University of Dundee Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes Rotroff,

Metformin is the first line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucoselowering mechanism for metformin is incompletely understood. Here we used a genome-wide association approach in a diverse group of individuals with T2D from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial to identify common and rare variants associated with HbA1c response to metformin treatment, and followed up these findings in four replication cohorts. Common variants in PRPF31 and CPA6, were associated with worse and better metformin response, respectively (p<5x10), and meta-analysis in independent cohorts displayed similar associations with metformin response (p=1.2x10 and p=0.005, respectively). Previous studies have shown that PRPF31(+/-) knockout mice have increased total body fat (p=1.78x10) and increased fasted circulating glucose (p=5.73x10). Furthermore, rare variants in STAT3 associated with worse metformin response(q<0.1). STAT3 is a ubiquitously expressed pleiotropic transcriptional activator that participates in the regulation of metabolism and feeding behavior. Here we provide novel evidence for associations of common and rare variants in PRPF31, CPA6, and STAT3 with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D. Introduction The incidence of Type 2 Diabetes (T2D) is increasing and the Centers for Disease Control and Prevention estimate that 11% of U.S. adults, aged 20 years or older, have diagnosed or undiagnosed T2D, and 35% of people in the same age group have prediabetes based on fasting glucose or hemoglobin A1c (HbA1c) levels(1). T2D is now considered a global epidemic with prevalence increasing from 108 million in 1980 to 422 million in 2014(2). Individuals with T2D are at an increased risk of developing blindness and kidney failure, and are at risk for lower limb amputations. Furthermore, individuals with T2D are 2-4x more likely to develop cardiovascular disease (CVD), including heart attack and stroke(3). Metformin, a member of the biguanide class of drugs, is now considered first line therapy for individuals with T2D(4). Despite intensive investigation, the molecular mechanisms mediating metformin’s beneficial effects on glycemic control remain controversial and poorly understood. Studies performed predominantly in animal models have implicated various mechanisms and molecules as participating in metformin’s beneficial effects, including direct inhibitory effects on mitochondrial function, activation of hepatic AMPK, and alterations in glucagon signaling pathways(5–10). The relative importance of these mechanisms for metformin’s beneficial effects on glycemic control in humans is