biostudies-literatureRotroff DMNIDDK NIH HHSNIA NIH HHSNational Heart, Lung, and Blood InstituteNHLBI NIH HHSMedical Research CouncilNational Institutes of HealthNIAMS NIH HHSWellcome TrustNIGMS NIH HHS1428-1440https://www.ebi.ac.uk/biostudies/studies/S-EPMC6014560biostudies-literatureUnknown67(7)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> DiabetesGenetic Variants in <i>CPA6</i> and <i>PRPF31</i> Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes.PMC6014560GM117163HDR-5006GM61390U01 GM061390R01 GM117163R01 HL1104005R01HL110380-04R00 AG047255R01 HL110380102820/Z/13/ZP30 DK036836U19 GM061390R01 AR073017Rotroff DMMotsinger-Reif AAMcLeod HLHavener TMDoria AHerman MAGao HShah HSMarvel SWGiacomini KMWagner MJYee SWPearson ERBuse JBMychaleckyi JCMetGen InvestigatorsACCORD/ACCORDion InvestigatorsHedderson MMZhou KJack JRKubo MfalseGenetic Variants in <i>CPA6</i> and <i>PRPF31</i> Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes.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> 2018-01-01T00:00:00Z2018 Jul2026-04-30T17:53:52.614Z2019-07-24T07:21:39ZS-EPMC60145602965077410.2337/db17-1164