Genetics of Coronary Artery Disease in Type 2 Diabetes

描述(申请人提供)：糖尿病是导致冠状动脉疾病(CAD)的最重要的危险因素之一。这种影响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的加速所致。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的联系机制，以便开发专门针对糖尿病患者的新干预措施。我们的策略是通过基因研究获得这方面的知识。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。来自我们小组的证据表明，其中一些基因可能与高血糖有协同作用，导致在糖尿病人群中产生特别强烈的影响。使用一种新的DNA池方法，我们已经完成了来自Joslin心脏研究(JHS)的一小部分CAD阳性和CAD阴性的2型糖尿病患者(T2D)的300,000个SNP全基因组关联(GWA)研究的第一阶段。本研究已经发现了几个等位基因频率在病例和对照之间存在较大差异的SNP，其中一些SNP聚集在第2、5、6、9和14号染色体上。本应用的具体目标是：1.完成对JHS的CAD病例和对照的扩展集合(n=2600)的GWA研究。更大的样本量将提供区分真实关联和由于多次测试而产生的假阳性结果的能力。2.在护士健康研究和健康专业人员随访研究的一组独立的病例和对照(n=3200)中，复制与冠心病相关的重要发现。复制将增强对积极结果的信心，并将使人们能够更准确地估计遗传影响的程度。3.在T2D中确定与CAD相关的基因组区域中的候选因果变异。识别可能的功能变异将为调节T2D中CAD风险的细胞通路提供洞察力。这项研究有三个重要特点。首先，这个项目有很高的成功几率，正如我们最近在染色体9p21上发现的一个与高血糖相互作用的CAD风险等位基因所表明的那样。其次，它涉及一个到目前为止被基因研究忽视的话题。已经完成或正在进行的GWA研究中没有一项专注于糖尿病的CAD，部分原因是很少有其他研究人员能够接触到大量患有CAD和T2D的人。第三，本研究具有重要意义。作为一项不偏不倚的全基因组研究，它有可能确定将糖尿病与动脉粥样硬化联系起来的新的分子途径，对开发专门针对糖尿病患者冠心病预防或治疗的新药具有明显的意义。公共卫生相关性：该项目的目标是在2型糖尿病患者中识别参与调节冠状动脉疾病的基因。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来预防或治疗这种糖尿病并发症的新策略。冠心病易感性增加的遗传标记的获得也将使糖尿病患者能够识别出心血管疾病风险增加的个体，这样预防计划就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.