GENCAC - Birmingham Field Center

所提议的研究，冠状动脉和主动脉钙化的遗传学（GENCAC）的目的是鉴定确定对（a）冠状动脉和主动脉粥样硬化和（B）炎症反应的个体间变异性的易感性的遗传因素。我们建议量化441个选定的、信息丰富的家系（约3,000人）的冠状动脉和主动脉钙体积，这些家系先前通过NHLBI家族心脏研究进行了检查和广泛的基因分型（约400个跨越基因组的标记物），以确定与人类动脉粥样硬化相关的基因。将纳入另外275名非裔美国人同胞（约600名个体，也进行了检查和基因分型），以解决该高风险人群中的这些研究问题。对炎症负荷和宿主反应的个体间差异的评估，以及对这些家系已经收集的广泛的代谢、行为和环境数据的评估，将提供增强的表型同质性和增加的分析能力，以评估动脉粥样硬化的遗传基础。最先进的实验室和统计学方法将被用来发现，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的问题，并优化影响表型易感性的基因组区域的检测。基因组扫描中臭名昭著的多重比较问题将通过使用新的全球测试程序而被绕过。基于信息谱系的成本效益设计。采用新的方法，这项研究将有助于目前尚未获得的关于动脉粥样硬化的遗传和环境决定因素的信息，重点是预防这种广泛流行的疾病，这与社会的高成本负担有关。本申请对应于伯明翰亚拉巴马大学提交的GENCAC伯明翰现场中心，作为GENCAC遗传流行病学网络的一部分。

The purpose or 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 interindividual 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 Birmingham field center submitted by the University of Alabama at Birmingham as part of the GENCAC genetic epidemiology network.