GenHAT

基本信息

批准号：
7942051
负责人：
JOHN H ECKFELDT
金额：
$ 13.97万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-01 至 2012-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7942051
关键词：
Accounting Adrenergic Antagonists Adult Advisory Committees Amlodipine Ancillary Study Angiotensin-Converting Enzyme Inhibitors Antihypertensive Agents Arts Atherosclerosis Bioinformatics Calcium Channel Blockers Candidate Disease Gene Cardiovascular Diseases Categories Chlorthalidone Clinical Communities Consensus Coronary Coronary heart disease Cox Proportional Hazards Models DNA analysis Data Diabetes Mellitus Disease Outcome Diuretics Doxazosin Drug Interactions End stage renal failure Event Funding Genes Genetic Variation Genotype Goals Haplotypes Heart failure Homeostasis Hypertension Individual Joints Kidney Diseases Laboratories Lipids Lisinopril Logistic Regressions Methods Minnesota Modeling Myocardial Infarction National Heart, Lung, and Blood Institute Outcome Participant Pathway interactions Patients Peer Review Peripheral arterial disease Persons Pharmaceutical Preparations Pharmacogenetics Population Population Control Procedures Proportional Hazards Models Randomized Renin-Angiotensin-Aldosterone System Research Design Research Personnel Resources Risk Sample Size Sampling Single Nucleotide Polymorphism Sodium Stratification Stroke Structure Sympathetic Nervous System System Testing Universities Variant arm base cardiovascular disorder risk clinically relevant cohort comparison group density design familial hypertension follow-up genetic analysis genetic variant high risk mortality pharmacogenetic testing programs randomized trial response treatment response

项目摘要

DESCRIPTION (provided by applicant): This is one of four collaborative R01s, representing the University of Minnesota, for the competitive renewal of the Genetics of Hypertension Associated Treatments (GenHAT) study. The goal of this competitive renewal is to comprehensively evaluate the pharmacogenetic basis of antihypertensive treatment response using state-of-the-art methods. There is large between-person variation in response to drugs, and genetic variation contributes to variable treatment response. To determine if genetic variants interact with antihypertensive medications to modify the risk of fatal coronary heart disease and non-fatal myocardial infarction and other cardiovascular disease outcomes in high-risk hypertensive adults. GenHAT is an ancillary study to ALLHAT, a randomized trial of four antihypertensive treatments (chlorthalidone, amlodipine, lisinopri and doxazosin) conducted in 42,418 high-risk hypertensive patients who were followed an average of 4.9 years (3.2 years for the truncated doxazosin arm). Using a case-cohort design, in Aim 1 we will examine whether single SNPs (both htSNPs and nonsynonomous SNPs) within genes in candidate-gene pathways of relevance for the ALLHAT medications (e.g., the renin-angiotensin-aldosterone system, the sodium homeostasis pathway, the endothelial system, and lipid and diabetes pathways) interact with antihypertensive treatments to modify risk of fatal and non-fatal coronary heart disease or stroke, heart failure, peripheral arterial disease, end state renal disease and all-cause mortality. We will genotype 96 ancestry-informative markers on all cases and the cohort random sample and use structured association testing (SAT) methods to control for potential population stratification. We will implement false discovery rate (FDR) methods to take multiple testing into account. For Aim 2 we will examine whether multiple SNPs in multiple genes within selected candidate-gene pathways interact with antihypertensive treatments to modify risk of CHD and other outcomes, as outlined for Aim 1. SAT and FDR methods will also be used for Aim 2 to control for population stratification and multiple testing. Finally, Aim 3 will enhance the overall utility of GenHAT data to the scientific community by establishing a mechanism for external investigators to undertake genetic analysis within GenHAT for 20 genetic variants for the case-cohort sample. GenHAT offers an unparalleled opportunity to determine the pharmacogenetic basis of antihypertensive treatment.

描述（由申请人提供）：这是代表明尼苏达大学的四个合作R01之一，以竞争性更新高血压相关治疗（Genhat）研究的遗传学。这个竞争的目标更新将全面评估降压治疗反应的药物遗传基础使用最先进的方法。对药物的响应和遗传变异有助于可变治疗反应。确定遗传变异是否与降压药物可改变致命性冠心病和非致命心肌的风险高风险高血压成年人的梗塞和其他心血管疾病结局。 Genhat是一个辅助研究Allhat，这是一项四种降压治疗的随机试验（氯噻酮，在42,418例高危患者中进行的氨氯地平，位甲诺普里和多克萨斯素）平均为4。9年（截短的多克萨唑嗪组为3。2年）。使用Case-Ohort设计，在AIM 1中我们将检查候选基因中基因中的单个SNP（HTSNP和非语言SNP）是否是否与allhat药物相关的途径（例如，肾素 - 血管紧张素 - 醛固酮系统，钠稳态途径，内皮系统以及脂质和糖尿病途径）与降压治疗可改变致命和非致命性冠心病或中风的风险，心脏衰竭，周围动脉疾病，终结状态肾脏疾病和全因死亡率。我们将基因型96 所有情况下的祖先信息标记和队列随机样本并使用结构化关联测试（SAT）控制潜在种群分层的方法。我们将实施虚假发现率（FDR）考虑多次测试的方法。对于目标2，我们将检查是否有多个SNP 选定的候选基因途径中的多个基因与降压治疗相互作用以修饰正如AIM 1所述的冠心病和其他结果的风险。SAT和FDR方法也将用于AIM 2 控制人口分层和多次测试。最后，AIM 3将增强通过建立外部研究人员的机制来向科学界的Genhat数据对案例 - 霍特样品进行20种遗传变异的Genhat中进行遗传分析。 Genhat 提供无与伦比的机会来确定降压治疗的药物遗传基础。