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

Josephine H. Li, James A. Perry, Kathleen A. Jablonski, Shylaja Srinivasan, Ling Chen, Jennifer N. Todd, Maegan Harden, Josep M. Mercader, Qing Pan, Adem Y. Dawed, Sook Wah Yee, Ewan R. Pearson, Kathleen M. Giacomini, Ayush Giri, Adriana M. Hung, Shujie Xiao, L. Keoki Williams, Paul W. Franks, Robert L. Hanson, Steven E. KahnWilliam C. Knowler, Toni I. Pollin, Jose C. Florez (Lead / Corresponding author),

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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 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.

Original languageEnglish
Pages (from-to)1161–1172
Number of pages12
JournalDiabetes
Volume72
Issue number8
Early online date16 Dec 2022
DOIs
Publication statusPublished - Aug 2023

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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