Genetics of Coronary Artery Disease in Type 2 Diabetes

描述（由申请人提供）：糖尿病是冠状动脉疾病（CAD）最强有力的风险因素之一。这种效应是由于高血糖和糖尿病环境的其他方面引起的动脉粥样硬化加速。为了减少这种疾病的心血管负担，需要更好地了解糖尿病与动脉粥样硬化之间的联系机制，以便开发专门针对糖尿病受试者的新干预措施。我们的策略是通过遗传学研究获得这些知识。遗传因素长期以来被认为是普通人群和糖尿病人群心血管风险的重要调节因子。来自我们小组的证据表明，这些基因中的一些可能与高血糖症有协同作用，导致糖尿病人群中特别强烈的影响。使用一种新的DNA池方法，我们已经完成了一个300，000 SNP全基因组关联（GWA）研究的第一阶段，在一小组CAD阳性和CAD阴性的2型糖尿病（T2D）患者中，来自Joslin心脏研究（JHS）。这项研究导致了几个SNP的鉴定，这些SNP在病例和对照之间的等位基因频率上显示出很大的差异，其中一些在染色体2，5，6，9和14上的基因座上聚集。本申请的具体目的是：1.在来自JHS的CAD病例和对照的扩展集（n=2600）中完成GWA研究。更大的样本量将提供区分真实关联与由于多次测试导致的假阳性结果的能力。2.在护士健康研究和健康专业随访研究的一组独立病例和对照组（n=3200）中复制与T2D患者CAD相关的显著结果。复制将提高对阳性结果的信心，并将允许更精确地估计遗传效应的大小。3.识别与T2D中CAD相关的基因组区域中的候选致病变异。鉴定可能的功能变体将提供对调节T2D中CAD风险的细胞途径的见解。这项研究有三个重要特点。首先，我们最近在染色体9p21上发现了一个与高血糖相互作用的CAD风险等位基因，这表明该项目成功的可能性很高。其次，它涉及到一个迄今为止被遗传学研究忽视的主题。已经完成或正在进行的GWA研究都没有关注糖尿病中的CAD，部分原因是很少有其他研究者能够接触到大量CAD和T2D患者。第三，本研究具有重要意义。作为一项无偏见的全基因组研究，它有可能确定将糖尿病与动脉粥样硬化形成联系起来的新分子途径，这对开发专门针对糖尿病患者CAD预防或治疗的新药具有明显的意义。 公共卫生相关性：该项目的目标是确定参与2型糖尿病患者冠状动脉疾病调制的基因。这些知识可能指向尚未发现的疾病机制，并建议开发新的药物干预措施以预防或治疗糖尿病并发症的新策略。CAD易感性增加的遗传标记的可用性也将允许识别心血管疾病风险增加的糖尿病个体，以便预防计划可以在生命早期专门针对这些受试者。

DESCRIPTION (provided by applicant): Diabetes mellitus is one of the most potent risk factors for coronary artery disease (CAD). This effect results from an acceleration of atherosclerosis induced by hyperglycemia and other aspects of the diabetic milieu. To decrease the cardiovascular burden of this disease, a better understanding of the mechanisms linking diabetes to atherosclerosis is needed, so that new interventions specifically targeted to diabetic subjects can be developed. Our strategy is to gain this knowledge through genetic studies. Genetic factors have long been recognized as important modulators of cardiovascular risk in both the general and the diabetic populations. Evidence from our group indicates that some of these genes may have a synergistic effect with hyperglycemia, resulting into an especially strong effect in the diabetic population. Using a novel DNA-pooling approach, we have completed the first stage of a 300,000 SNP genome-wide association (GWA) study in a small set of CAD-positive and CAD-negative individuals with type 2 diabetes (T2D) from the Joslin Heart Study (JHS). This study has led to the identification of several SNPs showing large differences in allele frequencies between cases and controls, some of which cluster at loci on chromosomes 2, 5, 6, 9, and 14. The specific aims of the present application are: 1. to complete the GWA study in an expanded set (n=2600) of CAD cases and controls from the JHS. The larger sample size will provide the power to discriminate true associations from false positive results due to multiple testing. 2. To replicate significant findings of association with CAD in T2D in an independent set of cases and controls (n=3200) from the Nurses Health Study and Health Professional Follow-up Study. Replication will enhance the confidence in positive results and will allow more precise estimates of the magnitude of genetic effects. 3. Identify candidate causal variants in the genomic regions showing association with CAD in T2D. Identification of possible functional variants will provide insights on the cellular pathways that modulate the risk of CAD in T2D. Three important features distinguish this study. First, this project has high probability of success, as indicated by our recent identification of a CAD risk allele interacting with hyperglycemia on chromosome 9p21. Second, it concerns a topic that has been so far overlooked by genetic studies. None of the GWA studies that were completed or are in progress are focused on CAD in diabetes, in part because few other investigators have access to large numbers of individuals with CAD and T2D. Third, this research has great significance. Being an unbiased, whole- genome study, it has the potential to identify new molecular pathways linking diabetes to atherogenesis with obvious implications for the development of new drugs specifically targeted to the prevention or treatment of CAD among diabetic patients. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify genes involved in the modulation of coronary artery disease among individuals with type 2 diabetes. This knowledge may point to as yet undiscovered disease mechanisms and suggest novel strategies for developing new pharmacological interventions for preventing or treating this complication of diabetes. Availability of genetic markers of increased susceptibility to CAD would also allow the identification of diabetic individuals at increased risk of cardiovascular disease, so that preventive programs can be specifically targeted at these subjects early in life.