Whole Genome Association Analysis of the Diabetes Heart Study

描述(由申请人提供)：这项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。糖尿病对心血管疾病的发展有着深远的影响。这项研究的重点是心血管疾病的亚临床指标：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，我们成功地招募了1443名受试者，并对564个患有多发性2型糖尿病(T2 DM)的受试者进行了广泛的表型分析。这为研究糖尿病患者(85%)的心血管疾病和其他相关特征创造了独特的数据资源。进行了广泛的遗传和流行病学分析。这些结果为利用基因组广谱关联研究方法识别重要基因奠定了坚实的基础。具体目标有：1)。糖尿病心脏研究受试者的基因分型和分析。整个欧美样本将在Affymetrix SNP阵列6.0平台上进行基因分型。将对基因数据进行综合分析，以确定与血管钙化斑块和颈动脉壁厚度的主要亚临床心血管指标相关的基因座/基因。2)。冠状动脉钙化斑块和颈动脉壁厚度的复制和Meta分析。弗雷明翰心脏研究、动脉病遗传流行病学网络(Genoa)、阿米什家族钙化研究(AFCS)和糖尿病心脏研究将对欧洲美洲样本进行荟萃分析，其中包括冠状动脉钙化斑块和可能的颈动脉壁厚度。3)。AIMS 2中得分较高的多态性将在其他研究样本中进行复制评估，以进一步测试与以下因素的相关性：a)欧美人中普遍存在的心血管疾病，b)其他种族/种族中的亚临床心血管疾病，以及c)其他民族/种族中普遍存在的心血管疾病。4)。密集的分子遗传分析、新的分析和生物信息学方法将被用来识别影响变异的性状。来自AIMS 2和3的最好复制的基因座将接受额外的基因分型(如果合适)和重新测序，以明确定义危险基因座。创新的分析方法将被用来定义与性状相关的变异。我们组建了一支经验丰富、工作效率高的跨学科团队来进行这项有希望的研究。

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.