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

Authors

Josephine H Li
James A Perry
Kathleen A Jablonski
Shylaja Srinivasan
Ling Chen
Jennifer N Todd
Maegan Harden
Josep M Mercader
Qing Pan
Adem Y Dawed
Sook Wah Yee
Ewan R Pearson
Kathleen M Giacomini
Ayush Giri
Adriana M Hung
Shujie Xiao
L Keoki Williams
Paul W Franks
Robert L Hanson
Steven E Kahn
William C Knowler
Toni I Pollin
Jose C Florez
Diabetes Prevention Program Research Group

Language

English

Publication Date

8-1-2023

Journal

Diabetes

DOI

10.2337/db22-0702

PMID

36525397

PMCID

PMC10382652

PubMedCentral® Posted Date

8-1-2023

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Humans, Metformin, Diabetes Mellitus, Type 2, Genome-Wide Association Study, Prediabetic State, Genetic Variation, Polymorphism, Single Nucleotide

Published Open-Access

yes

Recommended Citation

Li, Josephine H; Perry, James A; Jablonski, Kathleen A; et al., "Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)" (2023). Children’s Nutrition Research Center Staff Publications. 209.
https://digitalcommons.library.tmc.edu/staff_pub/209