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

基本信息

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
项目类别：
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

项目摘要

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.