Genome Wide Association of Coronary Artery Disease and Related Risk Factors

描述(申请人提供)：冠状动脉疾病(CAD)和心肌梗死(MI)是西方世界主要的死亡原因。大量的流行病学研究已经证明了各种危险因素的影响，如动脉高血压、高胆固醇血症和糖尿病。虽然这些风险因素部分受基因控制，但阳性家族史仍然是冠心病的另一个独立预测因素，这表明存在其他易感基因。为了识别新的MI基因，我们提出了一种基于家族的全基因组高密度关联扫描，使用1,000,000 Affymetrix SNP(单核苷酸多态性)芯片基因分型平台，在我们的1000个MI和CAD家系中进行。这一人群的表型数据包括标准危险因素、病史、广泛的生化特征以及血管造影术和后续检查确定的冠状动脉解剖的详细描述。有了如此广泛的数据集以及CAD和MI的复杂性质，基于家族的分析具有重要的优势。这尤其涉及到家系中表型异质性的降低，先前的证据表明有一个重要的遗传成分，如确定连锁信号所证明的那样，结合连锁和关联分析的可能性，结合共有的遗传和环境成分的分析，以及对多种表型的遗传和环境差异的分析。对于统计分析，我们将使用标准分析和线性模型，这些模型考虑了SNP(或单倍型或双倍型)与一个性状的直接关联，同时考虑和量化了家系中剩余的遗传和/或环境影响。这种方法应该使我们能够识别遗传标记，这些标记对冠心病、心肌梗死和相关的风险因素有显著的贡献。对于复制，我们已经建立了一个合作关系，使我们能够访问马什菲尔德诊所个性化研究项目的复制样本，该项目代表了一个基于人群的队列。此外，我们还将在接受冠状动脉造影术的非裔美国人和美国高加索人队列中测试重要的SNPs。这些人群将使我们能够测试在高加索家庭中最初关联的SNP在多大程度上导致其他群体的MI和CAD风险。公共卫生相关性：冠状动脉的风险在一定程度上由遗传因素决定。我们建议进行全基因组关联研究，以确定冠状动脉疾病、心肌梗死及其相关危险因素的易感基因。这项研究将提高我们对遗传和传统风险因素相互作用的理解。

DESCRIPTION (provided by applicant): Coronary artery disease (CAD) and myocardial infarction (MI) are the leading causes of death in the Western world. Numerous epidemiological studies have demonstrated the impact of various risk factors, such as arterial hypertension, hypercholesterolemia and diabetes mellitus. While these risk factors are partially under genetic control, a positive family history remains an additional independent predictor of CAD, suggesting the presence of additional susceptibility genes. In order to identify novel MI genes, we propose a family-based genome-wide high density association scan using the 1,000,000 Affymetrix SNP (single nucleotide polymorphism) chip genotyping platform in our large set of 1,000 families with MI and CAD. The phenotypic data in this population includes data on standard risk factors, medical history, extensive biochemical characterization, as well as a detailed description of the coronary anatomy as determined by angiography and follow-up examinations. With this extensive dataset and the complex nature of CAD and MI, a family-based analysis holds important advantages. This is related in particular to a reduced phenotypic heterogeneity in families, prior evidence of a significant genetic component as demonstrated by the identification of linkage signals, the possibility of combined linkage and association analyses, analyses incorporating shared genetic and environmental components as well as the analysis of genetic and environmental variance for multiple phenotypes. For the statistical analysis we will use standard analysis and linear models that consider the direct association of a SNP (or haplotype, or diplotype) on a trait while accounting for and quantifying residual genetic and/or environmental effects among the families. This approach should enable us to identify genetic markers, which contribute significantly to the risk of CAD, MI and associated risk factors. For replication, we have established a collaboration giving us access to a replication sample from the Marshfield Clinic Personalized Research Project which represents a population-based cohort. In addition, we will also test significant SNPs in an African American and US Caucasian cohort of patients with coronary angiographies. These populations will allow us to test the extent to which SNPs initially associated in the Caucasian families contribute to MI and CAD risk in other groups. PUBLIC HEALTH RELEVANCE: The risk of coronary artery is determined in part by genetic factors. We propose to perform a genome-wide association study to identify susceptibility genes for coronary artery disease, myocardial infarction and its related risk factors. This study will improve our understanding of the interplay of genetic and traditional risk factors.