GENOMIC SCAN FOR ATHEROSCLEROSIS PATHWAY GENES IN AFRICAN-AMERICANS FROM FHS-SCAN

描述(由申请人提供)：这项研究的总体目标是确定影响动脉粥样硬化的基因，通过冠状动脉钙化(CAC)、内膜中层厚度和踝臂指数来衡量，所有量化的动脉粥样硬化负担指标，以及非裔美国人动脉粥样硬化途径的内表型。非洲裔美国人的研究不足，但与高加索人相比，他们的动脉粥样硬化和冠心病的许多危险因素的比率更高，CAC的数量更低，但CHD/CVD终点更硬。我们使用已经从NHLBI家族心脏研究-亚临床动脉粥样硬化网络(FHS-SCAN)和约翰霍普金斯家族心脏研究(FHS-SCAN)收集的大规模(N=1,266)、流行病学定义的、纵向的、广泛的和深入的表型(在所有主要的动脉粥样硬化途径领域)受试者。我们将使用Illumina 650K Y芯片进行全基因组SNP扫描，这是专门为非洲裔受试者设计的。我们相信，我们的家庭研究可以优化非裔美国人GW扫描设计的几个方面。首先，我们将分析GW SNP数据作为混合图谱，它利用关于个体和特定座位祖先的信息，以增强检测QTL的能力。其次，我们将分析GW SNP数据作为LD关联扫描，以更精细地定位相关变体。最重要的是，基于家庭的关联分析将使我们能够强烈排除由于人口分层而产生的假阳性，这是非裔美国人样本中的一个关键问题。由于非洲裔美国人的LD区块结构不像其他种族那样广为人知(他们不是HapMap项目的主要目标)，我们将在Hit区域，特别是那些在生物学上看似合理的候选基因中，或在高度保守的区域，对额外的SNP进行更精细的基因分型，以便更好地定位信号。此外，我们将使用相关的荟萃分析技术将混合图和LD图分析的结果结合起来。我们的GW作图方法具有很高的能力，可以通过至少在R2=0.80的功能变异范围内的Ht-SNP来检测解释动脉粥样硬化途径中至少2%-5%性状的任何基因。随着FHS+JHFHS非裔美国人在FHS+JHFHS家系中表现出丰富的表型特征以及可用的连锁结果，全基因组关联扫描将能够快速有效地发现与人类动脉粥样硬化发展相关的基因。这些发现将具有重要意义：它们可以增强我们对导致动脉粥样硬化和冠状动脉终点的代谢和机制过程的理解，从而为研究不足但风险较高的非裔美国人群体提供可能的干预或治疗要点。

DESCRIPTION (provided by applicant): The overall aim of this study is to identify genes influencing atherosclerosis as measured by coronary artery calcification (CAC), intimal medial thickness, and ankle brachial index, all quantitative measures of atherosclerotic burden, as well as endophenotypes for the atherosclerosis pathway in African-Americans. African-Americans are understudied, and yet have higher rates of many of the risk factors for atherosclerosis and CHD, lower quantitative CAC, but more hard CHD/CVD endpoints than Caucasians. We use the already collected, large (N=1,266), epidemiologically defined, longitudinal, broadly and deeply phenotyped (on all major atherosclerosis pathway domains) subjects from both the NHLBI Family Heart Study-SubClinical Atherosclerosis Network (FHS-SCAN) and the Johns Hopkins Family Heart Study. We will conduct a whole genome SNP scan, using the Illumina 650K Y-chip, which is specifically designed for subjects of African descent. We believe our family study allows optimization of several aspects of GW scan design in African- Americans. First, we will analyze the GW SNP data as an admixture map, which leverages information on individual and locus-specific ancestry, to enhance power to detect QTLs. Second, we will analyze the GW SNP data as an LD association scan, to more finely localize associated variants. Most importantly, family- based association analyses will allow us to strongly rule out false positives due to population stratification, a critical issue in African-American samples. Since the LD block structures for African-Americans are less well known than for other ethnic groups (they were not a primary target of the HapMap project), we will more finely genotype additional SNPs in hit regions, especially those in biologically plausible candidate genes, or in highly conserved regions, in order to better localize the signal. Further, we will combine the results from both the admixture map and the LD map analyses using a correlated meta-analysis technique. Our GW mapping approach has high power to detect any gene explaining at least 2-5% of a trait in the atherosclerosis pathway, through ht-SNPs that are at least within R2=0.80 of a functional variant. With the wealth of phenotypic characterization of FHS+JHFHS African-American subjects in pedigrees and the available linkage results, a genome-wide association scan would allow rapid and efficient discovery of genes related to the development of atherosclerosis in humans. Such findings would be of great significance: they could enhance our understanding of the metabolic and mechanistic processes that lead to atherosclerosis and coronary endpoints and, thereby, suggest possible points of intervention or therapy in the understudied, but high risk African- American population.