Genetic Variants in <i>CPA6</i> and <i>PRPF31</i> Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes

Abstract

Metformin is the first-line treatment for type 2 diabetes (T2D). Although widely prescribed, the glucose-lowering 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 HbA_1c response to metformin treatment and followed up these findings in four replication cohorts. Common variants in <i>PRPF31</i> and <i>CPA6</i> were associated with worse and better metformin response, respectively (<i>P</i> < 5 × 10^-6), and meta-analysis in independent cohorts displayed similar associations with metformin response (<i>P</i> = 1.2 × 10^-8 and <i>P</i> = 0.005, respectively). Previous studies have shown that <i>PRPF31</i>(+/-) knockout mice have increased total body fat (<i>P</i> = 1.78 × 10^-6) and increased fasted circulating glucose (<i>P</i> = 5.73 × 10^-6). Furthermore, rare variants in <i>STAT3</i> associated with worse metformin response (<i>q</i> <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 <i>PRPF31, CPA6,</i> and <i>STAT3</i> with metformin response that may provide insight into mechanisms important for metformin efficacy in T2D.