학술논문
Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP).
Document Type
Academic Journal
Author
Li JH; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.; Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.; Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.; Department of Medicine, Harvard Medical School, Boston, MA.; Perry JA; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.; Jablonski KA; Department of Epidemiology and Biostatistics, George Washington University Biostatistics Center, Washington, DC.; Srinivasan S; Division of Pediatric Endocrinology and Diabetes, Department of Pediatrics, University of California, San Francisco, San Francisco, CA.; Chen L; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.; Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.; Todd JN; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.; Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.; Division of Endocrinology, Department of Pediatrics, Boston Children's Hospital, Boston, MA.; Harden M; Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.; Mercader JM; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.; Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.; Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.; Department of Medicine, Harvard Medical School, Boston, MA.; Pan Q; Department of Epidemiology and Biostatistics, George Washington University Biostatistics Center, Washington, DC.; Dawed AY; Division of Population Health and Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, U.K.; Yee SW; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA.; Pearson ER; Division of Population Health and Genomics, Ninewells Hospital and School of Medicine, University of Dundee, Dundee, U.K.; Giacomini KM; Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA.; Giri A; Division of Quantitative Sciences, Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, TN.; Hung AM; Division of Nephrology and Hypertension, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN.; Xiao S; Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI.; Williams LK; Center for Individualized and Genomic Medicine Research, Department of Internal Medicine, Henry Ford Health System, Detroit, MI.; Franks PW; Genetic and Molecular Epidemiology Unit, Lund University Diabetes Centre, Lund University, Malmö, Sweden.; Hanson RL; Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.; Kahn SE; Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, VA Puget Sound Health Care System and University of Washington, Seattle.; Knowler WC; Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, Phoenix, AZ.; Pollin TI; Department of Medicine, University of Maryland School of Medicine, Baltimore, MD.; Florez JC; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA.; Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA.; Programs in Metabolism and Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA.; Department of Medicine, Harvard Medical School, Boston, MA.
Source
Publisher: American Diabetes Association Country of Publication: United States NLM ID: 0372763 Publication Model: Print Cited Medium: Internet ISSN: 1939-327X (Electronic) Linking ISSN: 00121797 NLM ISO Abbreviation: Diabetes Subsets: MEDLINE
Subject
Language
English
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.
(© 2023 by the American Diabetes Association.)
(© 2023 by the American Diabetes Association.)