Identification of Genetic Variation Influencing Metformin Response in a Multiancestry 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 been replicated in the Diabetes Prevention Program (DPP). To assess 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 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 x 10(-9)). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF](AFR) = 0.07; MAF(EUR) = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, & beta; = 0.39 [95% CI 0.28, 0.50]; P = 2.8 x 10(-12)). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, & beta; = -7.55 [95% CI -9.88, -5.22]; P = 3.2 x 10(-10)) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(GxT) < 1.0 x 10(-4)]. 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.