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; Howard L. McLeod; Alessandro Doria; Kathleen M. Giacomini; Ewan R. Pearson; Michael J. Wagner; John B. Buse; Alison A. Motsinger-Reif; MetGen Investigators and the ACCORD/ACCORDion Investigators

doi:10.2337/db17-1164

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, Howard L. McLeod, Alessandro Doria, Kathleen M. Giacomini, Ewan R. Pearson, Michael J. Wagner, John B. Buse, Alison A. Motsinger-Reif (Lead / Corresponding author), MetGen Investigators and the ACCORD/ACCORDion Investigators

Research output: Contribution to journal › Article › peer-review

35 Citations (Scopus)

194 Downloads (Pure)

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.

Original language	English
Pages (from-to)	1428-1440
Number of pages	13
Journal	Diabetes
Volume	67
Issue number	7
Early online date	12 Apr 2018
DOIs	https://doi.org/10.2337/db17-1164
Publication status	Published - Jul 2018

ASJC Scopus subject areas

Internal Medicine
Endocrinology, Diabetes and Metabolism

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.2337/db17-1164

Author Accepted Manuscript
This is an author-created, uncopyedited electronic version of an article accepted for publication in Diabetes. The American Diabetes Association (ADA), publisher of Diabetes, is not responsible for any errors or omissions in this version of the manuscript or any version derived from it by third parties. The definitive publisher-authenticated version will be available in a future issue of Diabetes in print and online at http:// diabetes.diabetesjournals.org.
Accepted author manuscript, 893 KB

Cite this

Rotroff, D. M., Yee, S. W., Zhou, K., Marvel, S. W., Shah, H. S., Jack, J. R., Havener, T. M., Hedderson, M. M., Kubo, M., Herman, M. A., Gao, H., Mychaleckyi, J. C., McLeod, H. L., Doria, A., Giacomini, K. M., Pearson, E. R., Wagner, M. J., Buse, J. B., Motsinger-Reif, A. A., & MetGen Investigators and the 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

@article{4a255baab91542e9a513a64dc20d01b3,

title = "Genetic Variants in CPA6 and PRPF31 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 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.",

author = "Rotroff, {Daniel M.} and Yee, {Sook Wah} and Kaixin Zhou and Marvel, {Skylar W.} and Shah, {Hetal S.} and Jack, {John R.} and Havener, {Tammy M.} and Hedderson, {Monique M.} and Michiaki Kubo and Herman, {Mark A.} and He Gao and Mychaleckyi, {Josyf C.} and McLeod, {Howard L.} and Alessandro Doria and Giacomini, {Kathleen M.} and Pearson, {Ewan R.} and Wagner, {Michael J.} and Buse, {John B.} and Motsinger-Reif, {Alison A.} and {MetGen Investigators and the ACCORD/ACCORDion Investigators}",

note = "This research was supported by an NHLBI grant to the University of North Carolina at Chapel Hill (5R01HL110380-04) and R01 HL110400 to the Joslin Diabetes Center and the University of Virginia. S.W.Y and K.M.G. were supported by GM61390 and GM117163. E.R.P holds a Wellcome Trust Investigator Award (102820/Z/13/Z). ",

year = "2018",

month = jul,

doi = "10.2337/db17-1164",

language = "English",

volume = "67",

pages = "1428--1440",

journal = "Diabetes",

issn = "0012-1797",

publisher = "American Diabetes Association Inc.",

number = "7",

}

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 and the 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, vol. 67, no. 7, pp. 1428-1440. https://doi.org/10.2337/db17-1164

TY - JOUR

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 - McLeod, Howard L.

AU - Doria, Alessandro

AU - Giacomini, Kathleen M.

AU - Pearson, Ewan R.

AU - Wagner, Michael J.

AU - Buse, John B.

AU - Motsinger-Reif, Alison A.

AU - MetGen Investigators and the ACCORD/ACCORDion Investigators

N1 - This research was supported by an NHLBI grant to the University of North Carolina at Chapel Hill (5R01HL110380-04) and R01 HL110400 to the Joslin Diabetes Center and the University of Virginia. S.W.Y and K.M.G. were supported by GM61390 and GM117163. E.R.P holds a Wellcome Trust Investigator Award (102820/Z/13/Z).

PY - 2018/7

Y1 - 2018/7

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 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85048416785&partnerID=8YFLogxK

U2 - 10.2337/db17-1164

DO - 10.2337/db17-1164

M3 - Article

C2 - 29650774

SN - 0012-1797

VL - 67

SP - 1428

EP - 1440

JO - Diabetes

JF - Diabetes

IS - 7

ER -

Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)

Cite this

Genetic Variants in CPA6 and PRPF31 are Associated with Variation in Response to Metformin in Individuals with Type 2 Diabetes

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Projects

Stratified Medicine in Type 2 Diabetes: Insights from the Study of Drug Response (New Investigator Award)

Cite this