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

García-Calzón, Sonia LU ; Perfilyev, Alexander LU orcid ; Martinell, Mats ; Ustinova, Monta ; Kalamajski, Sebastian LU ; Franks, Paul W. LU ; Bacos, Karl LU orcid ; Elbere, Ilze ; Pihlajamäki, Jussi and Volkov, Petr LU , et al. (2020) In Science Translational Medicine 12(561).
Abstract

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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ANDIS, diabetes, diabetics
in
Science Translational Medicine
volume
12
issue
561
article number
eaaz1803
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:85091129880
  • pmid:32938793
ISSN
1946-6234
DOI
10.1126/SCITRANSLMED.AAZ1803
language
English
LU publication?
yes
id
42d5c223-4095-4445-81be-709626559adb
date added to LUP
2020-10-26 15:24:37
date last changed
2024-06-14 00:59:04
@article{42d5c223-4095-4445-81be-709626559adb,
  abstract     = {{<p>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. </p>}},
  author       = {{García-Calzón, Sonia and Perfilyev, Alexander and Martinell, Mats and Ustinova, Monta and Kalamajski, Sebastian and Franks, Paul W. and Bacos, Karl and Elbere, Ilze and Pihlajamäki, Jussi and Volkov, Petr and Vaag, Allan and Groop, Leif and Maziarz, Marlena and Klovins, Janis and Ahlqvist, Emma and Ling, Charlotte}},
  issn         = {{1946-6234}},
  keywords     = {{ANDIS; diabetes; diabetics}},
  language     = {{eng}},
  number       = {{561}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Translational Medicine}},
  title        = {{Epigenetic markers associated with metformin response and intolerance in drug-naïve patients with type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1126/SCITRANSLMED.AAZ1803}},
  doi          = {{10.1126/SCITRANSLMED.AAZ1803}},
  volume       = {{12}},
  year         = {{2020}},
}