Identification of Genetic Variation Influencing Metformin Response in a Multi-Ancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not replicated in the Diabetes Prevention Program (DPP). To assess pharmacogenetic interactions in pre-diabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in metformin (MET, n=876) and placebo (PBO, n=887) arms. Multiple linear regression assessed association with one-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal components. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes incidence. We identified four genome-wide significant variants after correcting for correlated traits (p<9×10-9). In MET, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR=0.07, MAFEUR=0.002) was associated with an increase in % glycated hemoglobin (per minor allele β=0.39 [95% CI 0.28, 0.50], p=2.8×10-12). Rs145591055 near OMSR (MAF=0.10 in American Indians), was associated with weight loss (kg) (per G allele β=-7.55 [95% CI -9.88, -5.22], p=3.2×10-10) in MET. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants (p(G×T)<1.0×10-4). Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in pre-diabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.
Li, Josephine H.; Perry, James A.; Jablonski, Kathleen A.; Srinivasan, Shylaja; Chen, Ling; Todd, Jennifer N.; Harden, Maegan; Mercader, Josep M.; Pan, Qing; Dawed, Adem Y.; Yee, Sook Wah; Pearson, Ewan R.; Giacomini, Kathleen M.; Giri, Ayush; Hung, Adriana M.; Xiao, Shujie; Williams, L Keoki; Franks, Paul W.; Hanson, Robert L.; Kahn, Steven E.; Knowler, William C.; Pollin, Toni I.; and Florez, Jose C., "Identification of Genetic Variation Influencing Metformin Response in a Multi-Ancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)" (2022). GW Authored Works. Paper 2086.