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

抗高血压药物-基因相互作用的全基因组病例研究

• 批准号: 7258677
• 负责人: Bruce M Psaty
• 金额: $ 194.69万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7258677
• 关键词: Adrenergic beta-Antagonists; Affect; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Antihypertensive Agents; Bioinformatics; Biological Assay; Blood Pressure; Calcium Channel Blockers; Candidate Disease Gene; Cardiovascular system; Case-Control Studies; Class; Clinical Trials; Complement; Complex; Control Groups; DNA Resequencing; Data; Databases; Direct Costs; Diuretics; Drug usage; Event; Exclusion; Funding; Generations; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Haplotypes; Health; Health Maintenance Organizations; Heart; Hypertension; Hypotension; Incidence; Maps; Methods; Myocardial Infarction; Other Resources; Outcome; Participant; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Pharmacy facility; Population; Population Attributable Risks; Purpose; Randomized Clinical Trials; Rate; Research; Research Personnel; Safety; Sampling; Signal Transduction; Specimen; Staging; Stroke; Sudden Death; Upper arm; Variant; Work; base; case control; computerized; cost; design; gene interaction; genetic variant; genome wide association study; interest; novel strategies; prescription document; prescription procedure; programs; response; size; trait; treatment effect

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.

描述（由申请人提供）：研究团队、数据和目标。这一修订是本申请允许的最后一次修订，代表了一项多学科的努力，它使用了来自 3 项大型基于人群的研究的样本和数据，这些研究涉及接受治疗的高血压患者的心肌梗塞 (MI)、猝死和中风。主要目标是：(1) 确定新的区域，这些区域是 4 种主要抗高血压药物类别中每一种对这些心血管结局的药物-基因相互作用的候选区域； (2) 重复研究结果以评估有效性。方法。拟议的研究有五个主要步骤。步骤 1 至 3 共同代表了用于识别基因组区域的单阶段仅案例设计。在第一步中，全基因组病例研究将分析 1400 个病例中的 317,000 个 SNP，以确定 4 个主要药物类别中每一个的 150 个“有趣”基因组区域（所有 4 个药物组 [利尿剂、β 受体阻滞剂、ACE 抑制剂、钙拮抗剂] 共 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，以验证人群中没有药物-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个案例中选择4个附近的SNP并进行基因分型，以识别信号变亮的区域，从而为前60个区域（每个药物类别15个）的选择提供经验支持。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。在内部复制研究中，来自团体健康人群的 600 例病例和 1200 例对照的新鲜样本将用于评估药物-基因相互作用。在外部复制研究中，将对来自心血管健康研究的 2700 名高血压患者和来自杰克逊心脏研究的 2000 名高血压患者进行相同的基因型检测。修订后的单阶段仅病例设计取代了之前的两阶段仅病例/病例对照研究。新方法比以前的方法更强大，而且成本更低。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。