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

描述（由申请人提供）：研究团队，数据和目的。该修订版是本申请允许的最后一次修订版，代表了多学科的努力，使用了来自3项大规模基于人群的高血压治疗患者心肌梗死（MI）、猝死和卒中研究的样本和数据。主要目标是：（1）确定4种主要抗高血压药物中每一种药物与心血管结局发生药物-基因相互作用的候选新区域;（2）复制研究结果以评估有效性。方法.拟议的研究有五个主要步骤。总之，步骤1至3代表了识别基因组区域的单阶段仅病例设计。在第1步中，全基因组病例研究将在1400例病例中测定317，000个SNP，以确定4种主要药物类别中每种药物的150个“感兴趣”基因组区域（所有4种药物组[利尿剂，β受体阻滞剂，ACE抑制剂，钙拮抗剂]为600个）。在步骤2中，将在1400个对照中对这600个SNP进行基因分型，以验证人群中无药物-基因关联的仅病例假设。在步骤3中，对于每个高信号区域，将在1400例病例中选择4个附近的SNP并进行基因分型，以识别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。将根据极端p值、群体归因分数和生物信息学选择它们进行进一步研究。在第4步中，将使用HapMap数据、20个基因的重测序和其他资源为60个区域中的每个区域选择种族特异性tag-SNP，以充分表征遗传变异。在步骤5中，将在3个群体中对这些tag-SNP进行基因分型以进行复制。在内部复制研究中，将使用来自健康人群的600例病例和1200例对照的新鲜样本来评价药物-基因相互作用。在外部复制研究中，将在接受治疗的高血压受试者中分析相同的基因型-2700例来自心血管健康研究，2000例来自杰克逊心脏研究。修订后的单阶段仅病例设计取代了先前的两阶段仅病例/病例对照研究。新的方法比以前的方法更强大，而且更便宜。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，具有很好的检测和复制抗高血压药物与常见遗传变异对CV事件的适度相互作用的能力。

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.