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Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)

Li, Josephine H. ; Perry, James A. ; Jablonski, Kathleen A. ; Srinivasan, Shylaja ; Chen, Ling ; Todd, Jennifer N. ; Harden, Maegan ; Mercader, Josep M. ; Pan, Qing and Dawed, Adem Y. , et al. (2023) In Diabetes 72(8). p.1161-1172
Abstract

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been repli-cated in the Diabetes Prevention Program (DPP). To as-sess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal compo-nents. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes inci-dence. We identified four genome-wide... (More)

Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been repli-cated in the Diabetes Prevention Program (DPP). To as-sess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal compo-nents. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes inci-dence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 1029). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, b = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10212). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, b = 27.55 [95% CI 29.88, 25.22]; P = 3.2 × 10210) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 1024 ]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.

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Contribution to journal
publication status
published
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Diabetes
volume
72
issue
8
pages
12 pages
publisher
American Diabetes Association Inc.
external identifiers
  • scopus:85151776838
  • pmid:36525397
ISSN
0012-1797
DOI
10.2337/db22-0702
language
English
LU publication?
yes
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Funding Information: Marketing, Slimast Foods Co., and Quaker Oats Co. McKesson BioServices Corp., Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. This work was also supported by the NIDDK grant R01DK072041 to J.C.F. and K.A.J. J.H.L. received individual support from National Institutes of Health grant T32DK007028. S.S. was funded by National Institutes of Health grant K23DK120932. A.G. was supported by NIDDK grant 1K01DK120631 when this work was performed. S.E.K. was supported in part by the Department of Veterans Affairs. Funding Information: Research reported in this publication was supported by the NIDDK of the National Institutes of Health under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400, by providing funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart, Lung, and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Pro-gram, and the Indian Health Service. The General Clinical Research Center Pro-gram, the National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP/DPPOS also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health-O-Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, LLC, Merck and Co., Nike Sports Marketing, Slimast Foods Co., and Quaker Oats Co. McKesson BioServices Corp.Matthews Media Group, Inc., and the Henry M. Jackson Foundation provided support services under subcontract with the Coordinating Center. This work was also supported by the NIDDK grant R01DK072041 to J.C.F. and K.A.J. J.H.L. received individual support from National Institutes of Health grant T32DK007028. S.S. was funded by National Institutes of Health grant K23DK120932. A.G. was supported by NIDDK grant 1K01DK120631 when this work was performed. S.E.K. was supported in part by the Department of Veterans Affairs. The sponsor of this study, the NIH/NIDDK, was represented on the steering committee and played a part in study design, how the study was done, and publication. All authors in the writing group had access to aldata. The opinions expressed are those of the study group and do nonecessarily reflect the views of the funding agencies or the National Institutes of Health. Funding Information: Acknowledgments. The DPP Research Group gratefully acknowledges the commitment and dedication of the participants of the DPP and DPP Outcomes Study (DPPOS). Funding. Research reported in this publication was supported by the NIDDK of the National Institutes of Health under award numbers U01 DK048489, U01 DK048339, U01 DK048377, U01 DK048349, U01 DK048381, U01 DK048468, U01 DK048434, U01 DK048485, U01 DK048375, U01 DK048514, U01 DK048437, U01 DK048413, U01 DK048411, U01 DK048406, U01 DK048380, U01 DK048397, U01 DK048412, U01 DK048404, U01 DK048387, U01 DK048407, U01 DK048443, and U01 DK048400, by providing funding during DPP and DPPOS to the clinical centers and the Coordinating Center for the design and conduct of the study, and collection, management, analysis, and interpretation of the data. Funding was also provided by the National Institute of Child Health and Human Development, the National Institute on Aging, the National Eye Institute, the National Heart, Lung, and Blood Institute, the National Cancer Institute, the Office of Research on Women’s Health, the National Institute on Minority Health and Health Disparities, the Centers for Disease Control and Prevention, and the American Diabetes Association. The Southwestern American Indian Centers were supported directly by the NIDDK, including its Intramural Research Program, and the Indian Health Service. The General Clinical Research Center Program, the National Center for Research Resources, and the Department of Veterans Affairs supported data collection at many of the clinical centers. Merck KGaA provided medication for DPPOS. DPP/DPPOS also received donated materials, equipment, or medicines for concomitant conditions from Bristol-Myers Squibb, Parke-Davis, and LifeScan Inc., Health-O-Meter, Hoechst Marion Roussel, Inc., Merck-Medco Managed Care, LLC, Merck and Co., Nike Sports Publisher Copyright: © 2023 by the American Diabetes Association.
id
9c6b3577-af2a-4937-9e0d-3125bd080e0e
date added to LUP
2024-01-12 14:50:55
date last changed
2024-04-13 08:17:40
@article{9c6b3577-af2a-4937-9e0d-3125bd080e0e,
  abstract     = {{<p>Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been repli-cated in the Diabetes Prevention Program (DPP). To as-sess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal compo-nents. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes inci-dence. We identified four genome-wide significant variants after correcting for correlated traits (P &lt; 9 × 10<sup>29</sup>). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF]<sub>AFR</sub> = 0.07; MAF<sub>EUR</sub> = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, b = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10<sup>212</sup>). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, b = 27.55 [95% CI 29.88, 25.22]; P = 3.2 × 10<sup>210</sup>) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) &lt; 1.0 × 10<sup>24</sup> ]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.</p>}},
  author       = {{Li, Josephine H. and Perry, James A. and Jablonski, Kathleen A. and Srinivasan, Shylaja and Chen, Ling and Todd, Jennifer N. and Harden, Maegan and Mercader, Josep M. and Pan, Qing and Dawed, Adem Y. and Yee, Sook Wah and Pearson, Ewan R. and Giacomini, Kathleen M. and Giri, Ayush and Hung, Adriana M. and Xiao, Shujie and Williams, L. Keoki and Franks, Paul W. and Hanson, Robert L. and Kahn, Steven E. and Knowler, William C. and Pollin, Toni I. and Florez, Jose C.}},
  issn         = {{0012-1797}},
  language     = {{eng}},
  number       = {{8}},
  pages        = {{1161--1172}},
  publisher    = {{American Diabetes Association Inc.}},
  series       = {{Diabetes}},
  title        = {{Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)}},
  url          = {{http://dx.doi.org/10.2337/db22-0702}},
  doi          = {{10.2337/db22-0702}},
  volume       = {{72}},
  year         = {{2023}},
}