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: 7494142
• 负责人: Bruce M Psaty
• 金额: $ 182.86万
• 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/7494142
• 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。这项修订是该应用程序的最后一个允许的修订，代表了一种多学科的工作，该努力使用了3项基于人群的心肌梗塞（ML），猝死和中风的标本和数据。主要目的是：（1）确定在这些心血管结局的4个主要抗高血压药物类别中每一种的新区域，这些区域是候选药物相互作用的候选； （2）复制发现以评估有效性。方法。拟议的研究有五个主要步骤。步骤1至3共同代表仅单级病例设计以识别基因组区域。在步骤1中，全基因组唯一的研究将在1400例中分析317,000个SNP，以鉴定4个主要药物类别中的每一个中的每一个（所有4个药物组的600个[diuretics，β受体阻滞剂，ACE抑制剂，钙拮抗剂）的150个“有趣”的基因组区域）。在步骤2中，将在1400个对照中对这600个SNP进行基因分型，以验证只有病例的假设，即在人群中没有药物 - 基因关联。在步骤3中，对于每个高信号区域，将在1400例情况下选择4个附近的SNP并进行基因分型，以识别信号变得更明亮的区域，从而为选择前60个区域的选择提供经验支持（每个药物类别15）。他们将根据极端的p值，人口归因的部分和生物信息学进行进一步研究。在步骤4中，将使用HAPMAP数据，20个基因的重新取证以及其他资源来为60个区域中的每个区域中的每个区域选择特异性的TAG-SNP，以充分表征遗传变异。在步骤5中，这些TAG-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，将使用600例卫生人群的600例和1200个对照的新样本来评估药物的相互作用。在外部复制研究中，将在心血管健康研究中接受治疗的高血压-2700的参与者和杰克逊心脏研究的2000年中分析相同的基因型。修订后的单级案例 - 仅设计取代了先前的两阶段 /案例对照研究。新方法比以前的方法更强大，便宜。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，可检测和复制降压药与CV事件中常见遗传变异的适度相互作用。