Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.
Variation in genes controlling warfarin disposition and response in American Indian and Alaska Native people: CYP2C9, VKORC1, CYP4F2, CYP4F11, GGCX.
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DOI：
10.1097/fpc.0000000000000143
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发表时间：
2015-07
影响因子：
2.6
通讯作者：
Thummel KE
中科院分区：
文献类型：
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作者：
Fohner AE;Robinson R;Yracheta J;Dillard DA;Schilling B;Khan B;Hopkins S;Boyer B;Black J;Wiener H;Tiwari HK;Gordon A;Nickerson D;Tsai JM;Farin FM;Thornton TA;Rettie AE;Thummel KE
药物遗传测试预计将通过提高治疗效果和最大限度地减少药物毒性来改善健康结果并降低护理成本。美国印第安人和阿拉斯加原住民(AI/AN)历史上一直被排除在药物遗传学研究及其潜在好处之外，这是我们试图解决的一个不足。维生素K拮抗剂华法林是用于预防血栓栓塞症的处方，尽管其治疗指数较窄，个体间差异较大，因此有必要密切监测药物反应。因此，我们对编码对华法林活性和维生素K依赖的凝血因子合成至关重要的酶的CYP2C9、VKORC1、CYP4F2、CYP4F11和GGCX的变异很感兴趣。我们与阿拉斯加州安克雷奇的南中央基金会(SCF)和居住在阿拉斯加西南部育空-库斯科维姆三角洲的94名尤皮克人合作，对188名AI/AN患者的这些基因进行了重新测序，以确定已知或新的功能扰乱变异。我们在每个研究人群的较大队列(分别为380和350)中进行了特定SNP的基因分型。我们发现了较低华法林剂量的VKORC1单倍型(−1639G>；A和1173C>；T)和较高华法林剂量的CYP4F2*3变异体的高频率。我们还发现了两个相对常见的、新颖的、可能会扰乱功能的CYP2C9(M1L和N218I)变体，它们与CYP2C9*3、CYP2C9*2和CYP2C9*29一起预测，相当大比例的AI/AN患者将降低CYP2C9的活性。总体而言，我们预测阿拉斯加AI/AN人群的平均华法林剂量需求低于美国非AI/AN人群，这一发现与阿拉斯加的临床经验一致。
Pharmacogenetic testing is projected to improve health outcomes and reduce the cost of care by increasing therapeutic efficacy and minimizing drug toxicity. American Indian and Alaska Native (AI/AN) people historically have been excluded from pharmacogenetic research and its potential benefits, a deficiency we sought to address. The vitamin K antagonist warfarin is prescribed for prevention of thromboembolic events, although its narrow therapeutic index and wide inter-individual variability necessitate close monitoring of drug response. Therefore, we were interested in variation in CYP2C9, VKORC1, CYP4F2, CYP4F11, and GGCX, which encode enzymes important for the activity of warfarin and synthesis of vitamin K dependent blood clotting factors. We resequenced these genes in 188 AI/AN people in partnership with Southcentral Foundation (SCF) in Anchorage, AK and 94 Yup'ik people living in the Yukon-Kuskokwim Delta of southwest Alaska to identify known or novel function-disrupting variation. We conducted genotyping for specific SNPs in larger cohorts of each study population (380 and 350, respectively). We identified high frequencies of the lower-warfarin dose VKORC1 haplotype (−1639G>A and 1173C>T) and the higher-warfarin dose CYP4F2*3 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C9*3, CYP2C9*2 and CYP2C9*29, predict that a significant proportion of AI/AN people will have decreased CYP2C9 activity. Overall, we predict a lower average warfarin dose requirement in AI/AN populations in Alaska than that seen in non-AI/AN populations of the US, a finding consistent with clinical experience in Alaska.