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

强化血糖控制对 CVD 风险影响的遗传修饰

• 批准号: 8336910
• 负责人: Alessandro Doria
• 金额: $ 126.66万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-22 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8336910
• 关键词: 9p21; Accounting; Address; Adverse effects; Adverse event; Algorithms; Ancillary Study; Atherosclerosis; Biological Markers; Cardiovascular Diseases; Cardiovascular system; Characteristics; Clinic; Clinical; Clinical Trials; Collaborations; Complications of Diabetes Mellitus; Coronary Arteriosclerosis; Data; Data Set; Development; Event; Future; Genetic; Genetic Markers; Genome; Genotype; Glucose; Glycosylated Hemoglobin; Glycosylated hemoglobin A; Goals; Hypoglycemia; Hypotension; Individual; Intervention; Link; Lipids; Medicine; Meta-Analysis; Modeling; Molecular; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Other Genetics; Outcome; Participant; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Predisposition; Randomized; Research; Research Project Grants; Risk; Testing; Weight Gain; base; cardiovascular risk factor; clinical practice; cost effective; design; diabetic patient; genome wide association study; glycemic control; insight; intervention effect; mortality; novel; prevent; primary outcome; response; tool; treatment strategy

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.

强化血糖控制可显著降低非致命性心肌梗死的发生率 在ACCORD试验中，2型糖尿病(T2D)患者中的脑梗塞。这种有益的效果， 然而，与这一干预相关的死亡率上升抵消了这一影响。虽然原因是 这种不利影响是有争议的，任务是设计一种治疗策略，我们可以通过它来采取 在控制有害血糖的同时，强化血糖控制的有利影响。至 为此，我们在这项ACCORD辅助研究中寻求能够识别T2D患者的遗传标记 世卫组织将特别受益于密集的降血糖努力，因为对 这种干预的积极效果，对其不利影响的敏感性较低，或两者兼而有之。某些临床应用 可能有助于准确定位这些受试者的特征已经确定，但其他预测因素包括 需要建立一个健壮的算法。基于我们之前观察到的度数之间的相互作用 血糖控制和9p21心血管疾病基因座对T2D患者冠状动脉疾病风险的影响 假设遗传标记可以用于这项任务，并提出通过 对整个基因组的系统搜索。我们提出了以下具体目标：1.开展733K SNP全基因组关联研究(GWAS)以确定遗传修饰物的影响 强化血糖控制对心血管结局和不良事件的影响。我们会 测试733,000个基因座中的每一个与致命性和非致命性血糖强化控制的交互作用 心血管事件以及严重低血糖和体重增加等不良反应。我们会 通过与该小组的合作，将结果与Advance的结果进行Meta分析。2.至 调查ACCORD中确定的候选遗传修饰物是否也影响心血管疾病 在临床实践环境中的结果。我们将研究这些SNP与Long-SNP之间的相互作用。 长期血糖控制对来自Joslin诊所的2300名T2D患者的心血管结局的影响 丰富的HbA1c历史数据。3.建立预测模型以区分T2D患者中 与标准治疗相比，可能从强化血糖控制中受益。我们会 将ACCORD的临床和遗传数据整合到回归模型中，并将评估他们的 在预测与血糖类型有关的心血管结果或不良事件方面的表现- 降压疗法。通过确定血糖控制对发育的影响的遗传调节器 对于心血管疾病，本研究将为构建个性化医学提供一个起点 框架，以更具成本效益的方式治疗T2D患者。这些遗传因素的鉴定 也可能为过量葡萄糖与 动脉粥样硬化，对开发预防T2D心血管疾病的新药具有重要意义。