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

描述(申请人提供)：糖尿病患者的管理通常伴随着高血压(高血压)和高水平的低密度脂蛋白-胆固醇和甘油三酯，通常伴随着低高密度脂蛋白-胆固醇(血脂异常)。大多数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。有多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，使用他汀类药物控制低密度脂蛋白-胆固醇可降低糖尿病患者的心血管事件发生率，但不能达到非糖尿病患者特有的水平。ACCORD试验调查了糖尿病患者是否接受强化药物治疗，目的是 使血糖、血压和血脂正常化将进一步减少心血管事件。然而，强化的血压或血脂治疗没有额外的效果，强化的血糖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由于与所用药物的新陈代谢或作用机制有关的基因遗传多态导致个人对特定治疗方案的不同反应的结果。许多候选基因可以被认为是这种遗传变异的可能来源，但我们对所有影响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，我们建议对ACCORD试验进行一项遗传学研究，该试验着眼于人类基因组中所有基因在功能上的显著遗传变异，以调查以下具体目标：1)从ACCORD血脂试验中确定患者中预测非诺贝特治疗反应的基因变异。2)从ACCORD LIPID试验中确定患者中预测 对他汀类药物治疗的反应。3)从ACCORD血糖试验中确定患者的基因变异，这些变异可以预测对特定降糖药物治疗的急性反应，以及对强化治疗策略与标准治疗策略的长期反应。识别影响血糖和血脂调节疗法结果的基因变异，将使特定的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，改善心血管结果，并减少糖尿病引起的发病率和死亡率的负担。含有这些变异的基因可能会被证明是药物开发的新靶点，从而导致未来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.