Identification of Genetic Variation Influencing Metformin Response in a Multi-Ancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
Li JH, Perry JA, Jablonski KA, Srinivasan S, Chen L, Todd JN, Harden M, Mercader JM, Pan Q, Dawed AY, Yee SW, Pearson ER, Giacomini KM, Giri A, Hung AM, Xiao S, Williams LK, Franks PW, Hanson RL, Kahn SE, Knowler WC, Pollin TI, and Florez JC. Identification of Genetic Variation Influencing Metformin Response in a Multi-Ancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP). Diabetes 2022.
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.
ePub ahead of print