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Diabetes. 2018 Jul;67(7):1428-1440. doi: 10.2337/db17-1164. Epub 2018 Apr 12.

Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes.

Author information

1
Bioinformatics Research Center, North Carolina State University, Raleigh, NC.
2
Department of Statistics, North Carolina State University, Raleigh, NC.
3
Department of Bioengineering and Therapeutic Sciences and Institute for Human Genetics, University of California, San Francisco, San Francisco, CA.
4
School of Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland.
5
Joslin Diabetes Center and Harvard Medical School, Boston, MA.
6
Center for Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, Chapel Hill, NC.
7
Division of Research, Kaiser Permanente Northern California, Oakland, CA.
8
RIKEN Center for Integrative Medical Science, Yokohama, Japan.
9
Department of Medicine, Duke University, Durham, NC.
10
Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
11
Moffitt Cancer Center, Tampa, FL.
12
Division of Endocrinology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
13
Bioinformatics Research Center, North Carolina State University, Raleigh, NC alison_motsinger@ncsu.edu.

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 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 < 5 × 10-6), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 × 10-8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/-) knockout mice have increased total body fat (P = 1.78 × 10-6) and increased fasted circulating glucose (P = 5.73 × 10-6). 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.

PMID:
29650774
PMCID:
PMC6014560
[Available on 2019-07-01]
DOI:
10.2337/db17-1164
[Indexed for MEDLINE]
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