Thrombosis Genetics, MI and Stroke in Older Adults

描述（由申请人提供）：该项目代表了华盛顿大学、佛蒙特大学、北卡罗来纳州大学和约翰霍普金斯大学研究人员的合作努力。虽然抗血栓形成和抗炎治疗的治疗益处表明凝血和炎症在心肌梗死（MI）和卒中的病因学中起主要作用，但心血管疾病（CVD）风险的促血栓形成和促炎症组分的遗传决定因素仍缺乏特征。通过建立在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，人口和统计遗传学的生物学进展与心血管健康研究（CHS）的独特资源联系起来，CHS是一个大型的老年人双胞胎队列。通过CHS主合同，对5，888名老年人进行了超过15年的随访，累积了大量（> 2，000）临床CVD事件。基线传统风险因素、亚临床疾病和几种重要的炎症/血栓形成生物标志物（纤维蛋白原、C-反应蛋白、因子VII等）的数据也可用。通过拟议的更新，我们计划对8种血浆血栓形成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，将用作中间表型，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> 2，000个候选基因和现有CHS全基因组数据（Illumina Human Hap 370 CNV），我们建议彻底评估血栓形成/炎症基因与中间表型和事件MI和中风的关联。该应用程序的其他优势包括白人和非洲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，基因环境和基因间相互作用。将通过在具有大量CVD事件的其他队列中进行复制基因分型（ARIC、檀香山心脏计划、妇女健康倡议）以及相关SNP的体外和生物信息学评估来验证发现。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卒中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形成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血栓形成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的对晚期动脉粥样硬化的炎症或血栓反应而处于心血管高危状态的老年人，并可能为预防和治疗MI和卒中提供新的方向。

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.