Genetic and Environmental Determinants of Warfarin Response

华法林反应的遗传和环境决定因素

• 批准号: 8281482
• 负责人: NITA A LIMDI
• 金额: $ 71.29万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-20 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281482
• 关键词: Accounting; African American; Alabama; Alcohol consumption; Anticoagulation; Apolipoprotein E; Candidate Disease Gene; Caucasians; Caucasoid Race; Characteristics; Coagulation Process; Cohort Studies; Comorbidity; Cox Proportional Hazards Models; Cytochrome P450; Cytochromes; Demographic Aging; Diet; Disease; Dose; Drug Kinetics; Education; European; Event; Factor VIII; Foundations; Frequencies; Future; Genes; Genetic; Genomics; Genotype; Grant; Haplotypes; Hemorrhage; Incidence; Individual; Intake; International Normalized Ratio; Knowledge; Life Style; Linear Regressions; Logistic Regressions; Maintenance; Metabolism; Methods; Minor; Modeling; Morbidity - disease rate; Myocardial Infarction; Occupations; Outcome; Participant; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Physical activity; Population; Prevention; Process; Protein C; Proteins; Prothrombin; Qualifying; Race; Regression Analysis; Regulation; Relative (related person); Resources; Risk; Risk Management; Role; Smoking; Source; Stratification; Stroke; Testing; Thrombin; Thromboembolism; Time; Training; Transportation; Universities; Variant; Venous Thrombosis; Vitamin K; Warfarin; base; cohort; demographics; dosage; evidence base; follow-up; gamma-glutamyl carboxylase; genetic association; genetic profiling; genetic regulatory protein; hazard; human CYP2C9 protein; income insurance; medication compliance; men; mortality; non-genetic; novel; pregnane X receptor; prospective; response; sex; socioeconomics; treatment response; trend

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.

描述（由申请人提供）：尽管华法林在治疗和预防血栓栓塞性疾病（TED）方面的功效已得到证实，但由于管理困难和并发症风险是主要阻碍因素，它的利用率极低。对华法林反应基因调控的认识推动了量化这种影响的努力，但焦点仅限于主要在白种人中的选定基因和结果。我们于 2003 年通过 K23 资助 (NS045598) 开始努力了解遗传对华法林反应的影响：抗凝治疗的药物遗传学优化 (POAT)。虽然这项培训资助的重点是评估单个基因的影响；由于华法林剂量的细胞色素 P450 2C9 (CYP2C9) 基因型、国际标准化比值 (INR) 超出目标范围的频率以及并发症的风险，该队列为扩大我们的药物遗传学工作提供了宝贵的种族多样化资源。据我们所知，POAT 队列是最大的前瞻性队列（n=578，51% 男性，273 名非裔美国人 (AA)），从治疗开始进行了 2 年纵向随访。该提案将进一步实现 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（>80%，α=0.001）来测试三个假设。该提案将纳入涉及凝血级联、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。非遗传协变量包括社会人口统计、生活方式、饮食和医疗特征。目标 1 将评估遗传和非遗传协变量对华法林剂量的相对影响。目标 2 将评估候选基因在确定抗凝效果的实现和维持以及过度抗凝风险（INR > 4）方面的贡献。目标 3 将确定候选基因与出血或血栓栓塞风险之间的关联。该研究还将探索基因*基因和基因*非遗传协变量相互作用。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，提供先前研究不足的人群（即非裔美国人）治疗反应的新遗传关联。这些知识将为未来的处方前基因分型提供证据基础，以实现准确的华法林剂量，并促进其在合格患者中的使用。