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）最有力的危险因素之一。这种效应是由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造成的。为了减轻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。我们的策略是通过基因研究获得这些知识。长期以来，遗传因素一直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素。我们小组的证据表明，其中一些基因可能与高血糖具有协同作用，从而对糖尿病人群产生特别强烈的影响。我们使用一种新颖的 DNA 池方法，在 Joslin 心脏研究 (JHS) 的一小部分 CAD 阳性和 CAD 阴性 2 型糖尿病 (T2D) 个体中完成了 300,000 个 SNP 全基因组关联 (GWA) 研究的第一阶段。这项研究已鉴定出多个 SNP，这些 SNP 在病例和对照之间的等位基因频率上显示出巨大差异，其中一些聚集在 2、5、6、9 和 14 号染色体上的基因座上。本申请的具体目标是： 1. 在来自 JHS 的 CAD 病例和对照的扩展组 (n=2600) 中完成 GWA 研究。较大的样本量将能够区分真实关联与多次测试导致的假阳性结果。 2. 在护士健康研究和健康专业人员随访研究的一组独立病例和对照 (n=3200) 中复制 T2D 与 CAD 相关的重要发现。复制将增强对积极结果的信心，并将允许更精确地估计遗传效应的程度。 3. 识别基因组区域中与 T2D 中 CAD 相关的候选因果变异。识别可能的功能变异将为调节 T2D 中 CAD 风险的细胞途径提供见解。这项研究有三个重要特点。首先，正如我们最近在染色体 9p21 上发现的与高血糖相互作用的 CAD 风险等位基因所表明的，该项目成功的可能性很高。其次，它涉及一个迄今为止被遗传学研究忽视的话题。已完成或正在进行的 GWA 研究均未关注糖尿病中的 CAD，部分原因是很少有其他研究人员能够接触到大量 CAD 和 T2D 患者。第三，本研究具有重大意义。作为一项公正的全基因组研究，它有可能确定糖尿病与动脉粥样硬化形成之间的新分子途径，对开发专门用于预防或治疗糖尿病患者 CAD 的新药具有明显的意义。 公共健康相关性：该项目的目标是确定 2 型糖尿病患者中参与调节冠状动脉疾病的基因。这些知识可能指出尚未发现的疾病机制，并提出开发新的药物干预措施来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还可以识别患有心血管疾病风险增加的糖尿病个体，以便可以在生命早期专门针对这些受试者制定预防计划。

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.