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

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. 8; pp. 1161 - 1172
• Main Authors: 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, Florez, Jose C
• Format: Journal Article
• Language: English
• Published: United States American Diabetes Association 01.08.2023
• Subjects: Alleles; Antidiabetics; Clinical Medicine; Diabetes; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - prevention & control; Endocrinology and Diabetes; Endokrinologi och diabetes; Gene frequency; Genetic diversity; Genetic Variation; Genetics/Genomes/Proteomics/Metabolomics; Genome-wide association studies; Genome-Wide Association Study; Genomes; Hemoglobin; Humans; Klinisk medicin; Medical and Health Sciences; Medicin och hälsovetenskap; Metformin; Metformin - therapeutic use; Polymorphism, Single Nucleotide; Prediabetic State - drug therapy; Prevention programs
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db22-0702

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 × 10-9). In the MET arm, rs144322333 near ENOSF1 (minor allele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of 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 (kilograms) (per G allele, β = -7.55 [95% CI -9.88, -5.22]; P = 3.2 × 10-10) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 10-4]. 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.