Genome-wide case-only study of antihypertensive drug-gene interactions

描述(由申请人提供)：研究团队、数据和目标。这次修订是允许应用的最后一次修订，代表了一项多学科的努力，使用了3项关于治疗高血压患者的心肌梗死(ML)、猝死和中风的大型人群研究的样本和数据。主要目的是：(1)确定4类主要抗高血压药物中每一类对这些心血管结果的候选药物-基因相互作用的新区域；以及(2)复制这些发现以评估有效性。方法：研究方法。拟议的研究有五个主要步骤。总而言之，步骤1到3代表了识别基因组区域的单阶段仅病例设计。在第一步中，一项全基因组病例研究将分析1400个病例中的317,000个SNPs，以确定4种主要药物类别中每一种的150个“感兴趣”的基因组区域(所有4种药物组[利尿剂、β-受体阻滞剂、血管紧张素转换酶抑制剂、钙拮抗剂]有600个)。在步骤2中，这600个SNP将在1400个对照中进行基因分型，以验证在人群中没有药物与基因关联的仅病例假设。在步骤3中，对于每个高信号区，将选择附近的4个SNPs，并在1400例病例中进行基因分型，以确定信号变得更亮的区域，从而为选择前60个区域(每个药物类别15个)提供经验支持。他们将被选作进一步研究的基础上的极端p值，人口归因分数，和生物信息学。在步骤4中，将使用HapMap数据、20个基因的重新测序和其他资源来为60个区域中的每个区域选择稀有特定的Tag-SNP，以充分表征遗传变异。在步骤5中，这些标签-SNP将在3个群体中进行基因分型以供复制。在内部复制研究中，将使用来自集团健康人群的600例患者和1200名对照的新鲜样本来评估药物与基因的相互作用。在外部复制研究中，将在接受高血压治疗的参与者中检测相同的基因类型--心血管健康研究中的2700种，杰克逊心脏研究中的2000种。修订后的单阶段病例对照设计取代了以前的两阶段病例/病例对照研究。新的方法比以前的方法更强大，成本更低。这项全基因组关联研究是对正在进行的候选基因方法的补充，具有出色的能力来检测和复制抗高血压药物与心血管事件中常见遗传变异的适度相互作用。

DESCRIPTION (provided by applicant): Research team, data, and aims. This revision, the last one permitted for this application, represents a multi- disciplinary effort that uses specimens and data from 3 large population-based studies of myocardial infarction (Ml), sudden death, and stroke in patients with treated hypertension. The major aims are: (1) to identify new regions that are candidates for drug-gene interactions for each of 4 major anti-hypertensive drug classes on these cardiovascular outcomes; and (2) to replicate the findings to assess validity. Methods. The proposed study has five major steps. Together, Steps 1 to 3 represent a single-stage case-only design to identify genomic regions. In Step 1, a whole-genome case-only study will assay 317,000 SNPs in 1400 cases to identify 150 "interesting" genomic regions for each of the 4 major drug classes (600 for all 4 drug groups [diuretics, beta-blockers, ACE inhibitors, calcium antagonists]). In Step 2, these 600 SNPs will be genotyped in 1400 controls to verify the case-only assumption of no drug-gene association in the population. In Step 3, for each high-signal region, 4 nearby SNPs will be selected and genotyped in the 1400 cases to identify regions where the signal becomes brighter and thus provide empiric support for the selection of the top 60 regions (15 per drug class). They will be selected for further study on the basis of extreme p-values, population attributable fractions, and bioinformatics. In Step 4, HapMap data, resequencing of 20 genes, and other resources will be used to select ethinic-specific tag-SNPs for each of the 60 regions to fully characterize the genetic variation. In Step 5, these tag-SNPs will be genotyped in 3 populations for replication. In the internal replication study, a fresh sample of 600 cases and 1200 controls from the Group Health population will be used to evaluate the drug-gene interactions. In the external replication study, the same genotypes will be assayed in participants with treated hypertension-2700 from the Cardiovascular Health Study and 2000 from the Jackson Heart Study. The revised single-stage case- only design replaces the previous two-stage case-only / case-control study. The new approach is at once more powerful and less expensive than the previous one. This genome-wide association study, which serves as a complement to on-going candidate-gene approaches, has excellent power to detect and replicate modest-sized interactions of antihypertensive drugs with common genetic variants on CV events.