Thrombosis Genetics, MI and Stroke in Older Adults

老年人的血栓形成遗传学、心肌梗死和中风

• 批准号: 7802141
• 负责人: ALEXANDER P REINER
• 金额: $ 51.9万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7802141
• 关键词: Accounting; Acute myocardial infarction; Address; African American; Age; Anti-Inflammatory Agents; Anti-inflammatory; Anticoagulation; Architecture; Atherosclerosis; Biochemical Markers; Bioinformatics; Biological Markers; Biology; Blood Coagulation Factor VII; C-reactive protein; Candidate Disease Gene; Cardiovascular Diseases; Cardiovascular system; Clinical; Coagulation Process; Complex; Computer Simulation; Contracts; Coronary heart disease; Data; Development; Disease; Elderly; Environment; Etiology; Event; Fibrinogen; Floods; Funding; Gene Expression; Genes; Genetic; Genetic Determinism; Genome; Genotype; Grant; Haplotypes; Health; Heart; Human; In Vitro; Individual; Inflammation; Inflammatory; Link; Measurement; Measures; Methods; Molecular; Myocardial Infarction; North Carolina; Nucleotides; Oral; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Plasma; Population; Predisposition; Prevention; Procedures; Proteins; Public Health; Randomized; Research Personnel; Resources; Risk; Risk Factors; Role; Screening procedure; Smoking; Stratification; Stroke; Systematic Bias; Testing; Therapeutic; Thrombosis; Tissue Sample; Universities; Validation; Variant; Vermont; Washington; Women' s Health; analytical method; base; cardiovascular disorder risk; cardiovascular risk factor; cohort; disability; disease phenotype; flexibility; functional genomics; gene environment interaction; gene interaction; genetic association; genetic risk factor; genetic variant; genome wide association study; human tissue; innovation; interest; novel; programs; public health relevance; response; trait; vascular inflammation

DESCRIPTION (provided by applicant): This project represents a collaborative effort among investigators of the University of Washington, the University of Vermont, University of North Carolina, and Johns Hopkins. While the therapeutic benefits of anti-thrombotic and anti-inflammatory therapies suggest a major role for clotting and inflammation in the etiology of myocardial infarction (MI) and stroke, the genetic determinants of the pro-thrombotic and pro-inflammatory components of cardiovascular disease (CVD) risk remain poorly characterized. By building on candidate gene-CVD clinical and intermediate phenotype association results from our first grant cycle, the proposed renewal application links biologic advances in thrombosis and vascular inflammation pathways, functional genomics, population and statistical genetics, with the unique resources of Cardiovascular Health Study (CHS), a large, biracial cohort of older adults. Through the CHS main contract, 5,888 older adults have been followed for over 15 years, with the accrual of large number (>2,000) of clinical CVD events. Data on baseline traditional risk factors, subclinical disease, and several important inflammation/thrombosis biomarkers (fibrinogen, C-reactive protein, factor VII, and others) are also available. Through the proposed renewal, we plan to perform additional measurements of 8 plasma thrombosis biomarkers, selected on basis of our preliminary findings and rigorously defined biologic criteria, which will be utilized as intermediate phenotypes to strengthen evidence for CVD event-candidate gene association. By integrating existing candidate gene genotype data from the first cycle with >2,000 candidate genes from the NHLBI-supported CARE study and existing CHS genome-wide data (Illumina Human Hap 370CNV), we propose to evaluate thoroughly the association of thrombosis/inflammation genes with intermediate phenotypes and incident MI and stroke. Additional strengths of the application include excellent candidate gene SNP coverage in whites and African-Americans, and a flexible analytic approach that includes assessment of single- and multi-locus genotypes, haplotypes, gene-environment and gene-gene interaction. Validation of findings will occur through replication genotyping in additional cohorts with large numbers of CVD events (ARIC, Honolulu Heart Program, Women's Health Initiative), as well as in vitro and bioinformatics assessment of associated SNPs. PUBLIC HEALTH RELEVANCE: While the therapeutic benefits of anti-thrombotic therapies suggest a major role for clotting and inflammation in the etiology of coronary disease and stroke, the specific genetic determinants that underlie the predisposition toward vascular inflammation and thrombosis associated with cardiovascular risk remains largely unknown in older adults. Understanding the molecular background of these common but complex atherothrombotic disorders may help identify older individuals at high cardiovascular risk because of genetic or environmental differences in the inflammatory or thrombotic response to advanced atherosclerosis and may provide new directions for prevention and treatment of MI and stroke.

描述（由申请人提供）：该项目代表了华盛顿大学、佛蒙特大学、北卡罗来纳大学和约翰·霍普金斯大学的研究人员之间的合作努力。虽然抗血栓和抗炎疗法的治疗益处表明凝血和炎症在心肌梗塞（MI）和中风的病因学中发挥着重要作用，但心血管疾病（CVD）风险的促血栓和促炎症成分的遗传决定因素仍然知之甚少。通过建立在我们第一个拨款周期的候选基因-CVD临床和中间表型关联结果的基础上，拟议的更新申请将血栓形成和血管炎症途径、功能基因组学、群体和统计遗传学方面的生物学进展与心血管健康研究（CHS）的独特资源联系起来，心血管健康研究是一个大型的、混血的老年人队列。通过CHS主合同，对5,888名老年人进行了超过15年的跟踪，积累了大量（>2,000）临床CVD事件。还提供了有关基线传统危险因素、亚临床疾病和几种重要炎症/血栓生物标志物（纤维蛋白原、C 反应蛋白、因子 VII 等）的数据。通过拟议的更新，我们计划对 8 种血浆血栓生物标志物进行额外的测量，这些生物标志物是根据我们的初步发现和严格定义的生物学标准进行选择的，这些生物标志物将用作中间表型，以加强 CVD 事件与候选基因关联的证据。通过将第一个周期的现有候选基因基因型数据与来自 NHLBI 支持的 CARE 研究的超过 2,000 个候选基因以及现有的 CHS 全基因组数据 (Illumina Human Hap 370CNV) 相结合，我们建议彻底评估血栓形成/炎症基因与中间表型以及事件 MI 和中风的关联。该应用程序的其他优势包括白人和非裔美国人中出色的候选基因 SNP 覆盖率，以及灵活的分析方法，包括评估单基因座和多基因座基因型、单倍型、基因-环境和基因-基因相互作用。研究结果的验证将通过在具有大量 CVD 事件的其他队列（ARIC、檀香山心脏计划、妇女健康倡议）中进行复制基因分型以及相关 SNP 的体外和生物信息学评估来进行。公共卫生相关性：虽然抗血栓治疗的治疗效果表明凝血和炎症在冠心病和中风的病因学中发挥着重要作用，但老年人中与心血管风险相关的血管炎症和血栓形成倾向的具体遗传决定因素仍然很大程度上未知。了解这些常见但复杂的动脉粥样硬化血栓性疾病的分子背景可能有助于识别因晚期动脉粥样硬化的炎症或血栓反应的遗传或环境差异而处于心血管高风险的老年人，并可能为预防和治疗心肌梗死和中风提供新的方向。