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

描述（由申请人提供）：本研究的总体目的是确定影响动脉粥样硬化的基因，这些基因通过冠状动脉钙化（CAC）、内膜中层厚度和踝臂指数（所有动脉粥样硬化负荷的定量指标）以及非裔美国人动脉粥样硬化途径的内在表型来测量。非裔美国人研究不足，但与白人相比，其动脉粥样硬化和CHD的许多危险因素发生率较高，定量CAC较低，但CHD/CVD终点较难。我们使用已经收集的来自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的大型（N= 1，266）流行病学定义的纵向、广泛和深入表型（所有主要动脉粥样硬化途径域）受试者。我们将使用Illumina 650 K Y芯片进行全基因组SNP扫描，该芯片专为非洲裔受试者设计。我们相信我们的家族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，其利用关于个体和位点特异性祖先的信息来增强检测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导致的假阳性，这是非洲裔美国人样本中的一个关键问题。由于非裔美国人的LD块结构不如其他种族的人所知（他们不是HapMap项目的主要目标），我们将更精细地对命中区域中的其他SNP进行基因分型，特别是那些在生物学上可能的候选基因或高度保守的区域，以便更好地定位信号。此外，我们将使用相关荟萃分析技术将混合图和LD图分析的结果联合收割机结合起来。我们的GW作图方法具有高的功率来检测任何基因，其通过至少在功能变体的R2=0.80内的ht-SNP来解释动脉粥样硬化途径中至少2-5%的性状。随着FHS+JHFHS非洲裔美国人受试者在家系中丰富的表型特征和可用的连锁结果，全基因组关联扫描将允许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械过程的理解，从而为研究不足但高风险的非裔美国人人群提供可能的干预或治疗点。

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.