Genetic and Environmental Determinants of Warfarin Response

描述(申请人提供)：尽管华法林在治疗和预防血栓栓塞症(TED)方面的疗效已被证明，但它的利用远远不足，管理困难，并发症的风险是主要的威慑因素。对华法林反应的基因调控的认识推动了量化这种影响的努力，但重点主要限于选择基因和结果，主要是在高加索人。我们在了解基因对华法林反应的影响方面的努力始于2003年K23基金(NS045598)：抗凝治疗的药物遗传学优化(POAT)。虽然这项培训拨款侧重于评估单个基因；细胞色素P450 2C9(CYP2C9)基因对华法林剂量、目标范围外国际标准化比率(INR)的频率以及并发症风险的影响，但该队列为扩大我们的药物遗传学努力提供了宝贵的种族多样性资源。据我们所知，POAT队列是最大的预期队列(n=578，51%的男性，273名非裔美国人(AA))，从开始治疗开始进行为期2年的纵向随访。这项建议将进一步促进POAT的目标，在1200名参与者(50%AA)的队列中使用综合药物遗传学方法来测试三个假设。这项建议将包括参与凝血级联反应、维生素K循环以及华法林药效学和药代动力学的50个基因。非遗传协变量将包括社会人口统计、生活方式、饮食和医学特征。目的1将评估遗传和非遗传协变量对华法林剂量的相对影响。目的2将评估候选基因在决定抗凝的获得和维持以及过度抗凝的风险方面的贡献(INR&GT；4)。目标3将确定候选基因与出血或血栓栓塞症风险之间的关联。这项研究还将探索基因*基因和基因*非遗传协变量的相互作用。我们预计，这项研究的结果将进一步阐明华法林反应的遗传贡献，为以前研究不足的人群，即非裔美国人的治疗反应提供新的遗传关联。这些知识将为未来准确的华法林剂量的处方前基因分型提供证据基础，并促进其在符合条件的患者中的使用。

DESCRIPTION (provided by applicant): Although the efficacy of warfarin in the treatment and prevention of thromboembolic disorders (TEDs) is proven, it is vastly underutilized with difficulties in management & risk of complications being the main deterrents. Recognition of genetic regulation of warfarin response has fueled efforts to quantify this influence, but the focus has been restricted to select genes and outcomes mainly in Caucasians. Our effort in understanding genetic influences on warfarin response began in 2003 with a K23 grant (NS045598): Pharmacogenetic Optimization of Anticoagulation Therapy (POAT). Although this training grant focused on evaluating the influence of a single gene; cytochrome P450 2C9 (CYP2C9) genotype on warfarin dose, frequency of International Normalized Ratio (INR) outside target range, and risk of complications, the cohort provides a valuable racially diverse resource to expand our pharmacogenetic effort. The POAT cohort is, to our knowledge the largest prospective cohort (n=578, 51% men, 273 African Americans (AA)) with a 2-year longitudinal follow-up from initiation of therapy. This proposal will further the aims of POAT using a comprehensive pharmacogenetic approach in a cohort of 1200 participants (50% AA) powered (>80%, alpha=0.001) to test three hypotheses. This proposal will incorporate 50 genes involved in the clotting cascade, vitamin K cycle, and warfarin pharmacodynamics and pharmacokinetics. Non-genetic covariates will include socio-demographics, lifestyle, diet, and medical characteristics. Aim 1 will assess the relative effects of genetic and non-genetic covariates on warfarin dose. Aim 2 will assess the contribution of candidate genes in determining attainment and maintenance of anticoagulation and risk of over- anticoagulation (INR >4). Aim 3 will determine the association between candidate genes and risk of hemorrhage or thromboembolism. The study will also explore gene*gene and gene*non-genetic covariate interactions. We anticipate that the results of this study will further elucidate the genetic contributions of warfarin response, provide novel genetic associations of treatment response in a previously understudied population, namely, African Americans. This knowledge will provide an evidence base for future pre-prescription genotyping for accurate warfarin dosing and facilitate its use in qualifying patients.