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

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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.