Genome Wide Association of Coronary Artery Disease and Related Risk Factors

冠状动脉疾病和相关危险因素的全基因组关联

• 批准号: 8127836
• 负责人: ULRICH BROECKEL
• 金额: $ 77.29万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8127836
• 关键词: Accounting; African American; Anatomy; Angiography; Biochemical; Case-Control Studies; Caucasians; Caucasoid Race; Cause of Death; Classification; Clinic; Clinical; Collaborations; Complex; Coronary; Coronary Angiography; Coronary Arteriosclerosis; Coronary artery; Data; Data Set; Development; Diabetes Mellitus; Disease; Disease Outcome; Disease Progression; Disease susceptibility; Epidemiologic Studies; European; Family; Foundations; Funding; Genes; Genetic; Genetic Markers; Genotype; Goals; Grant; Hand; Haplotypes; Health; Heterogeneity; Hypertension; Individual; Linear Models; Medical History; Medicine; Methodology; Myocardial Infarction; Nature; Patients; Phenotype; Population; Predisposition; Preventive; Public Health; Recording of previous events; Research Design; Research Project Grants; Residual state; Risk; Risk Factors; Sampling; Scanning; Signal Transduction; Single Nucleotide Polymorphism; Susceptibility Gene; Testing; Therapeutic; Western World; base; burden of illness; cardiovascular risk factor; case control; cohort; cost; density; design; disease phenotype; disorder risk; follow-up; genetic analysis; genetic linkage analysis; genome wide association study; genome-wide; genome-wide linkage; hypercholesterolemia; improved; interest; new technology; novel; population based; proband; trait; translational medicine

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.

描述（由申请人提供）：冠状动脉疾病（CAD）和心肌梗塞（MI）是西方世界的主要死亡原因。许多流行病学研究表明，各种危险因素，例如动脉高血压，高胆固醇血症和糖尿病。尽管这些危险因素部分在遗传控制下，但积极的家族史仍然是CAD的附加独立预测指标，表明存在其他易感基因。为了鉴定新型的MI基因，我们建议使用1,000,000个Affymetrix SNP（单核苷酸多态性）芯片基因分型平台在我们的1,000个具有MI和CAD的家庭中进行基于家庭的高密度关联扫描。该人群中的表型数据包括有关标准风险因素，病史，广泛的生化特征以及对冠状动脉解剖结构的详细描述，这些数据由血管造影和随访检查确定。凭借这种广泛的数据集以及CAD和MI的复杂性，基于家庭的分析具有重要的优势。这特别与家族中表型异质性的降低有关，这是通过识别链接信号的遗传成分的先前证据，结合联系和关联分析的可能性，分析纳入了共享遗传和环境成分以及对多种现象的遗传和环境变异的分析。对于统计分析，我们将使用标准分析和线性模型，这些模型在特征上考虑SNP（或单倍型或外交类型）的直接关联，同时考虑和量化家庭之间残留的遗传和/或环境影响。这种方法应该使我们能够识别遗传标记，这对CAD，MI和相关风险因素的风险产生了重大贡献。为了复制，我们已经建立了一项合作，使我们可以从Marshfield诊所个性化研究项目中访问复制样本，该项目代表了一个基于人群的同伙。此外，我们还将测试非裔美国人和美国高加索人群冠状动脉血管造影患者的重要SNP。这些人群将使我们能够测试SNP最初在高加索家庭中与其他群体中MI和CAD风险贡献的程度。 公共卫生相关性：冠状动脉的风险部分取决于遗传因素。我们建议进行全基因组关联研究，以鉴定冠状动脉疾病，心肌梗塞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危险因素相互作用的理解。