Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes

Daniel M. Rotroff, Sook Wah Yee, Kaixin Zhou, Skylar W. Marvel, Hetal S. Shah, John R. Jack, Tammy M. Havener, Monique M. Hedderson, Michiaki Kubo, Mark A. Herman, He Gao, Josyf C. Mychaleckyi, Michiaki Kubo, Alessandro Doria, Kathleen M. Giacomini, Ewan R. Pearson, Michael J. Wagner, John B. Buse, Alison A. Motsinger-Reif

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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 PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 3 10 26 ), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 3 10 2 8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/2) knockout mice have increased total body fat (P = 1.78 3 10 26 ) and increased fasted circulating glucose (P = 5.73 3 10 26 ). 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.

Original languageEnglish
Pages (from-to)1428-1440
Number of pages13
JournalDiabetes
Volume67
Issue number7
DOIs
Publication statusPublished - 01-07-2018

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Metformin
Type 2 Diabetes Mellitus
Glucose
Feeding Behavior
Knockout Mice
Meta-Analysis
Adipose Tissue
Clinical Trials
Genome

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Rotroff, D. M., Yee, S. W., Zhou, K., Marvel, S. W., Shah, H. S., Jack, J. R., ... Motsinger-Reif, A. A. (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. ; Yee, Sook Wah ; Zhou, Kaixin ; Marvel, Skylar W. ; Shah, Hetal S. ; Jack, John R. ; Havener, Tammy M. ; Hedderson, Monique M. ; Kubo, Michiaki ; Herman, Mark A. ; Gao, He ; Mychaleckyi, Josyf C. ; Kubo, Michiaki ; Doria, Alessandro ; Giacomini, Kathleen M. ; Pearson, Ewan R. ; Wagner, Michael J. ; Buse, John B. ; Motsinger-Reif, Alison A. / Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes. In: Diabetes. 2018 ; Vol. 67, No. 7. pp. 1428-1440.
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Rotroff, DM, Yee, SW, Zhou, K, Marvel, SW, Shah, HS, Jack, JR, Havener, TM, Hedderson, MM, Kubo, M, Herman, MA, Gao, H, Mychaleckyi, JC, Kubo, M, Doria, A, Giacomini, KM, Pearson, ER, Wagner, MJ, Buse, JB & Motsinger-Reif, AA 2018, '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, pp. 1428-1440. https://doi.org/10.2337/db17-1164

Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes. / Rotroff, Daniel M.; Yee, Sook Wah; Zhou, Kaixin; Marvel, Skylar W.; Shah, Hetal S.; Jack, John R.; Havener, Tammy M.; Hedderson, Monique M.; Kubo, Michiaki; Herman, Mark A.; Gao, He; Mychaleckyi, Josyf C.; Kubo, Michiaki; Doria, Alessandro; Giacomini, Kathleen M.; Pearson, Ewan R.; Wagner, Michael J.; Buse, John B.; Motsinger-Reif, Alison A.

In: Diabetes, Vol. 67, No. 7, 01.07.2018, p. 1428-1440.

Research output: Contribution to journalArticle

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T1 - Genetic variants in CPA6 and PRPF31 are associated with variation in response to metformin in individuals with type 2 diabetes

AU - Rotroff, Daniel M.

AU - Yee, Sook Wah

AU - Zhou, Kaixin

AU - Marvel, Skylar W.

AU - Shah, Hetal S.

AU - Jack, John R.

AU - Havener, Tammy M.

AU - Hedderson, Monique M.

AU - Kubo, Michiaki

AU - Herman, Mark A.

AU - Gao, He

AU - Mychaleckyi, Josyf C.

AU - Kubo, Michiaki

AU - Doria, Alessandro

AU - Giacomini, Kathleen M.

AU - Pearson, Ewan R.

AU - Wagner, Michael J.

AU - Buse, John B.

AU - Motsinger-Reif, Alison A.

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N2 - 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 PRPF31 and CPA6 were associated with worse and better metformin response, respectively (P < 5 3 10 26 ), and meta-analysis in independent cohorts displayed similar associations with metformin response (P = 1.2 3 10 2 8 and P = 0.005, respectively). Previous studies have shown that PRPF31(+/2) knockout mice have increased total body fat (P = 1.78 3 10 26 ) and increased fasted circulating glucose (P = 5.73 3 10 26 ). 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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