An Exome-Focused Approach to Pharmacogenetic Analysis of the ACCORD Trial

描述（由申请人提供）：糖尿病患者的治疗通常伴有高血压（高血压）、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（血脂异常）。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，心血管风险随着血糖、血压和血脂水平的升高而增加。有各种各样的药物可用于治疗这些疾病，其中一些已被证明对心血管风险有影响。例如，用他汀类药物治疗控制低密度脂蛋白胆固醇可以降低糖尿病患者的心血管事件发生率，但不能降低到非糖尿病患者的水平。ACCORD试验旨在研究强化药物治疗是否对糖尿病患者有效

DESCRIPTION (provided by applicant): The management of diabetic patients is often complicated by concomitant high blood pressure (hypertension) and high levels of LDL-cholesterol and triglycerides, often coupled with low HDL- cholesterol (dyslipidemia).The majority of diabetes related mortality is due to cardiovascular events, and epidemiological studies have shown that cardiovascular risk increases with increasing levels of blood sugar, blood pressure, and blood lipids. A variety of drugs are available to treat each of these conditions, and some have been shown to have an effect on cardiovascular risk. For example, controlling LDL-cholesterol with statin therapy reduces the rate of cardiovascular events in diabetic patients, but not to the level characteristic of non-diabetic individuals. The ACCORD trial investigated whether intensive pharmacological therapy in diabetic patients, with the goal of normalizing glycemia, blood pressure, and blood lipids, would further reduce cardiovascular events. However, no additional effect was seen with intensive blood pressure or lipid therapy, and intensive glycemia management actually increased mortality. These failures of seemingly rational treatment approaches could be the result of differential response of individuals to particular therapeutic regimens due to genetic polymorphism in genes relating to the metabolism or mechanism of action of the medicines used. Many candidate genes could be advanced as possible sources of this genetic variation, but our knowledge of all genes contributing to metabolic and cardiovascular phenotypes is incomplete, and therefore a candidate gene approach cannot be assured of identifying the relevant genes. We therefore propose a genetic study of the ACCORD trial that looks at functionally significant genetic variation in all genes in the human genome to investigate the following specific aims: 1) Identify genetic variants in patients from the ACCORD Lipid Trial that predict responses to treatment with fenofibrate. 2) Identify genetic variants in patients from the ACCORD Lipid Trial that predict responses to treatment with statins. 3) Identify genetic variants in patients from the ACCORD Glycemia Trial that predict acute responses to treatment with specific anti-hyperglycemic agents, and long-term responses to intensive vs. standard treatment strategies. Identification of genetic variants affecting outcomes of glycemia and lipid modifying therapies would enable the targeting of particular interventions to patients most likely to benefit and least likely to be harmed, improving cardiovascular outcomes and reducing the burden of morbidity and mortality attributable to diabetes. The genes containing these variants may prove to be novel targets for drug development, leading to new medicines for improving outcomes for diabetic patients in the future. PUBLIC HEALTH RELEVANCE: Diabetes is a major cause of morbidity and mortality, due in large measure to effects of the disease on cardiovascular health. The ACCORD clinical trial investigated the hypothesis that intensive management of glycemia, blood pressure, and lipid levels would reduce cardiovascular events in diabetic patients, but failed to demonstrate a benefit for these interventions. The ancillary study proposed here will identify genes responsible for variation in response to the ACCORD lipid and glycemia interventions, which will enable personalized treatment so as to avoid adverse effects and improve patient cardiovascular health, reducing diabetes-related morbidity and mortality.