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

强化血糖控制对 CVD 风险影响的基因修饰

• 批准号: 8698456
• 负责人: Alessandro Doria
• 金额: $ 59.47万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698456
• 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.

强化血糖控制导致非致命心肌的发生显着降低 协议试验中2型糖尿病（T2D）患者的梗塞。这种有益的效果， 但是，与此干预相关的死亡率增加所抵消。而原因 辩论这种不利影响，任务是制定一种治疗策略，我们可以采取这种策略 密集性血糖控制的有益作用的优势在包含有害的血糖控制的同时。到 这一目的，我们在本协议辅助研究中寻求找到可以识别T2D患者的遗传标记 谁会特别受益于降低葡萄糖的努力，因为对 这种干预的积极影响，对其不良影响的敏感性较小，或两者兼而有之。某些临床 可能有助于查明这些主题的特征已被确定，但其他预测因素是 需要构建强大的算法。根据我们以前对学位相互作用的观察 血糖控制和9p21 CVD基因座关于T2D患冠状动脉疾病的风险 假设遗传标记可以用于此任务，并通过 系统地搜索整个基因组。我们提出以下特定目的：1。进行733K SNP全基因组关联研究（GWAS），以鉴定遗传修饰符 对心血管结局和不良事件的强化血糖控制。我们将 测试733,000个基因座中的每个位置，以与致命和非致命性高血糖控制的相互作用 心血管事件以及不良反应，例如严重的低血糖和体重增加。我们将 通过与该小组的合作，荟萃分析的结果与Advance的结果相关。 2 研究候选遗传修饰符是否也会影响CVD 在临床实践环境中的结果。我们将研究这些SNP与长期之间的相互作用 乔斯林诊所的2,300名T2D患者中心血管结局的术语血糖控制 丰富的历史HBA1C数据。 3。建立预测模型以区分最多的T2D患者 与标准疗法相比，可能受益于密集的血糖控制。我们将 将一致性的临床和遗传数据整合到回归模型中，并将评估其 与葡萄糖类型相关的心血管结局或不良事件的表现 降低治疗。通过鉴定血糖控制对发育的影响的遗传调节剂 在心血管疾病中，这项研究将为建立个性化药物提供一个起点 以更具成本效益的方式治疗T2D患者的框架。这些遗传因素的识别 还可能提供有关将多余葡萄糖连接到的分子途径的新见解 动脉粥样硬化，对开发新药物的开发具有至关重要的影响，以防止T2D中的CVD。