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  • Li, Josephine H.Massachusetts General Hospital,Broad Institute,Harvard Medical School (author)

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

  • Article/chapterEnglish2023

Publisher, publication year, extent ...

  • 2022-12-16
  • American Diabetes Association,2023
  • 12 s.

Numbers

  • LIBRIS-ID:oai:lup.lub.lu.se:9c6b3577-af2a-4937-9e0d-3125bd080e0e
  • https://lup.lub.lu.se/record/9c6b3577-af2a-4937-9e0d-3125bd080e0eURI
  • https://doi.org/10.2337/db22-0702DOI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:art swepub-publicationtype
  • Subject category:ref swepub-contenttype

Notes

  • 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 and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Perry, James A.University of Maryland School of Medicine (author)
  • Jablonski, Kathleen A.George Washington University (author)
  • Srinivasan, ShylajaUniversity of California, San Francisco (author)
  • Chen, LingMassachusetts General Hospital,Broad Institute (author)
  • Todd, Jennifer N.Boston Children's Hospital,Broad Institute,Massachusetts General Hospital (author)
  • Harden, MaeganBroad Institute (author)
  • Mercader, Josep M.Broad Institute,Massachusetts General Hospital,Harvard Medical School (author)
  • Pan, QingGeorge Washington University (author)
  • Dawed, Adem Y.University of Dundee (author)
  • Yee, Sook WahUniversity of California, San Francisco (author)
  • Pearson, Ewan R.University of Dundee (author)
  • Giacomini, Kathleen M.University of California, San Francisco (author)
  • Giri, AyushVanderbilt University Medical Center (author)
  • Hung, Adriana M.Vanderbilt University Medical Center (author)
  • Xiao, ShujieHenry Ford Health System (author)
  • Williams, L. KeokiHenry Ford Health System (author)
  • Franks, Paul W.Lund University,Lunds universitet,Genetisk och molekylär epidemiologi,Forskargrupper vid Lunds universitet,Genetic and Molecular Epidemiology,Lund University Research Groups(Swepub:lu)med-plf (author)
  • Hanson, Robert L.National Institute of Diabetes and Digestive and Kidney Diseases (author)
  • Kahn, Steven E.Washington University School of Medicine (author)
  • Knowler, William C.National Institute of Diabetes and Digestive and Kidney Diseases (author)
  • Pollin, Toni I.University of Maryland School of Medicine (author)
  • Florez, Jose C.Harvard Medical School,Broad Institute,Massachusetts General Hospital (author)
  • Massachusetts General HospitalBroad Institute (creator_code:org_t)

Related titles

  • In:Diabetes: American Diabetes Association72:8, s. 1161-11720012-17971939-327X

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