Genetic Markers of CHD in Type 2 Diabetes

描述（由申请人提供）：冠心病（CHD）是发病率和死亡率的主要原因，在2型糖尿病中尤为常见。遗传和环境因素共同决定了CHD的发生发展。最近的全基因组关联（GWA）研究已经确定了一般人群中CHD的几种遗传变异。目前，对糖尿病患者进行冠心病的GWA研究是当务之急。此外，更好地了解冠心病的病因需要仔细调查中间生化变化和基因-环境相互作用。护士健康研究（NHS）和卫生专业人员随访研究（HPFS）是特征良好的队列，其存储的DNA样本和详细的生活方式信息可用。通过单独的NIH拨款，我们将在2008年7月前完成NHS/HPFS的3,000例糖尿病病例（950例CHD/2,050例非CHD）的GWA扫描（Affyssynp SNP Array 6.0;约100万个SNP）。我们建议在两项糖尿病患者CHD病例对照研究中分析GWA数据与CHD风险，并复制前1200- 1,400个SNP：Joslin心脏研究（N= 1，400）和哥斯达黎加研究（N=890）。我们还将评估与冠心病生化危险因素的相关性，并研究基因-环境相互作用。GWA扫描、生化标志物测量和收集生活方式因素的详细信息已分别获得批准。因此，拟议的项目将具有极高的成本效益。我们已经组建了一个经验丰富和忠诚的合作者团队，他们在遗传流行病学，统计遗传学，生物信息学，心血管疾病，糖尿病和营养方面具有专业知识。我们相信，该项目中前所未有的资源将提供一个独特的机会，以确定糖尿病患者CHD过度风险的遗传因素。2型糖尿病患者的冠心病（CHD）发病率是普通人群的2- 4倍。全基因组关联（GWA）研究提供了一种强有力的无偏方法来发现易感基因，并提供对疾病病因学的见解。该项目的总体目标是进行GWA分析（Affyssoft SNP Array 6.0;约100万个SNP），以确定糖尿病患者中CHD过度风险的新遗传变异，并评估遗传对中间生化变化的影响，以及检查基因-环境相互作用。

DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is a leading cause of morbidity and mortality and particularly frequent in type 2 diabetes. Both genetic and environmental factors determine the development of CHD. Recent genome-wide association (GWA) studies have identified several genetic variants for CHD in the general population. It is now a high priority to conduct GWA study for CHD in diabetic patients. In addition, a better understanding of the etiology of CHD requires a careful investigation of intermediate biochemical changes and gene- environment interactions. The Nurses' Health Study (NHS) and Health Professionals' Follow-up Study (HPFS) are well-characterized cohorts whose stored DNA sample and detailed lifestyle information are available. Through a separate NIH grant, we will complete a GWA scan (Affymetrix SNP Array 6.0; ~1 million SNPs) in 3,000 diabetic cases (950 CHD/2,050 non-CHD) from NHS/HPFS by July, 2008. We propose to analyze GWA data with the CHD risk and replicate the top 1200-1400 SNPs in two CHD case-control studies of diabetic patients: Joslin Heart Study (N=1,400) and Costa Rica study (N=890). We will also assess the associations with biochemical risk factors for CHD and examine the gene-environment interactions. The GWA scan, biochemical marker measurement, and collection of detailed information on lifestyle factors have been separately granted. Therefore the proposed project will be extremely cost-efficient. We have assembled a solid group of experienced and committed collaborators with expertise in genetic epidemiology, statistical genetics, bioinformatics, cardiovascular disease, diabetes, and nutrition. We believe that the unprecedented resources available in this project will provide a unique opportunity to identify genetic factors for excessive risk of CHD in diabetic patients. PUBLIC HEALTH RELEVANCE Coronary heart disease (CHD) is 2- to 4-fold higher in patients with type 2 diabetes than the general population. Genome-wide association (GWA) study offers a powerful unbiased method to discover susceptibility genes and provide insights into the etiology of the disease. The overall goal of this project is to conduct GWA analyses (Affymetrix SNP Array 6.0; ~1 million SNPs) to identify new genetic variants for the excessive risk of CHD in diabetic patients and to assess the genetic effects on the intermediate biochemical changes, as well as to examine the gene-environment interactions.