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Identification of G...
Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
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- Li, Josephine H. (author)
- Broad Institute,Harvard Medical School,Massachusetts General Hospital
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- Perry, James A. (author)
- University of Maryland School of Medicine
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- Jablonski, Kathleen A. (author)
- George Washington University
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- Srinivasan, Shylaja (author)
- University of California, San Francisco
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- Chen, Ling (author)
- Broad Institute,Massachusetts General Hospital
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- Todd, Jennifer N. (author)
- Boston Children's Hospital,Broad Institute,Massachusetts General Hospital
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- Harden, Maegan (author)
- Broad Institute
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- Mercader, Josep M. (author)
- Broad Institute,Harvard Medical School,Massachusetts General Hospital
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- Pan, Qing (author)
- George Washington University
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- Dawed, Adem Y. (author)
- University of Dundee
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- Yee, Sook Wah (author)
- University of California, San Francisco
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- Pearson, Ewan R. (author)
- University of Dundee
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- Giacomini, Kathleen M. (author)
- University of California, San Francisco
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- Giri, Ayush (author)
- Vanderbilt University Medical Center
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- Hung, Adriana M. (author)
- Vanderbilt University Medical Center
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- Xiao, Shujie (author)
- Henry Ford Health System
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- Williams, L. Keoki (author)
- Henry Ford Health System
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- Franks, Paul W. (author)
- Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups
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- Hanson, Robert L. (author)
- National Institute of Diabetes and Digestive and Kidney Diseases
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- Kahn, Steven E. (author)
- Washington University School of Medicine
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- Knowler, William C. (author)
- National Institute of Diabetes and Digestive and Kidney Diseases
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- Pollin, Toni I. (author)
- University of Maryland School of Medicine
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- Florez, Jose C. (author)
- Harvard Medical School,Broad Institute,Massachusetts General Hospital
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(creator_code:org_t)
- 2022-12-16
- 2023
- English 12 s.
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:8, s. 1161-1172
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Abstract
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- Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been repli-cated in the Diabetes Prevention Program (DPP). To as-sess 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 compo-nents. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes inci-dence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 1029). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, b = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10212). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, b = 27.55 [95% CI 29.88, 25.22]; P = 3.2 × 10210) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 1024 ]. 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
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Diabetes
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- By the author/editor
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Li, Josephine H.
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Perry, James A.
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Jablonski, Kathl ...
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Srinivasan, Shyl ...
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Chen, Ling
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Todd, Jennifer N ...
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show more...
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Harden, Maegan
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Mercader, Josep ...
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Pan, Qing
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Dawed, Adem Y.
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Yee, Sook Wah
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Pearson, Ewan R.
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Giacomini, Kathl ...
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Giri, Ayush
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Hung, Adriana M.
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Xiao, Shujie
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Williams, L. Keo ...
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Franks, Paul W.
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Hanson, Robert L ...
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Kahn, Steven E.
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Knowler, William ...
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Pollin, Toni I.
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Florez, Jose C.
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Endocrinology an ...
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Diabetes
- By the university
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Lund University