Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP).
Publication/Presentation Date
8-1-2023
Abstract
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.
Volume
72
Issue
8
First Page
1161
Last Page
1172
ISSN
1939-327X
Published In/Presented At
Li, J. H., Perry, J. A., Jablonski, K. A., Srinivasan, S., Chen, L., Todd, J. N., Harden, M., Mercader, J. M., Pan, Q., Dawed, A. Y., Yee, S. W., Pearson, E. R., Giacomini, K. M., Giri, A., Hung, A. M., Xiao, S., Williams, L. K., Franks, P. W., Hanson, R. L., Kahn, S. E., … Diabetes Prevention Program Research Group: (2023). Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP). Diabetes, 72(8), 1161–1172. https://doi.org/10.2337/db22-0702
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
36525397
Department(s)
Administration and Leadership
Document Type
Article