GENCAC - Arterial Calcium Reading Center

这项研究的目的，冠状动脉和主动脉钙化的遗传学（GENCAC），是确定遗传因素，建立冠状动脉和主动脉粥样硬化的易感性和高炎症宿主反应。我们建议量化441个信息丰富的家系（3,000人）中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个基因组标记），以确定与动脉粥样硬化相关的基因。将对另外275名非裔美国人同胞（约600人）进行检查，以解决该高风险人群中的这些研究问题。将测量炎性细胞因子和炎性反应的标志物，以表征炎性负荷和宿主反应。炎症宿主反应的个体间差异，以及FHS中这些家系收集的广泛的代谢、行为和环境数据，将提供增强的表型同质性和增加的分析能力，以评估动脉粥样硬化的遗传基础。新的实验室方法和最先进的统计方法将被用来发现，定位和表征易感基因对动脉粥样硬化和炎症宿主反应的影响，注意表型，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，以及影响表型易感性的基因组区域的检测。这项研究的成本效益设计将基于兄弟姐妹和大谱系，所有人都经过检查，并有基因组扫描数据可用。这项研究将提供有关遗传变异的新信息，以及与动脉粥样硬化易感性相关的背景依赖性效应，动脉粥样硬化是美国死亡的头号原因，也是我们社会医疗保健支出的主要驱动力。本申请对应于维克森林大学医学院提交的动脉钙阅读中心，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 coronary and aortic atherosclerosis and to the hyperinflammatory host response. We propose to quantify coronary and aortic artery calcium volume in 441 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 atherosclerosis. An additional 275 African American sibships (-600 individuals) will be examined to address these study questions in this high-risk population. Inflammatory cytokines and markers of the inflammatory response will be measured, to characterize both the inflammatory burden, and the host response. Interindividual variability in the inflammatory host response, and the extensive metabolic, behavioral, and environmental data collected on these pedigrees in the FHS will provide enhanced phenotypic homogeneity and increased analytic power in assessing the genetic basis of atherosclerosis. Novel laboratory methodology and state of the art statistical methods will be used to find, localize and characterize the influence of predisposing genes to atherosclerosis and the inflammatory host response, with attention to phenotypic, genetic and population heterogeneity, epistasis, complex interactions among the genetic and environmental risk factors, and the detection of genomic regions affecting phenotypic susceptibility. The cost-efficient design of this study will be based on sibships and large pedigrees, all of whom have been examined and have genome scan data available. This study will contribute new information on genetic variation, and context-dependent effects associated with susceptibility to atherosclerosis which is the number one cause of death in the U.S. and is the primary driver of health care expenditures in our society. This application corresponds to the Arterial Calcium Reading Center submitted by Wake Forest University School of Medicine as part of the GENCAC genetic epidemiology network.