Inflammation Genomics and Atherosclerosis

描述(申请人提供)：生物学方面的进展表明，动脉粥样硬化可能部分反映了慢性炎症的血管后果。利用华盛顿大学NHLBI基因组应用计划(PGA)产生的一组候选基因的全序列变异和常见单倍型的信息，我们建议在青年冠状动脉危险因素发展(CARDIA)研究中检查炎症/血栓形成基因的常见变异与中等数量表型和亚临床冠状动脉粥样硬化的相关性，CARDIA研究是一项大型的双种族队列研究。这组25个候选基因涉及通路(细胞因子、趋化因子及其受体；细胞黏附分子；以及凝血蛋白)，并包括几个受体-配体对。利用分支分析和PGA的资源，我们将确定一组有限的单核苷酸多态(每个基因3-10个SNPs)，以表征非洲裔和欧洲裔人中这些候选基因的常见单倍型。CARDIA第10年检查的DNA(n=3950名受试者)将对常见单倍型的选定变异进行基因分型。关于常见变异和单倍型存在的数据将被纳入CARDIA研究数据库。两个重要的中间表型，纤维蛋白原和C反应蛋白(CRP)的水平已经被检测。冠状动脉粥样硬化的非侵入性评估，定义为冠状动脉钙化(CAC)的存在，在15岁的CARDIA参与者身上获得。分析将按种族/民族分层，重点放在常见单倍型与成年早期测量的纤维蛋白原、C反应蛋白和CAC的相关性上。其次，我们将探索可能的基因-基因和基因-环境相互作用。拟议的多学科合作将提高评估炎症/血栓形成候选基因组的共同变异与年轻人心血管风险之间的相关性的敏感性和特异性。

DESCRIPTION (provided by applicant): Advances in biology suggest that atherosclerosis may reflect, in part, the vascular consequences of chronic inflammation. Using information on complete sequence variation and common haplotypes on a set of candidate genes generated through the NHLBI Program in Genomic Applications (PGA) at the University of Washington, we propose to examine the associations of common variation in inflammation/thrombosis genes with intermediate quantitative phenotypes and subclinical coronary atherosclerosis in the Coronary Artery Risk Factor Development in Young Adult (CARDIA) Study, a large, bi-racial cohort study. The set of 25 candidate genes involve pathways (cytokines, chemokines, and their receptors; cellular adhesion molecules; and, coagulation proteins) and include several receptor-ligand pairs. Using cladistic analysis and the resources of the PGA, we will identify a limited set of single nucleotide polymorphisms (range 3-10 SNPs per gene) that characterize common haplotypes in these candidate genes within persons of African descent and European descent. DNA from the CARDIA Year 10 examination (n = 3,950 subjects) will be genotyped for the selected variants that characterize the common haplotypes. Data on the presence of common variants and haplotypes will be incorporated into the CARDIA Study database. Levels of two important intermediate phenotypes, fibrinogen and C-reactive protein (CRP) were previously determined. Non-invasive assessment of coronary atherosclerosis, defined as the presence of coronary artery calcification (CAC), was obtained on CARDIA participants at the Year 15 exam. Analyses will be stratified by race/ethnicity and focus on the associations of the common haplotypes with fibrinogen, CRP, and CAC measured in early adult life. Secondarily, we will explore possible gene-gene and gene-environment interactions. The proposed multi-disciplinary collaboration should enhance the sensitivity and specificity of efforts to assess the associations of common variation in sets of inflammation/thrombosis candidate genes and cardiovascular risk in young adults.