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

糖尿病患者的管理通常是复杂的，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，通常伴随着低高密度脂蛋白胆固醇。大多数糖尿病相关死亡是由心血管事件引起的，流行病学研究表明，随着血糖、血压和血脂水平的增加，心血管疾病的风险增加。控制糖尿病心血管风险的行动临床试验调查了以使血糖、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事件。我在ACCORD试验中继续我在药物基因组学方面的工作。这些项目是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正在进行的合作，以及通过大型财团的努力进行的各种合作。 在哈佛大学合作者的带领下，我们调查了编码贝特类药物靶点的PPARA基因的遗传变异性是否可以用于改善对2型糖尿病患者的选择，这些患者可能从他汀类药物的治疗中获得心血管益处。在ACCORD-Lipid试验中，我们在3,065名接受辛伐他汀治疗并随机服用非诺贝特或安慰剂的自述白人受试者中发现了一种常见的PPARA基因变异，该变异对整个研究范围内非诺贝特对主要心血管事件的影响具有显著影响。值得注意的是，即使在没有致动脉粥样硬化性血脂异常的情况下，rs6008845T/T纯合子也能体验到贝特对心血管的好处。综上所述，我们发现了一种影响非诺贝特心血管效应的常见PPARA调节变量，该变量可用于确定除了那些动脉粥样硬化性血脂异常的患者外，哪些2型糖尿病患者将从非诺贝特治疗中受益。 我们也有使用ACCORD数据的正在进行的项目。我们正在对罗格列酮的反应以及体重增加的不良后果进行关联分析。我们还在研究血红蛋白糖化指数的遗传学。HGI量化了糖基化倾向的个体间差异，是糖尿病并发症和强化降糖不良反应的预测因子。我们发现了有希望的结果，我们最近在外部队列中复制了这些结果。我们还参与了几个与药物反应有关的联盟，并帮助该领域的其他人利用ACCORD队列复制他们的结果。我们目前正在与国际抗高血压药物药物基因组学研究联盟(ICAPS)联盟进行一项荟萃分析。

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.