Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes.
Pharmacogenetics in American Indian populations: analysis of CYP2D6, CYP3A4, CYP3A5, and CYP2C9 in the Confederated Salish and Kootenai Tribes.
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美洲印第安人种群的药物遗传学：CYP2D6，CYP3A4，CYP3A5和CYP2C9的分析。
DOI：
10.1097/fpc.0b013e3283629ce9
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发表时间：
2013-08
影响因子：
2.6
通讯作者：
Woodahl EL
中科院分区：
文献类型：
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作者：
Fohner A;Muzquiz LI;Austin MA;Gaedigk A;Gordon A;Thornton T;Rieder MJ;Pershouse MA;Putnam EA;Howlett K;Beatty P;Thummel KE;Woodahl EL
细胞色素P450酶在药物消除中起主导作用，这些基因的变异是药物反应个体间差异的主要来源。然而，鲜为人知的是，在美洲印第安人和阿拉斯加原住民（AI/AN）人群的药物遗传学变异。我们已经与蒙大拿州西北部的萨利希和库特奈部落联盟（CSKT）建立了合作伙伴关系，以解决这一知识差距。我们对187名CSKT受试者的CYP2D6和94名CSKT受试者的CYP3A4、CYP3A5和CYP2C9进行了重新测序。我们在CYP2D6中鉴定了67个变异体，在CYP3A4中鉴定了15个变异体，在CYP3A5中鉴定了10个变异体，在CYP2C9中鉴定了41个变异体。最常见的CYP2D6等位基因是CYP2D6 * 4和 * 41（分别为20.86%和11.23%）。CYP2D6 * 3、* 5、* 6、* 9、* 10、* 17、* 28、* 33、* 35、* 49、* 1xN、* 2xN和 * 4xN频率小于2%。CYP3A5 * 3、CYP3A4 * 1G和 * 1B的检出率分别为92.47%、26.81%和2.20%。CYP2C9的等位基因变异较低：CYP2C9 * 2（5.17%）和 * 3（2.69%）。一般而言，CYP2D6、CYP2C9和CYP3A5的等位基因频率与在欧洲裔美国人中观察到的相似。然而，CYP3A4 * 1G等位基因在CYP3A4中存在显著差异。我们还观察到CSKT中CYP3A4 * 1G和CYP3A5 * 1之间的低水平连锁。非功能性CYP3A5 * 3和推定的功能降低的CYP3A4 * 1G等位基因的组合可以预测CYP3A底物的清除减少。这些结果强调了在AI/AN人群中进行药物基因组学研究的重要性，并表明从其他人群中外推是不合适的。这些信息可能有助于优化CSKT人群的药物治疗。
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. We resequenced CYP2D6 in 187 CSKT subjects and CYP3A4, CYP3A5, and CYP2C9 in 94 CSKT subjects. 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. These results highlight the importance of conducting pharmacogenomic research in AI/AN populations and demonstrate that extrapolation from other populations is not appropriate. This information could help to optimize drug therapy for the CSKT population.