Fohner Alison E, Robinson Renee, Yracheta Joseph, Dillard Denise A, Schilling Brian, Khan Burhan, Hopkins Scarlett, Boyer Bert, Black Jynene, Wiener Howard, Tiwari Hemant K, Gordon Adam, Nickerson Deborah, Tsai Jesse M, Farin Federico M, Thornton Timothy A, Rettie Allan E, Thummel Kenneth E
Department of Pharmaceutics, University of Washington, Seattle, WA.
Southcentral Foundation, Anchorage, AK.
Pharmacogenet Genomics. 2015 Jul;25(7):343-353. doi: 10.1097/FPC.0000000000000143.
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 interindividual 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 in Anchorage, Alaska 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 single nucleotide polymorphisms 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 CYP4F23 variant. We also identified two relatively common, novel, and potentially function-disrupting variants in CYP2C9 (M1L and N218I), which, along with CYP2C93, CYP2C92, and CYP2C929, 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 USA, a finding consistent with clinical experience in Alaska.
药物遗传学检测预计可通过提高治疗效果和将药物毒性降至最低来改善健康结局并降低护理成本。美国印第安人和阿拉斯加原住民（AI/AN）历来被排除在药物遗传学研究及其潜在益处之外，我们试图解决这一缺陷。维生素K拮抗剂华法林用于预防血栓栓塞事件，尽管其治疗指数狭窄且个体间差异较大，因此需要密切监测药物反应。因此，我们对CYP2C9、VKORC1、CYP4F2、CYP4F11和GGCX的变异感兴趣，这些基因编码对华法林活性和维生素K依赖性凝血因子合成重要的酶。
我们与阿拉斯加安克雷奇的中南部基金会合作，对188名AI/AN人群以及居住在阿拉斯加西南部育空-库斯科基姆三角洲的94名Yup'ik人群的这些基因进行了重测序，以识别已知或新的功能破坏变异。我们对每个研究人群的更大队列（分别为380人和350人）中的特定单核苷酸多态性进行了基因分型。
我们发现了低华法林剂量的VKORC1单倍型（-1639G>A和1173C>T）和高华法林剂量的CYP4F23变体的高频率。我们还在CYP2C9中鉴定出两个相对常见、新的且可能破坏功能的变体（M1L和N218I），它们与CYP2C93、CYP2C92和CYP2C929一起预测，相当一部分AI/AN人群的CYP2C9活性将降低。
总体而言，我们预测阿拉斯加的AI/AN人群对华法林的平均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。
