Genetic Markers of CHD in Type 2 Diabetes

描述(申请人提供)：冠心病(CHD)是发病率和死亡率的主要原因，在2型糖尿病中尤其常见。遗传因素和环境因素共同决定着冠心病的发生发展。最近的全基因组关联(GWA)研究已经在普通人群中发现了几个CHD的遗传变异。开展糖尿病患者冠心病的GWA研究已成为当务之急。此外，要更好地了解CHD的病因，需要仔细研究中间生化变化和基因-环境相互作用。护士健康研究(NHS)和卫生专业人员后续研究(HPFS)是具有良好特征的队列，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月前完成来自NHS/HPFS的3,000例糖尿病患者(950例冠心病/2,050例非冠心病)的GWA扫描(Affymetrix SNP阵列6.0；约100万个SNP)。我们建议分析具有冠心病风险的GWA数据，并在两个糖尿病患者的CHD病例对照研究中复制前1200-1400个SNP：Joslin心脏病研究(N=1,400)和哥斯达黎加研究(N=890)。我们还将评估与CHD生化危险因素的关系，并检查基因与环境的相互作用。GWA扫描、生化标志物测量和收集有关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。我们聚集了一批经验丰富、坚定的合作者，他们拥有遗传流行病学、统计遗传学、生物信息学、心血管疾病、糖尿病和营养方面的专业知识。我们相信，这个项目中前所未有的可用资源将提供一个独特的机会，来确定糖尿病患者患冠心病风险过高的遗传因素。与公共健康相关的冠心病(CHD)在2型糖尿病患者中是普通人群的2-4倍。全基因组关联(GWA)研究为发现易感基因和深入了解疾病的病因提供了一种强大的、无偏见的方法。该项目的总体目标是进行GWA分析(Affymetrix SNP阵列6.0；约100万个SNPs)，以确定糖尿病患者冠心病过度风险的新基因变异，评估对中间生化变化的遗传影响，以及检查基因与环境的相互作用。

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.