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Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns, Which Associate With Future Diabetic Complications

Schrader, Silja LU ; Perfilyev, Alexander LU orcid ; Ahlqvist, Emma LU ; Groop, Leif LU ; Vaag, Allan LU ; Martinell, Mats ; García-Calzón, Sonia LU and Ling, Charlotte LU orcid (2022) In Diabetes Care 45(7). p.1621-1630
Abstract

BACKGROUND: Type 2 diabetes (T2D) was recently reclassified into severe insulin deficient diabetes (SIDD), severe insulin resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications.

RESEARCH DESIGN AND METHODS: Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and... (More)

BACKGROUND: Type 2 diabetes (T2D) was recently reclassified into severe insulin deficient diabetes (SIDD), severe insulin resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications.

RESEARCH DESIGN AND METHODS: Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications.

RESULTS: We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P < 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P < 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P < 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue.

CONCLUSIONS: We identified differential epigenetic patterns between T2D subgroups, which associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ANDIS, diabetes
in
Diabetes Care
volume
45
issue
7
pages
10 pages
publisher
American Diabetes Association
external identifiers
  • scopus:85134361207
  • pmid:35607770
ISSN
1935-5548
DOI
10.2337/dc21-2489
language
English
LU publication?
yes
additional info
© 2022 by the American Diabetes Association.
id
a2f5c88c-f041-40f9-8fe6-3b7e1468ec20
date added to LUP
2022-06-01 10:29:46
date last changed
2024-04-18 13:20:47
@article{a2f5c88c-f041-40f9-8fe6-3b7e1468ec20,
  abstract     = {{<p>BACKGROUND: Type 2 diabetes (T2D) was recently reclassified into severe insulin deficient diabetes (SIDD), severe insulin resistant diabetes (SIRD), mild obesity-related diabetes (MOD), and mild age-related diabetes (MARD), which have different risk of complications. We explored whether DNA methylation differs between these subgroups and whether subgroup-unique methylation risk scores (MRSs) predict diabetic complications.</p><p>RESEARCH DESIGN AND METHODS: Genome-wide DNA methylation was analyzed in blood from subjects with newly diagnosed T2D in discovery and replication cohorts. Subgroup-unique MRSs were built, including top subgroup-unique DNA methylation sites. Regression models examined whether MRSs associated with subgroups and future complications.</p><p>RESULTS: We found epigenetic differences between the T2D subgroups. Subgroup-unique MRSs were significantly different in those patients allocated to each respective subgroup compared with the combined group of all other subgroups. These associations were validated in an independent replication cohort, showing that subgroup-unique MRSs associate with individual subgroups (odds ratios 1.6-6.1 per 1-SD increase, P &lt; 0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (hazard ratio [HR] 0.65, P = 0.001) and renal (HR 0.50, P &lt; 0.001) disease, whereas higher SIRD-MRS and MARD-MRS were associated with an increased risk of these complications (HR 1.4-1.9 per 1-SD increase, P &lt; 0.01). Of 95 methylation sites included in subgroup-unique MRSs, 39 were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in the blood of 18 subgroup-unique sites mirrors epigenetic patterns in tissues relevant for T2D, muscle and adipose tissue.</p><p>CONCLUSIONS: We identified differential epigenetic patterns between T2D subgroups, which associated with future diabetic complications. These data support a reclassification of diabetes and the need for precision medicine in T2D subgroups.</p>}},
  author       = {{Schrader, Silja and Perfilyev, Alexander and Ahlqvist, Emma and Groop, Leif and Vaag, Allan and Martinell, Mats and García-Calzón, Sonia and Ling, Charlotte}},
  issn         = {{1935-5548}},
  keywords     = {{ANDIS; diabetes}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{7}},
  pages        = {{1621--1630}},
  publisher    = {{American Diabetes Association}},
  series       = {{Diabetes Care}},
  title        = {{Novel Subgroups of Type 2 Diabetes Display Different Epigenetic Patterns, Which Associate With Future Diabetic Complications}},
  url          = {{http://dx.doi.org/10.2337/dc21-2489}},
  doi          = {{10.2337/dc21-2489}},
  volume       = {{45}},
  year         = {{2022}},
}