Whole Genome Association Analysis of the Diabetes Heart Study

描述（由申请人提供）：本提案的目标是确定糖尿病患者中导致心血管疾病（CVD）的基因。糖尿病对CVD的发展有着深远的影响。本研究的重点是CVD的亚临床指标：血管钙化斑块和颈动脉粥样硬化。在糖尿病心脏研究的第一阶段，我们成功招募了564个患有多发性2型糖尿病（T2 DM）的受试者家庭中的1443名受试者，并对其进行了广泛的表型分析。这为研究糖尿病富集（85%）人群中的CVD和其他相关特征创造了独特的数据资源。进行了广泛的遗传学和流行病学分析。这些结果提供了一个强有力的基础，提出了使用全基因组关联研究（GWAS）的方法识别重要基因。具体目标是：1）。糖尿病心脏研究受试者的GWAS基因分型和分析。整个欧洲裔美国人样本将在Affytek SNP Array 6.0平台上进行基因分型。将对基因型数据进行全面分析，以确定与血管钙化斑块和颈动脉壁厚度的亚临床CVD的主要指标相关的基因座/基因。2）。冠状动脉钙化斑块与颈动脉壁厚度的重复性研究和Meta分析。将在Fragrance心脏研究、动脉病遗传流行病学网络（GENOA）、Amish家族钙化研究（AFCS）和糖尿病心脏研究中对具有冠状动脉钙化斑块和颈动脉壁厚度（如可能）GWAS数据的欧美样本进行Meta分析。3）。将评价目的2的高评分多态性在其他研究样本中的重复性，以进一步检测与以下因素的相关性：a）欧洲裔美国人中的普遍CVD，B）其他种族/人种中的亚临床CVD，和c）其他种族/人种中的普遍CVD。4）。密集的分子遗传学分析，新的分析和生物信息学方法将用于识别性状影响变异。来自目标2和3的最佳复制基因座将进行额外的基因分型（如果合适）和重新测序，以明确定义风险基因座。创新的分析方法将被用来定义性状相关的变异。我们已经组建了一支经验丰富，高效，跨学科的团队来进行这项有前途的研究。 公共卫生相关性：在这项研究中，将确定导致糖尿病患者心脏病的基因。

DESCRIPTION (provided by applicant): The goal of this proposal is to identify genes that contribute to cardiovascular disease (CVD) in people with diabetes. Diabetes is a profound influence on CVD development. The focus of this study is subclinical measures of CVD: vascular calcified plaque and carotid atherosclerosis. In the first phase of the Diabetes Heart Study we successfully recruited and extensively phenotyped 1443 subjects in 564 families with multiple type 2 diabetes (T2DM) affected subjects. This created a unique data resource for the study of CVD and other related traits in a diabetes-enriched (85%) population. Extensive genetic and epidemiological analyses were performed. These results provide a strong foundation for the proposed identification of important genes using a Genome Wide Association Study (GWAS) approach. Specific Aims are: 1). GWAS genotyping and analysis of subjects from the Diabetes Heart Study. The entire European American sample will be genotyped on the Affymetrix SNP Array 6.0 platform. A comprehensive analysis of the genotypic data will be carried out to identify loci/genes associated with the primary measures of subclinical CVD of vascular calcified plaque and carotid wall thickness. 2). Replication and meta analyses of coronary calcified plaque and carotid wall thickness. A meta analysis of European American samples with GWAS data for coronary calcified plaque and, where possible, carotid wall thickness, will be performed in the Framingham Heart Study, Genetic Epidemiology Network of Arteriopathy (GENOA), Amish Family Calcification Study (AFCS), and the Diabetes Heart Study. 3). High scoring polymorphisms from Aims 2 will be evaluated for replication in other study samples to further test for association with: a) prevalent CVD in European Americans, b) subclinical CVD in other ethnicities/races, and c) prevalent CVD in other ethnicities/races. 4). Intensive molecular genetic analysis, novel analytic, and bioinformatic approaches will be used to identify trait influencing variants. The best replicated loci from the Aims 2 & 3 will be subjected to additional genotyping (if appropriate) and resequencing to clearly define risk loci. Innovative analysis approaches will be used to define trait associated variants. We have assembled an experienced, highly productive, interdisciplinary team to perform this promising study. PUBLIC HEALTH RELEVANCE: In this research study, genes which contribute to heart disease in people with diabetes will be identified.