GENCAC - North Carolina Field Center

拟议研究的目的，冠状动脉和主动脉钙化的遗传学（GENCAC），是确定遗传因素，建立易感性(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。为了确定与人类动脉粥样硬化相关的基因，我们建议通过NHLBI家族心脏研究对441个选择的、信息丰富的谱系（- 3000人）进行量化，并对其进行广泛的基因分型（-400个跨越基因组的标记）。另外275名非裔美国人兄弟姐妹（- 600人，也进行了检查并进行了基因分型）将被纳入研究，以解决这些高风险人群的研究问题。评估炎症负担和宿主反应的个体间变异性，以及在这些谱系中收集的广泛的代谢、行为和环境数据，将为评估动脉粥样硬化的遗传基础提供增强的表型同质性和增强的分析能力。最先进的实验室和统计方法将用于发现，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。使用新的全球测试程序，将绕过基因组扫描中多次比较的臭名昭著的问题。基于具有成本效益的信息谱系设计和采用新颖的方法，本研究将提供目前无法获得的动脉粥样硬化遗传和环境决定因素的信息，重点是预防这种普遍存在的与社会高成本负担相关的疾病。该申请对应于维克森林大学医学院提交的GENCAC诊所，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 clinic submitted by the Wake Forest University School of Medicine as part of the GENCAC genetic epidemiology network.