Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes

被引:50
作者
Fohner, Alison [1 ]
Muzquiz, LeeAnna I.
Austin, Melissa A. [2 ]
Gaedigk, Andrea [8 ]
Gordon, Adam [4 ]
Thornton, Timothy [3 ]
Rieder, Mark J. [4 ]
Pershouse, Mark A. [6 ,7 ]
Putnam, Elizabeth A. [6 ,7 ]
Howlett, Kevin
Beatty, Patrick [6 ]
Thummel, Kenneth E. [5 ]
Woodahl, Erica L. [6 ,7 ]
机构
[1] Univ Washington, Sch Publ Hlth, Dept Publ Hlth Genet, Seattle, WA 98195 USA
[2] Univ Washington, Sch Publ Hlth, Dept Epidemiol, Seattle, WA 98195 USA
[3] Univ Washington, Sch Publ Hlth, Dept Biostat, Seattle, WA 98195 USA
[4] Univ Washington, Sch Med, Dept Genome Sci, Seattle, WA USA
[5] Univ Washington, Sch Pharm, Dept Pharmaceut, Seattle, WA 98195 USA
[6] Univ Montana, Montana Canc Inst Fdn, Missoula, MT 59812 USA
[7] Univ Montana, Dept Biomed & Pharmaceut Sci, Missoula, MT 59812 USA
[8] Childrens Mercy Hosp & Clin, Div Pediat Pharmacol & Med Toxicol, Kansas City, MO USA
关键词
Alaska Native; American Indian; CYP3A4; CYP3A5; CYP2C9; CYP2D6; cytochrome P450; indigenous populations; pharmacogenetics; pharmacogenomics; BREAST-CANCER; GENETIC POLYMORPHISMS; TAMOXIFEN METABOLISM; CYP3A4-ASTERISK-1G POLYMORPHISM; TACROLIMUS PHARMACOKINETICS; NATIVE-AMERICANS; MEXICAN-MESTIZO; GENOTYPE; ALLELE; PHENOTYPE;
D O I
10.1097/FPC.0b013e3283629ce9
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Objectives Cytochrome P450 enzymes play a dominant role in drug elimination and variation in these genes is a major source of interindividual differences in drug response. Little is known, however, about pharmacogenetic variation in American Indian and Alaska Native (AI/AN) populations. We have developed a partnership with the Confederated Salish and Kootenai Tribes (CSKT) in northwestern Montana to address this knowledge gap.Methods We resequenced CYP2D6 in 187 CSKT individuals and CYP3A4, CYP3A5, and CYP2C9 in 94 CSKT individuals.Results We identified 67 variants in CYP2D6, 15 in CYP3A4, 10 in CYP3A5, and 41 in CYP2C9. The most common CYP2D6 alleles were CYP2D6*4 and *41 (20.86 and 11.23%, respectively). CYP2D6*3, *5, *6, *9, *10, *17, *28, *33, *35, *49, *1xN, *2xN, and *4xN frequencies were less than 2%. CYP3A5*3, CYP3A4*1G, and *1B were detected with frequencies of 92.47, 26.81, and 2.20%, respectively. Allelic variation in CYP2C9 was low: CYP2C9*2 (5.17%) and *3 (2.69%). In general, allele frequencies in CYP2D6, CYP2C9, and CYP3A5 were similar to those observed in European Americans. There was, however, a marked divergence in CYP3A4 for the CYP3A4*1G allele. We also observed low levels of linkage between CYP3A4*1G and CYP3A5*1 in the CSKT. The combination of nonfunctional CYP3A5*3 and putative reduced function CYP3A4*1G alleles may predict diminished clearance of CYP3A substrates.Conclusion These results highlight the importance of carrying out pharmacogenomic research in AI/AN populations and show that extrapolation from other populations is not appropriate. This information could help optimize drug therapy for the CSKT population. (C) 2013 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins.
引用
收藏
页码:403 / 414
页数:12
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