Molecular Epidemiology of 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（UW）基因组科学系心血管健康研究单位和多中心心血管健康研究（CHS）（包括佛蒙特大学CHS血液实验室）的研究者之间的合作努力。该提案将血栓形成和炎症生物学，大规模人类基因组学以及人口和统计遗传学的进展与CHS的独特资源联系起来，CHS是一个大型的双种族老年人队列。在无临床明显血管疾病的老年男性和女性中，颈动脉内膜-中层厚度或IMT（亚临床动脉粥样硬化的测量）、C-反应蛋白（炎症的敏感标志物）和D-二聚体（止血系统激活的总体标志物）可预测随后的临床事件，如MI和卒中。虽然溶栓治疗和阿司匹林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着重要作用，但这些风险因素的遗传决定因素也受到传统生活方式风险因素（如吸烟和肥胖）的影响，在老年人中仍然很大程度上未被探索。这项研究的背景是心血管健康研究，这是一项针对5888名老年人的队列研究，旨在评估中风和冠心病的危险因素。关于传统风险因素、亚临床疾病指标和心血管事件的数据可用于拟定的辅助研究。通过整合最近关于年龄相关和血管床特异性调节血液凝固的临床和实验数据，并结合来自NHLBI资助的UW基因组应用计划的完整人类基因组DNA序列变异数据，我们建议彻底评估血栓形成和炎症基因与（1）颈动脉IMT，CRP，和D-二聚体水平，以及（2）>65岁的成年人中的MI和卒中事件，随访长达12年。该提案的优势包括关注几组生物学相关基因，基于每个候选基因的完整连锁不平衡或共同单倍型结构选择共同SNP，以及灵活的分析方法，允许评估单位点和多位点基因型，单倍型，以及基因-环境和基因-基因相互作用。我们期望这种多学科方法能够检测影响CVD易感性或改变对传统心血管危险因素反应的遗传变异。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由于对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高心血管风险的老年人，并为预防和治疗MI和卒中提供新的方向。

DESCRIPTION (provided by applicant): This project represents a collaborative effort among investigators of the Cardiovascular Health Research Unit, Department of Genome Sciences at the University of Washington (UW), and the multi-center Cardiovascular Health Study (CHS), including the CHS Blood Laboratory at the University of Vermont. The proposal links advances in thrombosis and inflammation biology, large-scale human genomics, and population and statistical genetics, with the unique resources of CHS, a large, bi-racial cohort of older adults. In older men and women without clinically apparent vascular disease, carotid intimal-medial thickness or IMT (a measure of subclinical atherosclerosis), C-reactive protein (a sensitive marker of inflammation), and D-dimer (a global marker of activation of the hemostatic system) predict subsequent clinical events such as MI and stroke. While the therapeutic benefits of thrombolytic therapy and aspirin suggest a major role for clotting and inflammation in the etiology of coronary disease and stroke, the genetic determinants of these risk factors, which are also influenced by traditional lifestyle risk factors such as smoking and obesity, remains largely unexplored in older adults. The setting for this study is the Cardiovascular Health Study, a cohort study of 5888 older adults designed to assess risk factors for stroke and coronary disease. Data on traditional risk factors, on measures of subclinical disease, and cardiovascular events are available to the proposed ancillary study. By integrating recent clinical and experimental data on age-related and vascular bed-specific regulation of blood coagulation, and incorporating complete human genomic DNA sequence variation data from the NHLBI-funded UW Program for Genomic Applications, we propose to evaluate thoroughly the association of thrombosis and inflammation genes with (1) carotid IMT, CRP, and D-dimer levels measured at baseline and (2) incident MI and stroke in adults >65 years old followed for up to 12 years. The strengths of the proposal include a focus on several sets of biologically related genes, the selection of common SNPs based on the complete linkage disequilibrium or common haplotype structure of each candidate gene, and a flexible analytic approach that allows assessment of single-locus and multi-locus genotypes, haplotypes, as well as gene-environment and gene-gene interaction. We expect this multi-disciplinary approach to enable the detection of genetic variants that influence CVD susceptibility or modify the response to conventional cardiovascular risk factors. Understanding the molecular background of these common but complex athero-thrombotic 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 provide new directions for prevention and treatment of MI and stroke.