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Alexander Perfilyev

Assistant researcher

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Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes

Author

  • Sonia García-Calzón
  • Alexander Perfilyev
  • Mats Martinell
  • Monta Ustinova
  • Sebastian Kalamajski
  • Paul W. Franks
  • Karl Bacos
  • Ilze Elbere
  • Jussi Pihlajamäki
  • Petr Volkov
  • Allan Vaag
  • Leif Groop
  • Marlena Maziarz
  • Janis Klovins
  • Emma Ahlqvist
  • Charlotte Ling

Summary, in English

Metformin is the first-line pharmacotherapy for managing type 2 diabetes (T2D). However, many patients with T2D do not respond to or tolerate metformin well. Currently, there are no phenotypes that successfully predict glycemic response to, or tolerance of, metformin. We explored whether blood-based epigenetic markers could discriminate metformin response and tolerance by analyzing genome-wide DNA methylation in drug-naïve patients with T2D at the time of their diagnosis. DNA methylation of 11 and 4 sites differed between glycemic responders/nonresponders and metformin-tolerant/intolerant patients, respectively, in discovery and replication cohorts. Greater methylation at these sites associated with a higher risk of not responding to or not tolerating metformin with odds ratios between 1.43 and 3.09 per 1-SD methylation increase. Methylation risk scores (MRSs) of the 11 identified sites differed between glycemic responders and nonresponders with areas under the curve (AUCs) of 0.80 to 0.98. MRSs of the 4 sites associated with future metformin intolerance generated AUCs of 0.85 to 0.93. Some of these blood-based methylation markers mirrored the epigenetic pattern in adipose tissue, a key tissue in diabetes pathogenesis, and genes to which these markers were annotated to had biological functions in hepatocytes that altered metformin- related phenotypes. Overall, we could discriminate between glycemic responders/nonresponders and participants tolerant/ intolerant to metformin at diagnosis by measuring blood-based epigenetic markers in drug-naïve patients with T2D. This epigenetics-based tool may be further developed to help patients with T2D receive optimal therapy.

Department/s

  • Diabetes - Epigenetics
  • EXODIAB: Excellence of Diabetes Research in Sweden
  • Genetic and Molecular Epidemiology
  • EpiHealth: Epidemiology for Health
  • Diabetic Complications
  • Genomics, Diabetes and Endocrinology

Publishing year

2020

Language

English

Publication/Series

Science Translational Medicine

Volume

12

Issue

561

Document type

Journal article

Publisher

American Association for the Advancement of Science (AAAS)

Topic

  • Endocrinology and Diabetes

Status

Published

Research group

  • Diabetes - Epigenetics
  • Genetic and Molecular Epidemiology
  • Diabetic Complications
  • Genomics, Diabetes and Endocrinology

ISBN/ISSN/Other

  • ISSN: 1946-6234