GENCAC - MOLECULAR GENETICS LABORATORY

这项名为“冠状动脉和主动脉钙化的遗传学”(GENCAC)的拟议研究的目的是确定导致(A)冠状动脉和主动脉动脉粥样硬化以及(B)炎症反应的个体差异的遗传因素。我们建议量化441个选定的、信息丰富的家系(3000人)，并由NHLBI家庭心脏研究进行广泛的基因分型(-400个跨越基因组的标记)，以确定与人类动脉粥样硬化相关的基因。另外275名非洲裔美国人的兄弟姐妹(-600人，也接受了检查，并进行了类似的基因分型)将被纳入，以解决这一高危人群中的这些研究问题。评估炎症负担和宿主反应的个体间变异性，以及已经收集到的关于这些家系的广泛的代谢、行为和环境数据，将提供增强的表型同质性和在评估动脉粥样硬化的遗传基础方面的分析能力。将使用最先进的实验室和统计方法来发现、定位和表征易感基因对动脉粥样硬化和炎症反应的影响。新的遗传分析方法将用于解决表型、遗传和群体异质性、上位性、遗传和环境风险因素之间的复杂相互作用等问题，并优化影响表型易感性的基因组区域的检测。通过使用新的全球测试程序，基因组扫描中臭名昭著的多重比较问题将被绕过。基于信息家系的成本效益设计和采用新的方法，这项研究将贡献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的信息，重点是预防这种与社会高成本负担相关的广泛流行的疾病。该申请对应于德克萨斯大学休斯顿健康科学中心提交的GENCAC-分子遗传学实验室，作为GENCAC遗传流行病学网络的一部分。

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. This application corresponds to the GENCAC-Molecular Genetics Laboratory submitted by the University of Texas-Houston Health Science Center as part of the GENCAC genetic epidemiology network.