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

National Institute Of Environmental Health Sciences

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Abstract

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. Working with the ICAPS consortium, we sought to identify genome-wide variants influencing antihypertensive drug response and adverse cardiovascular outcomes, utilizing data from four randomized controlled trials in the International Consortium for Antihypertensive Pharmacogenomics Studies (ICAPS). Genome-wide antihypertensive drug-single nucleotide polymorphism (SNP) interaction tests for four drug classes (-blockers, n = 9,195; calcium channel blockers (CCBs), n = 10,511; thiazide/thiazide-like diuretics, n = 3,516; ACE- inhibitors/ARBs, n = 2,559) and cardiovascular outcomes (incident myocardial infarction, stroke, or death) were analyzed among patients with hypertension of European ancestry. Top SNPs from the meta-analyses were tested for replication of cardiovascular outcomes in an independent Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) study (n = 21,267), blood pressure (BP) response in independent ICAPS studies (n = 1,552), and ethnic validation in African Americans from the Genetics of Hypertension Associated Treatment study (GenHAT; n = 5,115). One signal reached genome- wide significance in the -blocker-SNP interaction analysis (rs139945292, Interaction P = 1.56 108). rs139945292 was validated through BP response to -blockers, with the T-allele associated with less BP reduction (systolic BP response P = 6 10 , Beta = 1.53). The T-allele was also associated with increased diastolic BP response. The locus showed nominal replication in CHARGE, and consistent directional trends in - blocker treated African Americans. rs139945292 is an expression quantitative trait locus for the 50 kb upstream gene NTM (neurotrimin). No SNPs attained genome-wide significance for any other drugs classes. Top SNPs were located near CALB1 (CCB), FLJ367777 (ACE-inhibitor), and CES5AP1 (thiazide). The NTM region is associated with increased risk for adverse cardiovascular outcomes and less BP reduction in -blocker treated patients. Further investigation into this region is warranted. In collaboration with my former post doc, we searched for biomarkers of response to intensive treatment. Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio HR 0.34; P = 2.01 103) and microvascular outcomes (HR 0.86; P = 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in MAS1 reached suggestive significance in C4 (P = 4.34 107). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; P = 4.02 106), but not reduced risk of microvascular outcomes (P < 0.05). Mendelian randomization indicated causality between PS, on-trial HbA1c, and reduction in CVD outcomes (P < 0.05). We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation 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.