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

Publication ,  Journal Article
Rotroff, DM; Yee, SW; Zhou, K; Marvel, SW; Shah, HS; Jack, JR; Havener, TM; Hedderson, MM; Kubo, M; Herman, MA; Gao, H; Mychaleckyi, JC ...
Published in: Diabetes
July 2018

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.

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Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

July 2018

Volume

67

Issue

7

Start / End Page

1428 / 1440

Location

United States

Related Subject Headings

  • Treatment Outcome
  • STAT3 Transcription Factor
  • Polymorphism, Single Nucleotide
  • Pharmacogenomic Variants
  • Middle Aged
  • Metformin
  • Male
  • Humans
  • Genome-Wide Association Study
  • Female
 

Citation

APA
Chicago
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MLA
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Rotroff, D. M., Yee, S. W., Zhou, K., Marvel, S. W., Shah, H. S., Jack, J. R., … ACCORD/ACCORDion Investigators, . (2018). Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes. Diabetes, 67(7), 1428–1440. https://doi.org/10.2337/db17-1164
Rotroff, Daniel M., Sook Wah Yee, Kaixin Zhou, Skylar W. Marvel, Hetal S. Shah, John R. Jack, Tammy M. Havener, et al. “Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes.Diabetes 67, no. 7 (July 2018): 1428–40. https://doi.org/10.2337/db17-1164.
Rotroff DM, Yee SW, Zhou K, Marvel SW, Shah HS, Jack JR, et al. Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes. Diabetes. 2018 Jul;67(7):1428–40.
Rotroff, Daniel M., et al. “Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes.Diabetes, vol. 67, no. 7, July 2018, pp. 1428–40. Pubmed, doi:10.2337/db17-1164.
Rotroff DM, Yee SW, Zhou K, Marvel SW, Shah HS, Jack JR, Havener TM, Hedderson MM, Kubo M, Herman MA, Gao H, Mychaleckyi JC, McLeod HL, Doria A, Giacomini KM, Pearson ER, Wagner MJ, Buse JB, Motsinger-Reif AA, MetGen Investigators, ACCORD/ACCORDion Investigators. Genetic Variants in CPA6 and PRPF31 Are Associated With Variation in Response to Metformin in Individuals With Type 2 Diabetes. Diabetes. 2018 Jul;67(7):1428–1440.

Published In

Diabetes

DOI

EISSN

1939-327X

Publication Date

July 2018

Volume

67

Issue

7

Start / End Page

1428 / 1440

Location

United States

Related Subject Headings

  • Treatment Outcome
  • STAT3 Transcription Factor
  • Polymorphism, Single Nucleotide
  • Pharmacogenomic Variants
  • Middle Aged
  • Metformin
  • Male
  • Humans
  • Genome-Wide Association Study
  • Female