Genetic Influences on Coronary Artery Calcification

描述（由申请人提供）：该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的存在和数量可预测未来CVD事件的风险，并且CAC水平具有高度遗传性。该建议利用了两个大的队列的个人谁已经使用EBCT技术和基因组学的最新进展，通过全基因组关联（GWA）的方法，使可行的疾病易感基因的识别CAC的表型。我们假设，通过GWA分析密集间隔的SNP，可以很容易地识别出影响CAC变异的基因。为了检验这一假设，我们将进行2阶段设计，其中我们将首先使用GWA扫描筛选800名阿米什人受试者（第I阶段），然后在来自冠状动脉钙化流行病学研究的来自明尼苏达州罗切斯特的欧洲高加索血统个体的第二群体（第II阶段）中进行基因型相关SNP。阿米什人是一个特别有利的人口进行这样的研究，因为他们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，作为其他研究的一部分，我们目前正在对他们进行500 K Affyssin SNP芯片的基因分型。在具体目标1中，我们将对其余300名受试者进行基因分型，并对CAC进行GWA分析。在特定2中，我们将在ECAC研究的900名受试者中鉴定来自第1阶段的1，750个最显著相关的SNP（占检测的SNP总数的0.35%），并对这些SNP以及每个SNP的两个侧翼SNP进行基因分型。在这些分析之后，我们将（作为具体目标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）分子机制的重要见解;（ii）新的治疗靶点;（ii）早期发现高危人群的血液检测，以便制定预防性干预措施。这将对数百万美国中年人和老年人的死亡率、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.