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

Medientyp: E-Artikel

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

Beteiligte: 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.; Bray, George A.; [...]

Erschienen: American Diabetes Association, 2023

Sprache: Englisch

DOI: 10.2337/db22-0702

ISSN: 0012-1797

Schlagwörter: Endocrinology, Diabetes and Metabolism ; Internal Medicine

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Beschreibung: 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 &lt; 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) &lt; 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.

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