ABCC2 p.Met233Ile
| Predicted by SNAP2: | A: D (53%), C: N (57%), D: N (93%), E: D (59%), F: N (66%), G: D (66%), H: N (61%), I: N (57%), K: D (66%), L: N (61%), N: N (66%), P: D (66%), Q: N (53%), R: D (66%), S: D (53%), T: D (63%), V: N (57%), W: D (63%), Y: N (61%), |
| Predicted by PROVEAN: | A: N, C: N, D: N, E: N, F: N, G: N, H: N, I: N, K: N, L: N, N: N, P: N, Q: N, R: N, S: N, T: N, V: N, W: N, Y: N, |
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[hide] Association study of genetic polymorphisms of drug... J Hum Genet. 2012 Aug;57(8):531-44. doi: 10.1038/jhg.2012.63. Epub 2012 Jun 14. Endo S, Fukahori A, Tokuhiro S, Shinagawa A, Walker J, Yoshihara K, Ishizuka H, Ieiri I, Sugiyama Y
Association study of genetic polymorphisms of drug transporters, SLCO1B1, SLCO1B3 and ABCC2, in African-Americans, Hispanics and Caucasians and olmesartan exposure.
J Hum Genet. 2012 Aug;57(8):531-44. doi: 10.1038/jhg.2012.63. Epub 2012 Jun 14., [PMID:22695893]
Abstract [show]
It has been reported that organic anion-transporting polypeptide (OATP) 1B1, OATP1B3 and multidrug resistance-associated protein 2 are involved in the hepatobiliary transport of olmesartan. We investigated the association of SLCO1B1, SLCO1B3 and ABCC2 polymorphisms with the pharmacokinetics of olmesartan. We sequenced all exons, exon-intron junctions and the 5' and 3' flanking regions of the three genes in 115 individuals from African-American, Hispanic and Caucasian populations who had participated in our clinical studies. A total of 348 single-nucleotide polymorphisms (SNPs) were identified with a minor allele frequency of >/=0.01 in at least one population; 132 SNPs were detected in SLCO1B1, 130 in SLCO1B3 and 86 in ABCC2. We characterized the linkage disequilibrium (LD) and haplotypes shared across the populations and then evaluated the association between the haplotypes and the pharmacokinetics of olmesartan. Seven inter-ethnic LD blocks were observed in SLCO1B1, while three in SLCO1B3 and four in ABCC2. Although extensive variability in the sequences of SLCO1B1, SLCO1B3 and ABCC2 existed across the three populations, there was no remarkable difference in any pharmacokinetic parameters of olmesartan between subjects with and without any major haplotypes in the three transporter genes we tested.
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No. Sentence Comment
11 At least three nonsynonymous SNPs have been found so far, with 334T4G (S112A) and 699G4A (M233I) increasing transporter activity in vitro.11 With regard to ABCC2, several mutations and deletions have been identified in patients with Dubin-Johnson syndrome, an autosomal recessive disorder, each of which impairs either the expression or function of MRP2 protein.12-14 Beside mutations in Dubin-Johnson syndrome, the extensive genetic variation identified so far may have a potential effect on drug disposition.15,16 In fact, the T allele of À24C4T has been 1Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo, Tokyo, Japan; 2Discovery Science and Technology Department, Daiichi Sankyo RD Novare, Tokyo, Japan; 3Translational Medicine and Clinical Pharmacology Department, Daiichi Sankyo Pharma Development, Edison, NJ, USA; 4Department of Clinical Pharmacokinetics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan and 5Department of Molecular Pharmacokinetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan Correspondence: Dr I Ieiri, Kyushu University, Clinical Pharmacokinetics, 3-1-1, Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
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ABCC2 p.Met233Ile 22695893:11:90
status: NEW125 However, interestingly, there were 32 SNPs that showed a high LD (r240.8 in all populations) relationship with SNP 693, including the cSNPs at 683 (334T4G, S112A, rs4149117 in exon 4), 721 (699G4A, M233I, rs7311358 in exon 7) and 757 (1557A4G, A519A, rs2053098 in exon 12) (data not shown).
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ABCC2 p.Met233Ile 22695893:125:198
status: NEW