) 0.000 14 rs35587 chr16:16139714 c.1062T > C Exon 9 (Asn354Asn) 0.182 15 rs35592 chr16:16141823 c.1219 - 176T > C Intron 9 0.172 16 rs60782127 chr16:16142079 c.1299G > T Exon 10 (Arg433Ser) k Transport of leukotriene C4 and estrone sulfate [32] 0.008 17 rs3765129 chr16:16149901 c.1474 - 48C > T Intron 11 0.032 18 rs35597 chr16:16158034 c.1678 - 3979G > A Intron 12 0.320 19 rs35621 chr16:16168608 c.1913 - 1575C > T Intron 14 0.103 20 rs45511401 chr16:16173232 c.2012G > T Exon 16 (Gly671Val) 0.024 21 rs4148356 chr16:16177275 c.2168G > A Exon 17 (Arg723Gln) 0.000 22 rs3851713 chr16:16184873 c.2644 + 428A > T Intron 19 0.340 23 rs2239995 chr16:16192565 c.2645 - 3919G > A Intron 19 0.324 24 rs11864374 chr16:16201885 c.2871 + 1155G > A Intron 21 0.338 25 rs35529209 chr16:16205325 c.2965G > A Exon 22 (Thr989Ala) k Transport of estradiol 17b-glucuronide [32] 0.000 26 rs3887893 chr16:16205501 c.3079 + 62G > A Intron 22 0.448 27 rs13337489 chr16:16208683 c.3140G > C Exon 23 (Ser1047Cys) 0.000 28 rs2299670 chr16:16220858 c.3819 + 1090A > G Intron 26 0.399 29 rs8057331 chr16:16230411 c.4202C > T Exon 29 (Thr1401Met) 0.000 30 rs212090 chr16:16236004 c.5462T > A 30 UTR 0.357 31 rs212093 chr16:16237754 rs212093G > A Near gene region 0.429 32 rs4148382 chr16:16238494 rs4148382G > A Near gene region 0.034 ABCC2 1 g.-1774G > delG chr10:101535688 g.-1774G > delG Near gene region k Promoter activity [33] 0.000 2 rs1885301 chr10:101541053 c.-1549G > A Near gene region k Promoter activity [haplotype containing (- 1549A)-(- 24T)] [33] k Clearance of irinotecan (ABCC2*2 containing the G allele) [34] 0.379 450 Pharmacogenetics and Genomics 2012, Vol 22 No 6 Table 2 (continued) N dbSNP ida Positionb Allelesc Gene location (effect) Function MAF 3 rs2804402 chr10:101541583 c. Login to comment

PMID: 22688145 [PubMed] Parkman HP et al: "Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters."

No. Sentence Comment

87 SNPs Evaluated in This Study With Corresponding Genes and Functional Consequences of Polymorphisms Genes/Alleles SNP Markers Function Effect of Genetic Polymorphism CYP2D6 rs1080985 Oxidative metabolism SNP in intron Phenotype-associated allele CYP2D6 rs16947 Oxidative metabolism Cys245Arg Phenotype-associated allele CYP2D6 rs3892097 Oxidative metabolism SNP in intron Loss of function CYP1A2 rs2069514 Oxidative metabolism Upstream region Phenotype-associated allele CYP1A2 rs762551 Oxidative metabolism Upstream region Phenotype-associated allele DRD3 rs7625282 Dopamine receptor Intron DRD2 rs1799978 Dopamine receptor Upstream region Phenotype-associated allele DRD2 rs6275 Dopamine receptor His313His Phenotype-associated allele DRD2 rs6277 Dopamine receptor Pro319Pro Phenotype-associated allele ABCB1 rs1045642 Drug transporter Ile1145Ile Decreased function ABCB1 rs9282564 Drug transporter Asn21Asp Decreased function HTR4 rs10078551 Serotonin receptor 4 Forms a haplotype HTR4 rs7713886 Serotonin receptor 4 Forms a haplotype HTR4 rs7735184 Serotonin receptor 4 SNP in intron HTR4 rs9325104 Serotonin receptor 4 SNP in intron KCNH2 rs1805123 Potassium voltage-gated channel H (eag-related), member 2 K897T Phenotype-associated allele KCNH2 rs3807375 Potassium voltage-gated channel H (eag-related), member 2 Phenotype-associated allele (QT prolongation) KCNH2 rs3815459 Potassium voltage-gated channel H (eag-related), member 2 SNP in intron Phenotype-associated allele (QT interval) ADRA1D rs2236554 Adrenergic receptor a1D 30 -UTR ADRA1D rs709024 Adrenergic receptor a1D 30 -UTR SNP indicates single nucleotide polymorphism. Login to comment

PMID: 20504109 [PubMed] Choong E et al: "The permeability P-glycoprotein: a focus on enantioselectivity and brain distribution."

No. Sentence Comment

209 Different SNPs were associated with the phenotype of remission, and carriers of the C allele for the rs2032583 genotype had higher odds ratio for remission (7.72, 95% CI 2.8 -- 21.3) at 4 weeks Exon 7 Exon 13 Exon 11Exon 2 Exon 8 Exon 6 Exon 3 Exon 4 Exon 9 Exon 17 Exon 10 Exon 14 Exon 12 Exon 15 Exon 16 Exon 19 Exon 21 Exon 18 Exon 23 Exon 24 Exon 28 Exon 27 Exon 20 Exon 22 A893S Exon 25 Exon 26 Exon 5 N21D N183S N400S Variant (548G, Ser183) MDR1*1 (548A, Asn183) Variant (2677T, Ser893) S1141T ATP-binding domain ATP-binding domain MDR1*1 (2677g, Ala893) R492C A. B. Figure 2. Login to comment

PMID: 19285158 [PubMed] Fung KL et al: "A synonymous polymorphism in a common MDR1 (ABCB1) haplotype shapes protein function."

No. Sentence Comment

152 A study in our lab showed that common polymorphisms of MDR1 at 61ANG (N21D), 307TNC (F103L), 1199GNA (S400N), 2677GNT (A893S) and 2995GNA (A999T) do not change the transport of four MDR1 substrates when expressed at high levels in human cells [66]. Login to comment
153 A recent study by Gow et al. suggested that all of the SNPs they tested (N21D, S400N, R669C, A893S, A893T, S1141T, V1251I) produced small changes which in most cases are not statistically significant [59]. Login to comment
227 Protein function is different depending on substrate use 1236T-3435T 2677T-3435T 1236T-2677T-3435T 1236T-2677T-3435A Hung CC et al. 2008 [93] Flp-In HEK-293 Stable No difference 1236T-2677A Rhodamine 123 Calcein-AM, phenytoin, cyclosporine A, phenobarbital valproic acid, lamotrigine, carbamazepine, gabapentin, levetiracetam Certain inhibitors against Rhodamine 123 transport are less effective in double haplotype and TTT haplotype 1236T-2677T 1236T-3435T 2677A-3435T 2677T-3435T 1236T-2677A-3435T 1236T-2677T-3435T Salama NN et al. 2006 [91] LLC-PK1 Stable No apparent difference 1236T-2677T Rhodamine 123, vincristine, vinblastine Single or haplotype mutations had significant decrease in MDR1 function1236T-3435T 2677T-3435T 1236T-2677T-3435T GOW JM et al. 2008 [59] HEK-293T Transient No difference 1236T-2677T-3435T Calcein-AM, cyclosporine A, BODIPY-FL-paclitaxel TTT haplotype with N21D mutation reduces MDR1 function with BODIPY-FL-paclitaxel but not Calcein-AM. Login to comment
151 A study in our lab showed that common polymorphisms of MDR1 at 61ANG (N21D), 307TNC (F103L), 1199GNA (S400N), 2677GNT (A893S) and 2995GNA (A999T) do not change the transport of four MDR1 substrates when expressed at high levels in human cells [66]. Login to comment
226 Protein function is different depending on substrate use 1236T-3435T 2677T-3435T 1236T-2677T-3435T 1236T-2677T-3435A Hung CC et al. 2008 [93] Flp-In HEK-293 Stable No difference 1236T-2677A Rhodamine 123 Calcein-AM, phenytoin, cyclosporine A, phenobarbital valproic acid, lamotrigine, carbamazepine, gabapentin, levetiracetam Certain inhibitors against Rhodamine 123 transport are less effective in double haplotype and TTT haplotype 1236T-2677T 1236T-3435T 2677A-3435T 2677T-3435T 1236T-2677A-3435T 1236T-2677T-3435T Salama NN et al. 2006 [91] LLC-PK1 Stable No apparent difference 1236T-2677T Rhodamine 123, vincristine, vinblastine Single or haplotype mutations had significant decrease in MDR1 function 1236T-3435T 2677T-3435T 1236T-2677T-3435T GOW JM et al. 2008 [59] HEK-293T Transient No difference 1236T-2677T-3435T Calcein-AM, cyclosporine A, BODIPY-FL-paclitaxel TTT haplotype with N21D mutation reduces MDR1 function with BODIPY-FL-paclitaxel but not Calcein-AM. Login to comment

PMID: 16504381 [PubMed] Kerb R et al: "Implications of genetic polymorphisms in drug transporters for pharmacotherapy."

No. Sentence Comment

76 Table 3 Overview of the 15 most common ABCB1 (MDR1) genetic variants Position Location Effect Allelic frequency (%) CA AS AA K129TOC 50 UTR Non-coding 5 4 7 K1GOA 50 UTR Non-coding 8 5 0 61AOG Exon 2 Asn21Asp 8 2 2.5 Exon 5-25GOT Intron 4 16 7 30 Exon 10-44AOG Exon 10 Intron 9 45 69 26 1199GOA Exon 11 Ser400Asn 2.5 0 !1 1236COT Exon 12 Synonymous 46 69 21 Exon 11C44COT Intron 12 5 0 17 Exon 12C24COT Intron 13 52 54 54 Exon 13C38AOG Intron 14 50 68 54 Exon 19C24GOA Intron 20 12 7 15 2677GOT/A Exon 21 Ala893Ser/Thr 46/2 45/7 O1 3421TOA Exon 26 Ser1141Thr 0 0 10 3435COT Exon 26 Synonymous 56 40 10 IVSC21TOC Intron 28 0 8 0 AA, African American; AS, Asian; CA, Caucasian. Login to comment
75 Table 3 Overview of the 15 most common ABCB1 (MDR1) genetic variants Position Location Effect Allelic frequency (%) CA AS AA K129TOC 50 UTR Non-coding 5 4 7 K1GOA 50 UTR Non-coding 8 5 0 61AOG Exon 2 Asn21Asp 8 2 2.5 Exon 5-25GOT Intron 4 16 7 30 Exon 10-44AOG Exon 10 Intron 9 45 69 26 1199GOA Exon 11 Ser400Asn 2.5 0 !1 1236COT Exon 12 Synonymous 46 69 21 Exon 11C44COT Intron 12 5 0 17 Exon 12C24COT Intron 13 52 54 54 Exon 13C38AOG Intron 14 50 68 54 Exon 19C24GOA Intron 20 12 7 15 2677GOT/A Exon 21 Ala893Ser/Thr 46/2 45/7 O1 3421TOA Exon 26 Ser1141Thr 0 0 10 3435COT Exon 26 Synonymous 56 40 10 IVSC21TOC Intron 28 0 8 0 AA, African American; AS, Asian; CA, Caucasian. Login to comment

PMID: 16529292 [PubMed] Li YH et al: "MDR1 gene polymorphisms and clinical relevance."

No. Sentence Comment

43 The A61G mutationexpression and function (Asn21Asp) may contribute to a net charge change (basic to acidic) close to the N-terminus of P-gp, which appears to be of minor functional importance '3y1. Login to comment
52 Furthermore, Kimchi-Sarfaty and his colleagues carried out a study to characterize the functional consequences of five coding SNPs (Asn21Asp,Phel03Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system, but it was found that the distribution and function of P-gp in the cells were similar to wild-type P-gp in the human body'431.The mechanism of these contradictory results regarding the C2677T/A and C3435T polymorphisms function is unclear until now. Login to comment
50 The A61G mutation expression and function (Asn21Asp) may contribute to a net charge change (basic to acidic) close to the N-terminus of P-gp, which appears to be of minor functional importance '3y1. Login to comment
64 Furthermore, Kimchi-Sarfaty and his colleagues carried out a study to characterize the functional consequences of five coding SNPs (Asn21Asp,Phel03Leu, Ser400Asn, Ala893Ser, Ala999Thr) using a vaccinia virus-based transient expression system, but it was found that the distribution and function of P-gp in the cells were similar to wild-type P-gp in the human body'431.The mechanism of these contradictory results regarding the C2677T/A and C3435T polymorphisms function is unclear until now. Login to comment

PMID: 14610718 [PubMed] Brant SR et al: "MDR1 Ala893 polymorphism is associated with inflammatory bowel disease."

No. Sentence Comment

4 Two missense mutations, Asn21Asp and Ala893Ser/Thr, as well as the expression-associated polymorphism C3435T, described elsewhere, were genotyped in the entire cohort. Login to comment
5 Significant association of Ala893 with IBD was observed by both case-control analysis ( ) and the pedigreeP p .002 disequilibrium test (PDT [ ]) but not for the Asn21Asp or C3435T polymorphisms. Login to comment
41 In this article, we examine the Asn21Asp variant, as well as functionally associated polymorphisms on Ala893Ser/Thr and C3435T. Login to comment
65 The Asn21Asp (forward primer: 5-ATGGAGGAGCAAAGAAGAAG- AACTT-3; reverse primer: 5-CGCAACTATGTAAAC- TATGAAAATGAAAC-3; VIC [WT probe]: 5-AACTG- AACAATAAAAGG-3; FAM [rare probe]: 5-CTGAAC- GATAAAAGG-3) and C3435T polymorphisms (forward primer: 5 -AACAGCCGGGTGGTGTCA-3 ; reverse primer: 5 -ATGTATGTTGGCCTCCTTTGCT-3 ; VIC [WT probe]: 5 -CTCACGATCTCTTC-3 ; FAM [rare probe]: 5-CCTCACAATCTCTT-3) were genotyped using Taqman amplification and were detected using the ABI Prism 7700 Sequence Detection System. Login to comment
82 We identified four exonic SNPs: in exon 2 (A61G-Asn21Asp), exon 12 (C1236T), exon 21 (G2677T/A-Ala893Ser/Thr), and exon 26 (C3435T) (table 2). Login to comment
86 Because the Ala893Ser/Thr and C3435T polymorphisms have been associated with altered MDR1function, and because the Asn21Asp polymorphism represents a nonconserved amino acid variation that could potentially alter function, we typed these variants in a large cohort of patients with IBD to test for disease association. Login to comment
88 For the Asn21Asp variant, no evidence for IBD association was observed ( ). Login to comment
101 The combined analysis of the two ethnic groups (calculated as the sum of the individual cohort statistics) was for alleles and was for genotypes.P p .002 P p .008 Table 4 Global P Values by PDT Analysis of Exonic SNPs SNP GLOBAL P FOR PDT ANALYSIS FOR CD UC IBD Sum Average Sum Average Sum Average Asn21Asp .24 .15 .26 .56 .8 .39 Ala893Ser/Thr .0014 .00090 .29 .16 .00030 .00020 C3435T .42 .31 .93 .60 .63 .35 limited power to identify modest differences. Login to comment
110 Table 4 demonstrates the results by PDT for the Asn21Asp, Ala893Ser/ Thr, and C3435T polymorphisms among patients with CD, UC, and IBD. Login to comment
112 For the entire cohort with IBD, significant evidence for association was observed for the Ala893Ser/Thr polymorphism ( ), and no evidence was observedP p .00020-.00030 for the Asn21Asp or C3435T polymorphisms. Login to comment
113 Separate evaluation by CD and UC phenotypes showed no evidence of a CD association for the Asn21Asp or the C3435T polymorphisms. Login to comment
116 Because the numberP p .16-.29 of subjects with UC is significantly smaller than the num- Table 5 PDT Analysis of the Tri-Allelic Exon 21 SNP ALLELE TRANSMISSION P FOR PDT ANALYSIS FOR CD UC IBD Sum Average Sum Average Sum Average Ala893 Overtransmitted .0072 .0040 .31 .15 .0021 .0010 893Ser Undertransmitted .036 .028 .43 .23 .016 .0093 893Thr Undertransmitted .0046 .0046 .16 .16 .0025 .0032 Global score .0014 .00090 .29 .16 .00030 .00020 Table 6 Linkage Disequilibrium Values SNP Pair r2 Asn21Asp and Ala893Ser/Thr .10 Ala893Ser/Thr and C3435T .52 Asn21Asp and C3435T .09 ber of subjects with CD in this cohort, these trends do not support a significant association of the Ala893Ser/ Thr polymorphism with UC. Login to comment
117 In the cohort with UC, in contrast to a prior case-control study (Schwab et al. 2003), we observed no evidence for association with the 3435T polymorphism, nor was evidence observed for the Asn21Asp. Login to comment
126 Two-locus-haplotype analysis of the Asn21Asp-Ala893Ser/Thr haplotype demonstrates that the less common 21Asp variant occurs solely on the Ser893 background, which is unassociated with disease. Login to comment
135 OF HAPLOTYPES Transmitted Untransmitted Asn21Asp-Ala893Ser/Thr: Asn21-Thr893 2 17 Asn21-Ala893 203 128 Asn21-Ser893 131 188 21Asp-Ser893 48 51 Ala893Ser/Thr-C3435T: 893Thr-C3435 0 14 893Thr-3435T 2 2 Ala893-C3435 174 133 Ala893-3435T 69 51 893Ser-C3435 14 31 893Ser-3435T 130 158 NOTE.-Haplotypes were constructed using Genehunter, version 2.1; all affected individuals were included. Login to comment
6 Significant association of Ala893 with IBD was observed by both case-control analysis ( ) and the pedigree P p .002 disequilibrium test (PDT [ ]) but not for the Asn21Asp or C3435T polymorphisms. Login to comment
102 P p .002 P p .008 Table 4 Global P Values by PDT Analysis of Exonic SNPs SNP GLOBAL P FOR PDT ANALYSIS FOR CD UC IBD Sum Average Sum Average Sum Average Asn21Asp .24 .15 .26 .56 .8 .39 Ala893Ser/Thr .0014 .00090 .29 .16 .00030 .00020 C3435T .42 .31 .93 .60 .63 .35 limited power to identify modest differences. Login to comment
111 Table 4 demonstrates the results by PDT for the Asn21Asp, Ala893Ser/ Thr, and C3435T polymorphisms among patients with CD, UC, and IBD. Login to comment
114 Separate evaluation by CD and UC phenotypes showed no evidence of a CD association for the Asn21Asp or the C3435T polymorphisms. Login to comment
118 In the cohort with UC, in contrast to a prior case-control study (Schwab et al. 2003), we observed no evidence for association with the 3435T polymorphism, nor was evidence observed for the Asn21Asp. Login to comment
128 Two-locus-haplotype analysis of the Asn21Asp-Ala893Ser/Thr haplotype demonstrates that the less common 21Asp variant occurs solely on the Ser893 background, which is unassociated with disease. Login to comment
137 OF HAPLOTYPES Transmitted Untransmitted Asn21Asp-Ala893Ser/Thr: Asn21-Thr893 2 17 Asn21-Ala893 203 128 Asn21-Ser893 131 188 21Asp-Ser893 48 51 Ala893Ser/Thr-C3435T: 893Thr-C3435 0 14 893Thr-3435T 2 2 Ala893-C3435 174 133 Ala893-3435T 69 51 893Ser-C3435 14 31 893Ser-3435T 130 158 NOTE.-Haplotypes were constructed using Genehunter, version 2.1; all affected individuals were included. Login to comment

PMID: 12406646 [PubMed] Fromm MF et al: "The influence of MDR1 polymorphisms on P-glycoprotein expression and function in humans."

No. Sentence Comment

324 `[84] X. Decleves, S. Chevillard, C. Charpentier, P. Vielh, J.L. [87] J. Shon, H. Chun, K. Kim, E. Kim, Y. Yoon, I. Jang, S. Shin, Laplanche, A new polymorphism (N21D) in the exon 2 of J. Shin, The PK and PD of fexofenadine in relation to MDR1 the human MDR1 gene encoding the P-glycoprotein, Hum. Login to comment
322 ` [84] X. Decleves, S. Chevillard, C. Charpentier, P. Vielh, J.L. [87] J. Shon, H. Chun, K. Kim, E. Kim, Y. Yoon, I. Jang, S. Shin, Laplanche, A new polymorphism (N21D) in the exon 2 of J. Shin, The PK and PD of fexofenadine in relation to MDR1 the human MDR1 gene encoding the P-glycoprotein, Hum. genetic polymorphism in Korean healthy subjects, Clin. Mutat. Login to comment

PMID: 12235446 [PubMed] Siegmund W et al: "Effect of levothyroxine administration on intestinal P-glycoprotein expression: consequences for drug disposition."

No. Sentence Comment

38 MDR1 genotyping The following 10 most frequent or putatively functional single nucleotide polymorphisms of the MDR1 gene were identified as described recently: exon 2 G-1A, A61G (amino acid exchange Asn21Asp), T307C (Phe103Leu), exon 6 Cϩ139T, G1199A (Ser400Asn), C1236T, exon 17 T-76A, G2677T/A (Ala893Ser/Thr), and C3435T.18 In brief, the deoxyribonucleic acid (DNA) of venous blood was extracted by use of a standard phenol-chloroform procedure. Login to comment

PMID: 11495756 [PubMed] Brinkmann U et al: "Pharmacogenetics of the human drug-transporter gene MDR1: impact of polymorphisms on pharmacotherapy."

No. Sentence Comment

53 For example, SNPs that change amino acids, and thus possibly have an effect on protein function, are located at position A61G (replacement of Asn with Asp at position 21 of exon 2 of Pgp), a Phe-Leu change in position 103 next to the second TMD close to a glycosylation site, and a G1199A SNP in exon 11, which causes a Ser-Asn size- and charge- change close to the first ATP-binding domain. Login to comment
68 Single nucleotide polymorphisms (SNPs) in the MDR1 gene SNP Region Number Frequency of SNPsa [%] Effect Heterozygous Homozygous Observed Estimated T-12C E1 85 11.8 0 0.4 Non-coding G-1A E2 188 11.2 0 0.4 Translation initiation A61G E2 188 17.6 0.5 0.81 Asn21Asp G-25T I4 85 26.0 3.5 2.3 G-35C I4 85 1.2 0 0.01 T307C E5 85 1.2 0 0.01 Phe103Leu C+139T I5 85 48.2 16.5 16.8 C+145T I5 85 2.4 0 0.01 G1199A E11 85 12.9 0 0.4 Ser400Asn C1236T E12 188 48.9 13.3 14.4 Gly412Gly C+44T I12 188 11.7 0 0.4 T-76A I16 85 45.9 22.4 20.3 A+137G I17 85 1.2 0 0.01 G2677T E21 83b 43.4 42.2 38.4 Ala893Ser G2995A E24 36b 11.1 0 Ala999Thr C3435T E26 537 47.7 26.4 24.1 Ile1145Ile C3396T E26 188 0.53 0 0.01 Wobble aMDR1 sequences Genbank (gb) accession numbers AC002457 and AC005068 are defined as wildtype. Login to comment

PMID: 10790226 [PubMed] Decleves X et al: "A new polymorphism (N21D) in the exon 2 of the human MDR1 gene encoding the P-glycoprotein."

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0 HUMAN MUTATION Mutation and Polymorphism Report #115 (2000) Online Mutation and Polymorphism Report Authors: Xavier Declèves , Sylvie Chevillard2 , Charlotte Charpentier1 , Philippe Vielh3 , and Jean-Louis Laplanche1 Affiliations: 1 Service de Biochimie et Biologie Moléculaire, hôpital Lariboisière, Paris, France; 2 Laboratoire de cancérogenèse expérimentale, Commissariat à l`Energie Atomique, Fontenay aux Roses, France; 3 Service de cytopathologie, Institut Curie, Paris, France Corresponding Author Address and E-mail: Xavier Declèves, Service de Biochimie et Biologie Moléculaire, hôpital Lariboisière, 2 rue Ambroise Paré 75010 Paris, France; E-mail: xavier.decleves@inserm.lrb.ap-hop-paris.fr Title : A new polymorphism (N21D) in the exon 2 of the human MDR1 gene encoding the P-glycoprotein Keywords: P-glycoprotein; multidrug resistance-1; MDR1; ABCB1 Species: Homo sapiens Change is: Polymorphism Gene/Locus Name: ATP-biding cassette B1 (multidrug resistance 1) Symbol: ABCB1 Genbank accession number: M14758 (cDNA) OMIM accession number: 171050 Locus specific database: Chromosomal location: 7q21 Inheritance: Mutation / polymorphism name Nucleotide change-Systematic name: c485A>G Amino acid change-Trivial name: N21D Mutation / polymorphism type: Missense Polymorphism frequency: Detection method: DGGE Detection conditions: Sequence of primers: Forward primer 5`-psoralen-AAGGTCGGGATGGATCTTGAA-3` Reverse primer 5`-GTTCCCACCACCATATACAA-3` PCR conditions: 30 cycles, denaturation 94°C (1 min) annealing 55°C (2 min) elongation 72°C (2 min), magnesium concentration 1.5 mM Electrophoresis: 20%-60% denaturant concentration (100% denaturant: 7M urea, 40% formamide), 58 degrees, 3 hours, 160 volts. Login to comment
20 Direct sequencing revealed a change of A to G at position 485 (cDNA sequence) leading to a change of asparagine to aspartic acid at position 21 which is located in the first intracellular domain of P-gp. Login to comment

PMID: 15217301 [PubMed] Ieiri I et al: "The MDR1 (ABCB1) gene polymorphism and its clinical implications."

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162 [94] Recently, a new mechanism for the drug- Sarfaty et al.[89] also investigated functional conse- grapefruit juice interaction has been reported; the quences of MDR1 polymorphisms (Asn21Asp, bioavailability and serum concentrations of fex- Phe103Leu, Ser400Asn, Ala893Ser, and ofenadine were reduced when grapefruit juice was Ala998Thr) using a vaccinia virus-based transient taken. Login to comment

PMID: 21712189 [PubMed] Ikediobi O et al: "Analysis of pharmacogenetic traits in two distinct South African populations."

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73 G; N21D 0.0 0.0 0.0 NA NA 0.1 0.0 0.07 0.0 ABCB1 rs1045642 C 3435C . Login to comment

PMID: 24122874 [PubMed] Prasad B et al: "Interindividual variability in hepatic organic anion-transporting polypeptides and P-glycoprotein (ABCB1) protein expression: quantification by liquid chromatography tandem mass spectroscopy and influence of genotype, age, and sex."

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179 TABLE 4 Frequency of OATP1B1, OATP1B3, and P-gp SNPs detected in the University of Washington (UW) liver bank Marker ID Variant Change for Variant Frequency in UW liver Bank Homozygous Variant Heterozygous Variant Wild-Type OATP1B1 rs4149015 211187G.A Promoter 0 9 53 rs2306283 388A.G N130D 10 30 22 rs11045819 463C.A P155T 4 9 49 rs4149056 521T.C V174A 1 21 40 rs4149057 571T.C L191L 16 34 12 rs2291075 597C.T F199F 10 33 19 OATP1B3 rs4149117 334G.T A112S 0 45 17 rs7311358 699A.G I233M 0 45 17 rs2053098 1557G.A A519A 0 45 17 rs3764006 1833A.G G611G 0 42 20 P-gp rs2214102 21G.A 59UTR 0 6 56 rs2235015 287-25G.T Intron 0 19 43 rs10276036 IVS9-44A.G Intron 19 31 12 rs1128503 1236C.T G412G 18 33 11 rs2032588 1350+44C.T Intron 0 7 55 rs2235033 1554+24C.T Intron 22 32 8 rs2235013 1725+38A.G Intron 21 33 8 rs9282564 61A.G N21D 7 11 45 rs2235040 2481+24G.A Intron 0 12 50 rs2032582 2677G.T, 2677G.A A893S, A893T 17 32 13 rs3213619 2129T.C 59UTR 0 4 58 rs1045642 3435C.T I1145I 22 30 10 rs17064 *89A.T 39UTR 0 7 55 rs3842 *193A.G 39UTR 0 18 44 OATP, organic anion-transporting polypeptide; P-gp, P-glycoprotein; SNP, single nucleotide polymorphisms; UW, University of Washington. Login to comment

PMID: 26307985 [PubMed] Ruiz J et al: "Impact of Single Nucleotide Polymorphisms (SNPs) on Immunosuppressive Therapy in Lung Transplantation."

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59 There is a SNP in the ABCB1 gene, rs9282564, comprising the change Asn21Asp, due to the variation A > G, the biological effect of which has not been clearly established. Login to comment