ABCMdb

ABCB1 p.Glu109Lys

Predicted by SNAP2:	A: N (78%), C: D (63%), D: N (93%), F: D (80%), G: N (61%), H: N (66%), I: D (59%), K: N (78%), L: D (53%), M: D (53%), N: N (72%), P: D (63%), Q: N (72%), R: N (53%), S: N (82%), T: N (72%), V: N (53%), W: D (80%), Y: N (53%),
Predicted by PROVEAN:	A: D, C: D, D: N, F: D, G: D, H: D, I: D, K: N, L: D, M: D, N: D, P: D, Q: N, R: D, S: N, T: D, V: D, W: D, Y: D,

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[hide] Additive effects of drug transporter genetic polym... Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22. Sai K, Saito Y, Maekawa K, Kim SR, Kaniwa N, Nishimaki-Mogami T, Sawada J, Shirao K, Hamaguchi T, Yamamoto N, Kunitoh H, Ohe Y, Yamada Y, Tamura T, Yoshida T, Matsumura Y, Ohtsu A, Saijo N, Minami H
Additive effects of drug transporter genetic polymorphisms on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients.
Cancer Chemother Pharmacol. 2010 May;66(1):95-105. Epub 2009 Sep 22., [PMID:19771428]

Abstract [show]
PURPOSE: Effects of genetic polymorphisms/variations of ABCB1, ABCC2, ABCG2 and SLCO1B1 in addition to "UGT1A1*28 or *6" on irinotecan pharmacokinetics/pharmacodynamics in Japanese cancer patients were investigated. METHODS: Associations between transporter haplotypes/variations along with UGT1A1*28 or *6 and SN-38 area under the time-concentration curve (AUC) or neutropenia were examined in irinotecan monotherapy (55 patients) and irinotecan-cisplatin-combination therapy (62 patients). RESULTS: Higher SN-38 AUC values were observed in ABCB1 2677G>T (A893S) (*2 group) for both regimens. Associations of grade 3/4 neutropenia were observed with ABCC2 -1774delG (*1A), ABCG2 421C>A (Q141K) and IVS12 + 49G>T ((#) IIB) and SLCO1B1 521T>C (V174A) (*15 x 17) in the irinotecan monotherapy, while they were evident only in homozygotes of ABCB1*2, ABCG2 (#) IIB, SLCO1B1*15 x 17 in the cisplatin-combination therapy. With combinations of haplotypes/variations of two or more genes, neutropenia incidence increased, but their prediction power for grade 3/4 neutropenia is still unsatisfactory. CONCLUSIONS: Certain transporter genotypes additively increased irinotecan-induced neutropenia, but their clinical importance should be further elucidated.

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86 = UGT1A1*6 or *28. a BJL contains -1789G[A, *2 (block 1) = 325G[A (E109K), *3 (block 1) = 304G[A (G102R); b *2 (block 2) contains 2677G[T (A893S); c *1b (block 3) = IVS27-182G[T, *2 (block 3) = 3751G[ A (V1251I); d *1A contains -1774delG; e IIB contains 421C[A (Q141K) and IVS12 ? Login to comment

[hide] Haplotype analysis of ABCB1/MDR1 blocks in a Japan... Pharmacogenetics. 2003 Dec;13(12):741-57. Sai K, Kaniwa N, Itoda M, Saito Y, Hasegawa R, Komamura K, Ueno K, Kamakura S, Kitakaze M, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kitamura Y, Kamatani N, Ozawa S, Sawada J
Haplotype analysis of ABCB1/MDR1 blocks in a Japanese population reveals genotype-dependent renal clearance of irinotecan.
Pharmacogenetics. 2003 Dec;13(12):741-57., [PMID:14646693]

Abstract [show]
We performed comprehensive haplotyping of ABCB1/MDR1 gene blocks using 49 genetic polymorphisms, including seven novel ones, obtained from 145 Japanese subjects. The ABCB1/MDR1 gene was divided into four blocks (Blocks -1, 1, 2, and 3) based on linkage disequilibrium analysis of polymorphisms. Using an expectation-maximization based program, 1, 2, 8, and 3 haplotype groups (3, 12, 32, and 18 haplotypes) were identified in Blocks -1, 1, 2, and 3, respectively. Within Block 2, haplotype groups *1, *2, *4, *6, and *8 reported by Kim and colleagues (Clin Pharmacol Ther 2001; 70:189-199) were found, and additional three groups (*9 to *11) were newly defined. We analyzed the association of haplotypes with the renal clearance of irinotecan and its metabolites in 49 Japanese cancer patients given irinotecan intravenously. There was a significant association of the *2 haplotype in Block 2, which includes 1236C>T, 2677G>T and 3435C>T, with a reduced renal clearance of those compounds. Moreover, tendencies of reduced and increased renal clearance were also observed with *1f in Block 2 and *1b in Block 3, respectively. These findings suggest that the P-glycoprotein encoded by ABCB1/MDR1 in the proximal tubules plays a substantial role in renal exclusion of drugs and, moreover, that block-haplotyping is valuable for pharmacogenetic studies.

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102 Unauthorized reproduction of this article is prohibited. Copyright(c)LippincottWilliams&Wilkins.Unauthorizedreproductionofthisarticleisprohibited. Table 2 List of SNPs and deletion/insertion of the ABCB1 gene found in a Japanese population SNP IDÃ Position Nucleotide Effect on Block Site Our SNP ID NCBI IMS-JST NT_007933.10 cDNA-based change protein Frequency Block À1 59-Flanking MPJ6_AB1057 12472341 À8104 T.C 0.003 59-Flanking MPJ6_AB1059 12472207 À7970 C.T 0.007 Block 1 59-Flanking MPJ6_AB1002 rs2188524 ssj0000008 12464608 À371 A.G 0.128 Exon 1 (59-UTR) MPJ6_AB1003 12464382 À145 C.G 0.024 Exon 1 (59-UTR) MPJ6_AB1004 rs3213619 ssj0000009 12464366 À129 T.C 0.093 Intron 1 MPJ6_AB1005 rs3214119 ssj0000010 12463753 IVS1-74 delG 0.121 Intron 3 MPJ6_AB1008 rs2235074 12459219 IVS3+36 C.T 0.093 Intron 4 MPJ6_AB1010 rs2235014 12433788 IVS4-76 T.C 0.017 Intron 4 MPJ6_AB1011 rs2235015 12433737 IVS4-25 G.T 0.086 Exon 5 MPJ6_AB1012 12433674 325 G.A E109K 0.010 Intron 5 MPJ6_AB1013 rs2235016 12433585 IVS5+76 T.G 0.055 Block 2 Intron 5 MPJ6_AB1014 rs2235018 12433538 IVS5+123 A.G 0.141 Intron 5 MPJ6_AB1015 rs2235020 12433438 IVS5+223 A.T 0.548 Intron 5 MPJ6_AB1016 rs2235021 12433437 IVS5+224 G.T 0.548 Intron 6 MPJ6_AB1017 12429839 IVS6-109 G.T 0.007 Intron 7 MPJ6_AB1018 12429545 IVS7+14 G.A 0.010 Intron 8 MPJ6_AB1020 rs1922240 ssj0000016 12417527 IVS8-106 A.G 0.348 Intron 9 MPJ6_AB1021 12414371 IVS9-44 G.A 0.445 Intron 10 MPJ6_AB1023 rs2235029 12414108 IVS10-41 T.G 0.017 Exon 12 MPJ6_AB1025 rs1128503 12413774 1236 C.T G412G (silent) 0.555 Intron 12 MPJ6_AB1052 12413643 IVS12+17 G.A 0.010 Intron 13 MPJ6_AB1026 rs2235033 ssj0000018 12413316 IVS13+24 T.C 0.445 Intron 13 MPJ6_AB1027 rs2235035 ssj0000019 12413259 IVS13+81 C.T 0.348 Intron 14 MPJ6_AB1028 rs2235013 ssj0000020 12412799 IVS14+38 G.A 0.445 Intron 15 MPJ6_AB1029 12408557 IVS15-69 T.C 0.014 Intron 16 MPJ6_AB1030 rs2235046 12408239 IVS16+73 A.G 0.452 Intron 16 MPJ6_AB1031 rs1922242 12407840 IVS16-76 T.A 0.369 Intron 18 MPJ6_AB1034 12402869 IVS18-35 G.C 0.003 Intron 20 MPJ6_AB1035 rs2235040 ssj0000027 12399923 IVS20+24 G.A 0.090 Exon 21 MPJ6_AB1036 12394791 2677 G.A A893T 0.200 Exon 21 MPJ6_AB1037 rs2032582 12394791 2677 G.T A893S 0.403 Intron 21 MPJ6_AB1038 rs2032583 ssj0000031 12394734 IVS21+49 T.C 0.090 Intron 24 MPJ6_AB1040 12379982 IVS24+16 C.T 0.031 Exon 26 MPJ6_AB1041 rs1045642 ssj0000040 12372818 3435 C.T I1145I (silent) 0.441 Intron 26 MPJ6_AB1042 rs2235047 ssj0000048 12372705 IVS26+59 T.G 0.403 Intron 26 MPJ6_AB1043 rs2235048 ssj0000049 12372684 IVS26+80 T.C 0.448 Block 3 Exon 27 MPJ6_AB1068 12369435 3587 T.G I1196S 0.003 Intron 27 MPJ6_AB1044 12369323 IVS27+63 C.G 0.003 Intron 27 MPJ6_AB1053 12368127 IVS27-189 A.G 0.007 Intron 27 MPJ6_AB1045 rs1186745 ssj0000051 12368120 IVS27-182 G.T 0.200 Intron 27 MPJ6_AB1054 12368110 IVS27-172 G.A 0.010 Intron 27 MPJ6_AB1047 rs1186744 12368106 IVS27-168 T.C 0.010 Intron 27 MPJ6_AB1048 12368105 IVS27-167 A.G 0.014 Intron 27 MPJ6_AB1055 12368090 IVS27-152 A.G 0.003 Intron 27 MPJ6_AB1049 12368057 IVS27-119 C.T 0.021 Intron 27 MPJ6_AB1056 rs2235049 12368025 IVS27-87 A.G 0.007 Intron 27 MPJ6_AB1070 12368024 IVS27-86 T.C 0.003 Intron 27 MPJ6_AB1071 12368018 IVS27-80 ins C 0.003 Exon 28 MPJ6_AB1051 12367824 3751 G.A V1251I 0.010 ÃSNP ID assigned by our project team (MPJ-6). Login to 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
119 In Block 1, a haplotype having both a nonsynonymous SNP 325G.A (E109K) [34] and an intronic SNP IVS1- 74delG was defined as Ã2. Login to comment
132 *2 *1 Exon 1 5'-UTR Exon 1 5'-UTR Intron 1 Intron 3 Intron 4 Intron 4 Exon 5 Intron 5 TϾCCϾGAϾG -371 -145 -129 IVS1 -74 IVS3 ϩ36 IVS4 -76 IVS4 -25 325 IVS5 ϩ76 delG GϾTTϾCCϾT GϾA E109K TϾG *1/*1 N 63 23 9 10 7 4 6 5 1 1 1 2 2 2 1 1 1 1 1 1 1 2 N 194 32 15 13 11 9 6 5 1 1 2 1 Fig. 2 The diplotypes and haplotypes in Block À1 and Block 1 of the ABCB1 gene for 145 Japanese subjects. Login to comment

[hide] Genetic variations and haplotype structures of the... Ann Hum Genet. 2006 Sep;70(Pt 5):605-22. Sai K, Itoda M, Saito Y, Kurose K, Katori N, Kaniwa N, Komamura K, Kotake T, Morishita H, Tomoike H, Kamakura S, Kitakaze M, Tamura T, Yamamoto N, Kunitoh H, Yamada Y, Ohe Y, Shimada Y, Shirao K, Minami H, Ohtsu A, Yoshida T, Saijo N, Kamatani N, Ozawa S, Sawada J
Genetic variations and haplotype structures of the ABCB1 gene in a Japanese population: an expanded haplotype block covering the distal promoter region, and associated ethnic differences.
Ann Hum Genet. 2006 Sep;70(Pt 5):605-22., [PMID:16907707]

Abstract [show]
As functional ABCB1 haplotypes were recently reported in the promoter region of the gene, we resequenced the ABCB1 distal promoter region, along with other regions (the enhancer and proximal promoter regions, and all 28 exons), in a total of 533 Japanese subjects. Linkage disequilibrium (LD) analysis based on 92 genetic variations revealed 4 LD blocks with the same make up as previously described (Blocks -1, 1, 2 and 3), except that Block 1 was expanded to include the distal promoter region, and that a new linkage between polymorphisms -1,789G>A in the distal promoter region and IVS5 + 123A>G in intron 5 was identified. We re-assigned Block 1 haplotypes, and added novel haplotypes to the other 3 blocks. The reported promoter haplotypes were further classified into several types according to tagging variations within Block 1 coding or intronic regions. Our current data reconfirm the haplotype profiles of the other three blocks, add more detailed information on functionally-important haplotypes in Block 1 and 2 in the Japanese population, and identified differences in haplotype profiles between ethnic groups. Our updated analysis of ABCB1 haplotype blocks will assist pharmacogenetic and disease-association studies carried out using Asian subjects.

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93 Haplotype groups * 2 to * 5 were defined by the nonsynonymous SNPs 325G>A(E109K) (* 2), 304G>C(G102R) (* 3), 49T>C(F17L) (* 4) and 144G>T(K48N) (* 5). Login to comment
215 As indicated by the cladograms in the previous section, our study revealed that subgroup A, previously classified as wild-type, could be further classified into six types: the major * 1a type without any marker variation and five other types with either IVS1 -78delG (* 1c), IVS4 - 25G>T (* 1d), 325G>A(E109K) (* 2a), IVS5 + 123A>G (* 1n), or 304 G>C(G102R) (* 3a). Login to comment
264 In total our data revealed 11 tagging variations in Block 1: -1789G>A, -1461 -1457CATCdel, -371A>G, -145C>G, -129T>C, IVS1 - 78delG, IVS4 - 25G>T, 304G>C (G102R), 325G>A (E109K), IVS + 76T>G and IVS5 + 123A>G. Login to comment