| Title: |
Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP). |
| 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; Bray, George A; Gadde, Kishore M; Culbert, Iris W; Chatellier, Annie; Arceneaux, Jennifer; Dragg, Amber; Champagne, Catherine M; Duncan, Crystal; Eberhardt, Barbara; Greenway, Frank; Guillory, Fonda G; Herbert, April A; Jeffirs, Michael L; Kennedy, Betty M; Levy, Erma; Lockett, Monica; Lovejoy, Jennifer C; Morris, Laura H; Melancon, Lee E; Ryan, Donna H; Sanford, Deborah A; Smith, Kenneth G; Smith, Lisa L; St. Amant, Julia A; Tulley, Richard T; Vicknair, Paula C; Williamson, Donald; Zachwieja, Jeffery J; Polonsky, Kenneth S; Tobian, Janet; Ehrmann, David A; Matulik, Margaret J; Temple, Karla A; Clark, Bart; Czech, Kirsten; DeSandre, Catherine; Dotson, Brittnie; Hilbrich, Ruthanne; McNabb, Wylie; Quinn, Michael T; Semenske, Ann R; Caro, Jose F; Furlong, Kevin; Goldstein, Barry J; Watson, Pamela G; Smith, Kellie A; Mendoza, Jewel; Wildman, Wendi; Simmons, Marsha; Jensen, Genine; Liberoni, Renee; Spandorfer, John; Pepe, Constance; Donahue, Richard P; Goldberg, Ronald B; Prineas, Ronald; Rowe, Patricia; Giannella, Anna; Calles, Jeanette; Sanguily, Juliet; Cassanova-Romero, Paul; Castillo-Florez, Sumaya; Florez, Hermes J; Garg, Rajesh; Kirby, Lascelles; Lara, Olga; Larreal, Carmen; McLymont, Valerie; Mendez, Jadell; Perry, Arlette; Saab, Patrice; Veciana, Bertha; Haffner, Steven M; Hazuda, Helen P; Montez, Maria G; Isaac, Juan; Hattaway, Kathy |
| Source: |
Diabetes, vol 72, iss 8 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2023 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
3214 Pharmacology and Pharmaceutical Sciences (for-2020); 32 Biomedical and Clinical Sciences (for-2020); Prevention (rcdc); Nutrition (rcdc); Human Genome (rcdc); Genetics (rcdc); Diabetes (rcdc); Minority Health (rcdc); Metabolic and endocrine (hrcs-hc); Humans (mesh); Metformin (mesh); Diabetes Mellitus; Type 2 (mesh); Genome-Wide Association Study (mesh); Prediabetic State (mesh); Genetic Variation (mesh); Polymorphism; Single Nucleotide (mesh); Diabetes Prevention Program Research Group; 11 Medical and Health Sciences (for); Endocrinology & Metabolism (science-metrix) |
| Time: |
1161 - 1172 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt2tm8285d; https://escholarship.org/uc/item/2tm8285d; https://escholarship.org/content/qt2tm8285d/qt2tm8285d.pdf |
| DOI: |
10.2337/db22-0702 |
| Availability: |
https://escholarship.org/uc/item/2tm8285d; https://escholarship.org/content/qt2tm8285d/qt2tm8285d.pdf; https://doi.org/10.2337/db22-0702 |
| Rights: |
public |
| Accession Number: |
edsbas.40B6CAED |
| Database: |
BASE |