Thrombosis Genetics, MI and Stroke in Older Adults

描述（由申请人提供）：本项目由华盛顿大学、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共同完成。虽然抗血栓和抗炎治疗的治疗益处表明凝血和炎症在心肌梗死（MI）和中风的病因学中起主要作用，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缺乏特征。基于我们第一个资助周期的候选基因- cvd临床和中间表型关联结果，拟议的更新申请将血栓形成和血管炎症途径的生物学进展、功能基因组学、人口和统计遗传学与心血管健康研究（CHS）的独特资源联系起来，CHS是一个大型的老年双种族队列。通过CHS主合同，5,888名老年人已被跟踪超过15年，累积了大量临床心血管疾病事件（约2,000例）。关于基线传统危险因素、亚临床疾病和几个重要的炎症/血栓生物标志物（纤维蛋白原、c反应蛋白、因子VII等）的数据也可获得。通过拟议的更新，我们计划对8个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选择的，它们将被用作中间表型，以加强CVD事件候选基因关联的证据。通过整合来自第一个周期的现有候选基因基因型数据、来自nhlbi支持的CARE研究的bbbb2000个候选基因和现有的CHS全基因组数据（Illumina Human Hap 370CNV），我们建议彻底评估血栓/炎症基因与中间表型和心肌梗死和中风的关联。该应用程序的其他优势包括在白人和非洲裔美国人中出色的候选基因SNP覆盖范围，以及灵活的分析方法，包括单位点和多位点基因型，单倍型，基因环境和基因相互作用的评估。研究结果的验证将通过在其他具有大量心血管事件的队列（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益处表明凝血和炎症在冠心病和中风的病因学中起主要作用，但在老年人中，与心血管风险相关的血管炎症和血栓易感性的特定遗传决定因素在很大程度上仍然未知。了解这些常见但复杂的动脉粥样硬化性血栓性疾病的分子背景可能有助于识别由于遗传或环境差异导致晚期动脉粥样硬化的炎症或血栓反应而具有心血管高风险的老年人，并可能为心肌梗死和卒中的预防和治疗提供新的方向。

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.