Genetic Influences on Coronary Artery Calcification

描述（由申请人提供）：本提案的总体目标是通过影响冠状动脉钙化（CAC）水平来确定影响心血管疾病易感性的基因。CAC的存在和数量预测了未来心血管事件的风险，CAC的水平具有高度遗传性。本研究利用了两组使用EBCT技术对CAC进行表型分析的个体，以及基因组学的最新进展，这些进展使得通过全基因组关联（GWA）方法鉴定疾病易感基因成为可能。我们假设影响CAC变异的基因将很容易通过GWA分析与密集间隔的SNPs鉴定。为了验证这一假设，我们将进行两阶段的设计，首先使用GWA扫描筛选800名阿米什受试者（第一阶段），然后在第二阶段（第二阶段）来自明尼苏达州罗切斯特市的欧洲高加索血统个体中进行基因型相关的snp研究，这些个体来自冠状动脉钙化流行病学研究。阿米什人是进行这类研究的一个特别有利的群体，因为他们有共同的遗传祖先和同质的生活方式。通过以前的工作，我们已经测量了800名阿米什成年人的CAC，我们目前正在对他们进行500K Affymetrix SNP芯片的基因分型，作为其他研究的一部分。在Specific Aim 1中，我们将对剩余300名受试者进行基因分型，并对CAC进行GWA分析。在特异性2中，我们将从第一阶段确定1750个最显著相关的snp（占测试snp总数的0.35%），并将在来自ECAC研究的900名受试者中对这些snp以及每个snp进行基因型分析。在这些分析之后，我们将（作为Specific Aim 3）优先考虑最引人注目的位置候选基因，并对序列变异进行详尽的分析，然后进行关联分析，以确定最可能的致病snp /单倍型。CAC易感基因的发现将提供：(i)对分子机制的关键见解；（ii）新的治疗靶点；㈡进行血液检查，以便及早发现有危险的人，以便采取预防性干预措施。这将对数以百万计的中老年美国人的死亡率、生活质量和医疗保健费用产生重大影响。

DESCRIPTION (provided by applicant): The overall objective of this proposal is to identify genes that influence susceptibility to cardiovascular disease through their influence on levels of coronary artery calcification (CAC). The presence and quantity of CAC predicts risk of future CVD events and levels of CAC are highly heritable. This proposal takes advantage of two large cohorts of individuals who have been phenotyped for CAC using EBCT technology and recent advances in genomics that make feasible the identification of disease susceptibility genes through genome-wide association (GWA) approaches. We hypothesize that genes influencing variation in CAC will be readily identified through GWA analysis with densely spaced SNPs. To test this hypothesis, we will carry out a 2-stage design in which we will first screen 800 Amish subjects using a GWA scan (Stage I), and then genotype associated SNPs in a second (Stage II) population of European Caucasian ancestry individuals from Rochester, MN from the Epidemiology of Coronary Artery Calcification Study. The Amish are a particular advantageous population to carry out such studies because of their common genetic ancestry and homogenous lifestyle. Through previous work, we have measured CAC in 800 Amish adults, in whom we are currently genotyping 500K Affymetrix SNP chips as part of other studies. In Specific Aim 1, we will genotype the remaining 300 subjects and carry out a GWA analysis of CAC. In Specific 2, we will identify the 1,750 most significantly associated SNPs from Stage 1 (representing 0.35% of the total number of SNPs tested) and will genotype these, as well as two flanking SNPs for each, in 900 subjects from the ECAC Study. Following these analyses, we will (as Specific Aim 3), prioritize the most compelling positional candidate genes and perform exhaustive analysis for sequence variation followed by association analysis to identify the most likely causative SNPs/haplotypes. Discovery of CAC susceptibility genes will provide: (i) critical insights into molecular mechanisms; (ii) new targets for therapy; (ii) blood tests for early detection of at risk persons so that preventive interventions can be instituted. This will impact substantially on mortality, quality of life, and health care costs for millions of middle-aged and elderly Americans.