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Novel subgroups of type 2 diabetes display different epigenetic patterns which associate with future diabetic complications

posted on 24.05.2022, 00:10 authored by Silja Schrader, Alexander Perfilyev, Emma Ahlqvist, Leif Groop, Allan Vaag, Mats Martinell, Sonia García-Calzón, Charlotte Ling

Objective: 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 if subgroup-unique methylation risk scores (MRSs) predict diabetic complications. 

Methods: Genome-wide DNA methylation was analysed in blood from newly diagnosed T2D subjects 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 to 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 (OR 1.6-6.1 per 1SD increase, p<0.01). Subgroup-unique MRSs were also associated with future complications. Higher MOD-MRS was associated with lower risk of cardiovascular (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 increased risk of these complications (HR 1.4-1.9 per 1SD increase, p<0.01). 39 of 95 methylation sites included in subgroup-unique MRSs were annotated to genes previously linked to diabetes-related traits, including TXNIP and ELOVL2. Methylation in blood of 18 subgroup-unique sites mirror 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. 


The work was supported by grants from the EFSD, Swedish Heart Lung Foundation, the Novo Nordisk foundation, The Swedish Research Council, Region Skåne (ALF), ERC-Co Grant (PAINTBOX, No 725840), H2020-Marie Skłodowska-Curie grant agreement No 706081 (EpiHope), Exodiab, Swedish Foundation for Strategic Research for IRC15-0067 and Swedish Diabetes Foundation. The funders had no role in design and conduct of the study, collection, management, analysis, and interpretation of the data, preparation, review, and approval of the manuscript, or the decision to submit the manuscript for publication.