GENCAC - Framingham Field Center

描述(由申请人提供) 拟议研究的目的：冠状动脉和大动脉的遗传学 钙化(GENCAC)，是为了识别建立 对(A)冠状动脉和主动脉粥样硬化和(B)个体间的易感性 炎症反应的可变性。我们建议量化 精选441例冠状动脉和主动脉钙化容量，信息量 家系(约3,000人)以前检查过并进行了广泛的基因分型 (跨越基因组的约400个标记)，由NHLBI家庭心脏研究按顺序 以确定与人类动脉粥样硬化相关的基因。额外的275 非洲裔美国人兄弟会(约600人，也进行了检查和比较 基因分型)将被包括在这一高风险的研究问题中 人口。对生物多样性的个体间差异的评估 炎症负担和宿主反应，以及广泛的代谢， 已经收集到的关于这些家系的行为和环境数据将 提供增强的表型同质性和更强的分析能力 评估动脉粥样硬化的遗传基础。 将使用最先进的实验室和统计方法来寻找， 对易感基因的影响进行定位和表征 动脉粥样硬化和炎症反应。新的遗传分析方法 将用于解决表型、遗传和种群问题 异质性、上位性、基因和基因之间复杂的相互作用 环境风险因素，并优化基因组区域的检测 影响表型易感性。臭名昭著的多个问题 在基因组扫描中的比较将被使用新的全局 测试程序。 基于经济高效的信息家谱设计和使用小说 方法论，这项研究将提供目前无法获得的关于 动脉粥样硬化的遗传和环境决定因素，重点是 预防这种与高负担相关的广泛流行的疾病 给社会带来的代价。

DESCRIPTION (provided by applicant) The purpose of the proposed study, Genetics of Coronary and Aortic Calcification (GENCAC), is to identify genetic factors that establish susceptibility to (a) coronary and aortic atherosclerosis and (b) inter-individual variability in the inflammatory response. We propose to quantify coronary and aortic artery calcium volume in 441 selected, informative pedigrees (~ 3,000 individuals) previously examined and extensively genotyped (~400 markers spanning the genome) by the NHLBI Family Heart Study, in order to identify genes associated with human atherosclerosis. An additional 275 African American sibships (~600 individuals, also examined and comparably genotyped) will be included to address these study questions in this high-risk population. Assessment of the inter-individual variability in the inflammatory burden and the host response, and the extensive metabolic, behavioral, and environmental data already collected on these pedigrees will provide enhanced phenotypic homogeneity and increased analytic power in assessing the genetic basis of atherosclerosis. State of the art laboratory and statistical methods will be used to find, localize and characterize the influence of predisposing genes to atherosclerosis and the inflammatory response. Novel genetic analysis methods will be used to address the issues of phenotypic, genetic and population heterogeneity, epistasis, complex interactions among the genetic and environmental risk factors, and to optimize the detection of genomic regions affecting phenotypic susceptibility. The notorious issue of multiple comparisons in genome scans will be bypassed with the use of novel global testing procedures. Based on a cost-efficient design of informative pedigrees and employing novel methodology, this study will contribute currently unavailable information on genetic and environmental determinants of atherosclerosis, with a focus on the prevention of this widely prevalent condition associated with high burden of costs to society.