Inflammation Genomics and Atherosclerosis

描述（由申请人提供）：生物学进展表明，动脉粥样硬化可能部分反映了慢性炎症的血管后果。利用华盛顿大学基因组应用NHLBI项目（PGA）生成的一组候选基因的完整序列变异和共同单倍型信息，我们建议在年轻人冠状动脉危险因素发展（CARDIA）研究中，研究炎症/血栓形成基因的共同变异与中间定量表型和亚临床冠状动脉粥样硬化的关系。这组25个候选基因涉及途径（细胞因子、趋化因子及其受体、细胞粘附分子和凝血蛋白），并包括一些受体-配体对。利用进化分析和PGA资源，我们将确定一组有限的单核苷酸多态性（每个基因范围为3-10个snp），这些多态性表征了非洲人和欧洲人后裔中这些候选基因的共同单倍型。将对CARDIA 10年级检查（n = 3950名受试者）的DNA进行基因分型，以确定常见单倍型的选定变体。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。两种重要的中间表型，纤维蛋白原和c反应蛋白（CRP）的水平先前被确定。CARDIA参与者在15年级考试时获得冠状动脉粥样硬化的无创评估，定义为冠状动脉钙化（CAC）的存在。分析将按种族/民族分层，并重点关注在成年早期测量纤维蛋白原、CRP和CAC的常见单倍型的关联。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/血栓候选基因组共同变异与年轻人心血管风险之间关系的敏感性和特异性。

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.