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。这一修订是本应用程序允许的最后一项修订，代表了一个多学科的努力，它使用了来自3个大型人群研究的标本和数据，这些研究涉及高血压治疗患者的心肌梗死（Ml）、猝死和中风。主要目的是：(1)确定4种主要抗高血压药物对这些心血管结果的药物-基因相互作用的新候选区域；(2)重复研究结果以评估效度。方法。拟议中的研究有五个主要步骤。步骤1到步骤3共同代表了鉴定基因组区域的单阶段病例设计。在第一步中，一项仅限病例的全基因组研究将分析1400例病例中的317000个snp，以确定4种主要药物类别中每种药物的150个“有趣”基因组区域（利尿剂、受体阻滞剂、ACE抑制剂、钙拮抗剂等4种药物类别的600个基因组区域）。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基因关联的病例假设。在步骤3中，对于每个高信号区域，将在1400个病例中选择4个附近的snp进行基因分型，以确定信号变亮的区域，从而为选择前60个区域（每个药物类别15个）提供经验支持。他们将根据极端p值、群体归因分数和生物信息学选择进一步研究。在步骤4中，将使用HapMap数据，20个基因的重测序和其他资源来选择60个区域中每个区域的种族特异性标签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进行复制。在内部重复研究中，将使用来自组健康人群的600例病例和1200例对照的新样本来评估药物-基因相互作用。在外部复制研究中，同样的基因型将在接受治疗的高血压患者中进行分析——2700名来自心血管健康研究，2000名来自杰克逊心脏研究。修订后的单阶段病例设计取代了之前的两阶段病例/病例对照研究。新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，作为正在进行的候选基因方法的补充，在检测和复制抗高血压药物与常见基因变异对心血管事件的适度相互作用方面具有出色的能力。

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.