Statistical Genetics of Outcomes and Drug Response in Patients with Type 2 Diabetes.

2 型糖尿病患者的结果和药物反应的统计遗传学。

• 批准号: 10260284
• 负责人: Alison Motsinger-Reif
• 金额: $ 56.27万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260284
• 关键词: Adverse effects; Antihypertensive Agents; Blood Glucose; Blood Pressure; Cardiovascular Diseases; Cardiovascular system; Clinic; Clinical Trials; Code; Collaborations; Complications of Diabetes Mellitus; Coupled; Data; Diabetes Mellitus; Dyslipidemias; Event; Failure; Fenofibrate; Fibrates; Genes; Genetic; Genetic Variation; Glucose; Goals; Hemoglobin; High Density Lipoprotein Cholesterol; Homozygote; Hypertension; Individual; International; LDL Cholesterol Lipoproteins; Lead; Lipids; Meta-Analysis; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Patient Selection; Patient Self-Report; Patients; Pharmaceutical Preparations; Pharmacogenomics; Pharmacology; Placebos; Randomized; Regimen; Research Personnel; Simvastatin; Therapeutic; Triglycerides; Universities; Variant; Virginia; Weight Gain; Work; adverse outcome; blood lipid; cardiovascular disorder risk; cardiovascular risk factor; cohort; epidemiology study; experience; glycation; improved; indexing; individual response; inter-individual variation; medical schools; mortality; non-diabetic; response; rosiglitazone

The management of patients with diabetes is often complicated by concomitant high blood pressure and high levels of low-density lipoprotein -cholesterol and triglycerides, often coupled with low high-density lipoprotein -cholesterol. The majority of diabetes related mortality is due to cardiovascular events, and epidemiological studies have shown that cardiovascular disease risk increases with increasing levels of blood sugar, blood pressure, and blood lipids. The Action to Control Cardiovascular Risk in Diabetes clinical trial investigated whether intensive pharmacological therapy, with the goal of normalizing glycemia, blood pressure, and blood lipids, would further reduce CVD events in patients with diabetes. I have continued my work in pharmacogenomics within the ACCORD trial. These projects are ongoing collaborations with investigators at UNC Chapel Hill, Harvard Medical School, the Cleveland Clinic and the University of Virginia and a variety of collaborations through large consortia efforts. Lead by our Harvard collaborators, we investigated whether genetic variability in the PPARA gene, coding for the pharmacological target of fibrates, could be used to improve the selection of patients with type 2 diabetes who may derive cardiovascular benefit from addition of this treatment to statins. We identified a common variant at the PPARA locus displaying a study-wide significant influence on the effect of fenofibrate on major cardiovascular events among 3,065 self-reported white subjects treated with simvastatin and randomized to fenofibrate or placebo in the ACCORD-Lipid trial. Remarkably, rs6008845 T/T homozygotes experienced a cardiovascular benefit from fibrate even in the absence of atherogenic dyslipidemia. In summary, we have found a common PPARA regulatory variant that influences the cardiovascular effects of fenofibrate and that could be used to identify patients with type 2 diabetes who would derive benefit from fenofibrate treatment, in addition to those with atherogenic dyslipidemia. We have ongoing projects using the ACCORD data as well. We are working on association analyses of response to rosiglitazone, as well as the adverse outcome of weight gain. We are also working the genetics of the hemoglobin glycation index. HGI quantifies the interindividual variation in the propensity for glycation and is a predictor of diabetes complications and adverse effects of intensive glucose lowering. We have found promising results that we have recently replicated in an external cohort. We also participate in several consortia related to drug response and help others in the field replicate their results using the ACCORD cohort. We are currently leading a meta-analysis with the studies in the International Consortium for Antihypertensives Pharmacogenomics Studies (ICAPS) consortia.

糖尿病患者的管理通常伴随着高血压和高水平的低密度脂蛋白-胆固醇和甘油三酯，通常伴有低密度脂蛋白-胆固醇。大多数与糖尿病相关的死亡是由于心血管事件，流行病学研究表明，心血管疾病的风险随着血糖、血压和血脂水平的升高而增加。控制糖尿病心血管风险的行动临床试验研究了以血糖、血压和血脂正常化为目标的强化药物治疗是否会进一步减少糖尿病患者的心血管疾病事件。我在ACCORD试验中继续我的药物基因组学工作。这些项目正在与北卡罗来纳大学教堂山分校、哈佛医学院、克利夫兰诊所和弗吉尼亚大学的研究人员进行合作，并通过大型财团的努力进行各种合作。