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

TY - JOUR

T1 - Identification of Genetic Variation Influencing Metformin Response in a Multi-Ancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)

AU - Li, Josephine H.

AU - Perry, James A.

AU - Jablonski, Kathleen A.

AU - Srinivasan, Shylaja

AU - Chen, Ling

AU - Todd, Jennifer N.

AU - Harden, Maegan

AU - Mercader, Josep M.

AU - Pan, Qing

AU - Dawed, Adem Y.

AU - Yee, Sook Wah

AU - Pearson, Ewan R.

AU - Giacomini, Kathleen M.

AU - Giri, Ayush

AU - Hung, Adriana M.

AU - Xiao, Shujie

AU - Williams, L. Keoki

AU - Franks, Paul W.

AU - Hanson, Robert L.

AU - Kahn, Steven E.

AU - Knowler, William C.

AU - Pollin, Toni I.

AU - Florez, Jose C.

N1 - 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. Copyright: © 2023 by the American Diabetes Association.

PY - 2023/8

Y1 - 2023/8

N2 - 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 × 10 29). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF] AFR = 0.07; MAF EUR = 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 × 10 212). 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 × 10 210) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 10 24 ]. 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.

AB - 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 × 10 29). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF] AFR = 0.07; MAF EUR = 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 × 10 212). 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 × 10 210) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 10 24 ]. 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.

UR - https://www.scopus.com/pages/publications/85151776838

U2 - 10.2337/db22-0702

DO - 10.2337/db22-0702

M3 - Article

C2 - 36525397

SN - 0012-1797

VL - 72

SP - 1161

EP - 1172

JO - Diabetes

JF - Diabetes

IS - 8

ER -