Genetic modifiers of the effect of intensive glycemic control on CVD risk

强化血糖控制可显著降低非致命性心肌梗死的发生率， 雅阁试验中2型糖尿病（T2 D）患者的脑梗死。这种有益的效果， 但是，与这种干预措施有关的死亡率增加抵消了这一影响。虽然原因 这种不利影响的辩论，任务是制定一个治疗策略，我们可以采取 强化血糖控制的有益效果的优势，同时包含有害的。到 为此，我们在雅阁辅助研究中寻求找到可以识别T2 D患者的遗传标记 由于对葡萄糖的敏感性更高， 这种干预措施的积极影响，对其不利影响的敏感性较低，或两者兼而有之。某些临床 已经确定了可能有助于确定这些主题的特征，但其他预测因素包括 需要建立一个强大的算法。基于我们之前对度之间相互作用的观察， 血糖控制和9 p21 CVD位点对2型糖尿病患者冠状动脉疾病风险的影响， 假设遗传标记可用于这一任务，并建议通过 对整个基因组的系统搜索。我们提出以下具体目标：1。进行一次733 K SNP全基因组关联研究（GWAS），以确定遗传修饰剂的影响， 雅阁中强化血糖控制对心血管结局和不良事件的影响。我们将 检测733，000个基因座中的每一个与致命性和非致命性强化血糖控制的相互作用， 心血管事件以及严重低血糖和体重增加等不良反应。我们将 通过与ADVANCE团队的合作，对结果进行荟萃分析。2.到 研究雅阁中确定的候选遗传修饰因子是否也影响CVD 在临床实践中取得的成果。我们将研究这些SNP与长- 来自Joslin诊所的2，300名T2 D患者中的长期血糖控制对心血管结局的影响 丰富的HbA 1c历史数据。3.建立预测模型以区分T2 D患者， 与标准治疗相比，可能受益于强化血糖控制。我们将 将雅阁的临床和遗传数据整合到回归模型中，并将评估其 预测与葡萄糖类型相关的心血管结局或不良事件的性能- 降低治疗。通过鉴定血糖控制对发育影响的遗传调节剂， 心血管疾病，这项研究将提供一个起点，建立一个个性化的医疗 以更具成本效益的方式治疗T2 D患者。识别这些遗传因素 也可以提供新的见解，分子途径连接过量的葡萄糖， 动脉粥样硬化，与开发新药，以防止心血管疾病的T2 D的关键意义。

Intensive glycemic control caused a significant reduction in the occurrence of non-fatal myocardial infarctions among patients with type 2 diabetes (T2D) in the ACCORD trial. This beneficial effect, however, was offset by an increase in mortality associated with this intervention. While the reasons for this adverse effect are debated, the task is to devise a treatment strategy by which we can take advantage of the beneficial effects of intensive glycemic control while containing the detrimental ones. To this end, we seek in this ACCORD Ancillary Study to find genetic markers that can identify T2D patients who would especially benefit from intensive glucose-lowering efforts, because of greater sensitivity to the positive effects of this intervention, lesser susceptibility to its adverse effects, or both. Certain clinical characteristics that may help pinpoint these subjects have been identified, but additional predictors are needed to build a robust algorithm. Based on our previous observation of an interaction between degree of glycemic control and the 9p21 CVD locus on the risk of coronary artery disease in T2D, we hypothesize that genetic markers can be used for this task and propose their identification through a systematic search of the entire genome. We propose the following specific aims: 1. To conduct a 733K SNP genome-wide association study (GWAS) to identify genetic modifiers of the effect of intensive glycemic control on cardiovascular outcomes and adverse events in ACCORD. We will test each of the 733,000 loci for interaction with intensive glycemic control on fatal and non-fatal cardiovascular events as well as adverse effects such as severe hypoglycemia and weight gain. We will meta-analyze results with those from ADVANCE through a collaboration with that group. 2. To investigate whether the candidate genetic modifiers identified in ACCORD also influence CVD outcomes in a clinical practice setting. We will study the interaction between these SNPs and long- term glycemic control on cardiovascular outcomes among 2,300 T2D patients from the Joslin Clinic with rich historical HbA1c data. 3. To build prediction models to distinguish T2D patients who are most likely to benefit from intensive glycemic control as compared to standard therapy. We will integrate the clinical and genetic data from ACCORD into regression models and will evaluate their performance in predicting cardiovascular outcomes or adverse events in relation to the type of glucose- lowering therapy. By identifying genetic modulators of the effect of glycemic control on the development of cardiovascular disease, this research will provide a starting point to build a personalized medicine framework to treat T2D patients in a more cost-effective way. Identification of these genetic factors may also provide novel insights into the molecular pathways linking excess glucose to atherosclerosis, with critical implications for the development of novel drugs to prevent CVD in T2D.