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ObjectiveSulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction.Research design and methodsAs an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.ResultsAfter establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10-8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10-8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10-58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10-8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10-7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.ConclusionsWe have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs.

Objective: Environmental exposures may have greater predictive power for type 2 diabetes than polygenic scores (PGS). Studies examining environmental risk factors, however, have included only individuals with European ancestry, limiting the applicability of results. We conducted an exposome-wide association study in the multiancestry Personalized Environment and Genes Study to assess the effects of environmental factors on type 2 diabetes.Research Design and Methods: Using logistic regression for single-exposure analysis, we identified exposures associated with type 2 diabetes, adjusting for age, BMI, household income, and self-reported sex and race. To compare cumulative genetic and environmental effects, we computed an overall clinical score (OCS) as a weighted sum of BMI and prediabetes, hypertension, and high cholesterol status and a polyexposure score (PXS) as a weighted sum of 13 environmental variables. Using UK Biobank data, we developed a multiancestry PGS and calculated it for participants.Results: We found 76 significant associations with type 2 diabetes, including novel associations of asbestos and coal dust exposure. OCS, PXS, and PGS were significantly associated with type 2 diabetes. PXS had moderate power to determine associations, with larger effect size and greater power and reclassification improvement than PGS. For all scores, the results differed by race.Conclusions: Our findings in a multiancestry cohort elucidate how type 2 diabetes odds can be attributed to clinical, genetic, and environmental factors and emphasize the need for exposome data in disease-risk association studies. Race-based differences in predictive scores highlight the need for genetic and exposome-wide studies in diverse populations. [ABSTRACT FROM AUTHOR]

Objective: A genome-wide association study in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial identified two markers (rs57922 and rs9299870) that were significantly associated with cardiovascular mortality during intensive glycemic control and could potentially be used, when combined into a genetic risk score (GRS), to identify patients with diabetes likely to derive benefit from intensive control rather than harm. The aim of this study was to gain insights into the pathways involved in the modulatory effect of these variants.Research Design and Methods: Fasting levels of 65 biomarkers were measured at baseline and at 12 months of follow-up in the ACCORD-Memory in Diabetes (ACCORD-MIND) MRI substudy (n = 562). Using linear regression models, we tested the association of the GRS with baseline and 12-month biomarker levels, and with their difference (Δ), among white subjects, with genotype data (n = 351) stratified by intervention arm.Results: A significant association was observed between GRS and ΔGLP-1 (glucagon-like peptide 1, active) in the intensive arm (P = 3 × 10-4). This effect was driven by rs57922 (P = 5 × 10-4). C/C homozygotes, who had been found to derive cardiovascular benefits from intensive treatment, showed a 22% increase in GLP-1 levels during follow-up. By contrast, T/T homozygotes, who had been found to experience increased cardiac mortality with intensive treatment, showed a 28% reduction in GLP-1 levels. No association between ΔGLP-1 and GRS or rs57922 was observed in the standard treatment arm.Conclusions: Differences in GLP-1 axis activation may mediate the modulatory effect of variant rs57922 on the cardiovascular response to intensive glycemic control. These findings highlight the importance of GLP-1 as a cardioprotective factor. [ABSTRACT FROM AUTHOR]