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

描述（申请人提供）：糖尿病患者的管理往往是复杂的伴随高血压（高血压）和高水平的低密度脂蛋白胆固醇和甘油三酯，往往加上低密度脂蛋白胆固醇大多数糖尿病相关的死亡是由于心血管事件，并且流行病学研究已经表明，心血管风险随着血糖、血压、和血脂。各种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LDL-胆固醇降低了糖尿病患者的心血管事件发生率，但没有达到非糖尿病个体的特征水平。雅阁试验研究了糖尿病患者的强化药物治疗是否，目的是 使血压、血压和血脂正常化将进一步减少心血管事件。然而，强化血压或血脂治疗没有额外的效果，强化血压管理实际上增加了死亡率。这些看似合理的治疗方法的失败可能是个体对特定治疗方案的不同反应的结果，这是由于与所用药物的代谢或作用机制相关的基因中的遗传多态性。许多候选基因可以作为这种遗传变异的可能来源，但我们对所有有助于代谢和心血管表型的基因的了解是不完整的，因此候选基因方法不能确保识别相关基因。因此，我们提出了一项雅阁试验的遗传学研究，该研究着眼于人类基因组中所有基因的功能显著遗传变异，以研究以下特定目标：1）识别来自雅阁脂质试验的患者中预测非诺贝特治疗反应的遗传变异。2)识别来自雅阁脂质试验的患者的遗传变异， 对他汀类药物治疗的反应。3)确定雅阁血糖试验患者的遗传变异，预测对特定降糖药物治疗的急性反应，以及对强化与标准治疗策略的长期反应。鉴定影响糖尿病和调脂治疗结果的遗传变异将使特定干预措施能够针对最有可能受益和最不可能受到伤害的患者，改善心血管结局并降低糖尿病所致发病率和死亡率的负担。含有这些变异的基因可能被证明是药物开发的新靶点，从而在未来开发出改善糖尿病患者预后的新药。

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.