Pharmacogenomics and Risk of Cardiovascular Disease

描述(由申请人提供)：这笔赠款的总体目标是定义和确认他汀类药物治疗的临床反应中个体间差异较大的遗传因素。多学科研究团队在基因组学、统计遗传学和信息学、临床药理学和心脏病学、心血管风险因素实验室测量以及流行病学方面拥有专业知识。在一项顺序设计中，我们将使用来自总共10,000名接受不同他汀类药物治疗的受试者的样本，使用全基因组关联方法来识别与他汀类药物反应的实验室测量相关的SNPs(单核苷酸多态)，包括低密度脂蛋白和高密度脂蛋白亚组分，胆固醇吸收和合成的标志，以及炎症标志hs-CRP。来自辛伐他汀或普伐他汀试验的1000名高加索受试者的初步分析将基于一个由25万个全基因组SNPs组成的小组(目标1)。在接受瑞舒伐他汀(AIM 2)和阿托伐他汀(AIM 3)治疗的队列中进行的验证性分析将产生一组1100个SNP，这些SNP与高加索人和非裔美国人的低密度脂蛋白胆固醇和其他表型的他汀类反应的变化最一致。此外，全基因组SNP小组和候选基因SNPs将被用于在150例患者和300名匹配的对照组中识别与他汀类药物相关的肌病相关的基因。对AIMS 2和AIMS 3中与他汀类药物诱导的低密度脂蛋白胆固醇和其他信息表型的降低最相关的50个基因的基因组重测序将识别总共48名高加索人和48名非裔美国人的等位变异，这些变异是从这些表型在各自种族群体中分布最高和最低的5%中随机挑选出来的(AIM 4)。最后，将测试这些SNPs与实验室表型和临床心血管结果的相关性(目标5)。该计划提出了一种综合的方法，用于确定特定的基因类型对一类广泛用于预防心血管疾病的药物的反应的临床意义变化的影响。

DESCRIPTION (provided by applicant): The overall objective of this grant is to both define and confirm the genetic contribution to the large inter-individual variability in clinical response to treatment with statin drugs. The multidisciplinary research team has expertise in genomics, statistical genetics and informatics, clinical pharmacology and cardiology, laboratory measurements of cardiovascular risk factors, and epidemiology. In a sequential design, using samples from a total of 10,000 subjects treated with various statins, we will use a genome wide association approach to identify SNPs (single nucleotide polymorphisms) that are associated with laboratory measurements of statin response, including LDL and HDL subfractions, markers of cholesterol absorption and synthesis, and the inflammatory marker hs-CRP. Initial analyses in 1,000 Caucasian subjects from trials of simvastatin or pravastatin will be based on a panel of 250,000 genome-wide SNPs (Aim 1). Confirmatory analyses in cohorts treated with rosuvastatin (Aim 2) and atorvastatin (Aim 3) will yield a panel of 1,100 SNPs most consistently associated with variation in statin response of LDL cholesterol and other phenotypes in Caucasians and African-Americans. In addition, the genome-wide SNP panel along with candidate gene SNPs will be used to identify those associated with statin-related myopathy in 150 cases vs. 300 matched controls. Genomic resequencing of the 50 genes most strongly associated in Aims 2 and 3 with statininduced reductions in LDL cholesterol and other informative phenotypes will identify allelic variants in a total of 48 Caucasians and 48 African-American randomly selected from the highest and lowest 5% of the distributions of these phenotypes in the respective ethnic groups (Aim 4). Finally, these SNPs will be tested for associations with both laboratory phenotypes and clinical cardiovascular outcomes (Aim 5). This program presents a comprehensive approach for determining effects of specific genotypes on clinically meaningful variations in responsiveness to a class of drugs widely used to prevent cardiovascular disease.