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Review
. 2018 Feb;61(2):354-368.
doi: 10.1007/s00125-017-4497-7. Epub 2017 Nov 21.

DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA1c levels: a systematic review and replication in a case-control sample of the Lifelines study

Eliza Walaszczyk  1   2 , Mirjam Luijten  2 , Annemieke M W Spijkerman  3 , Marc J Bonder  4 , Helen L Lutgers  5 , Harold Snieder  1 , Bruce H R Wolffenbuttel  5 , Jana V van Vliet-Ostaptchouk  6
Affiliations
Review

DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA1c levels: a systematic review and replication in a case-control sample of the Lifelines study

Eliza Walaszczyk et al. Diabetologia. 2018 Feb.

Abstract

Aims/hypothesis: Epigenetic mechanisms may play an important role in the aetiology of type 2 diabetes. Recent epigenome-wide association studies (EWASs) identified several DNA methylation markers associated with type 2 diabetes, fasting glucose and HbA1c levels. Here we present a systematic review of these studies and attempt to replicate the CpG sites (CpGs) with the most significant associations from these EWASs in a case-control sample of the Lifelines study.

Methods: We performed a systematic literature search in PubMed and EMBASE for EWASs to test the association between DNA methylation and type 2 diabetes and/or glycaemic traits and reviewed the search results. For replication purposes we selected 100 unique CpGs identified in peripheral blood, pancreas, adipose tissue and liver from 15 EWASs, using study-specific Bonferroni-corrected significance thresholds. Methylation data (Illumina 450K array) in whole blood from 100 type 2 diabetic individuals and 100 control individuals from the Lifelines study were available. Multivariate linear models were used to examine the associations of the specific CpGs with type 2 diabetes and glycaemic traits.

Results: From the 52 CpGs identified in blood and selected for replication, 15 CpGs showed nominally significant associations with type 2 diabetes in the Lifelines sample (p < 0.05). The results for five CpGs (in ABCG1, LOXL2, TXNIP, SLC1A5 and SREBF1) remained significant after a stringent multiple-testing correction (changes in methylation from -3% up to 3.6%, p < 0.0009). All associations were directionally consistent with the original EWAS results. None of the selected CpGs from the tissue-specific EWASs were replicated in our methylation data from whole blood. We were also unable to replicate any of the CpGs associated with HbA1c levels in the healthy control individuals of our sample, while two CpGs (in ABCG1 and CCDC57) for fasting glucose were replicated at a nominal significance level (p < 0.05).

Conclusions/interpretation: A number of differentially methylated CpGs reported to be associated with type 2 diabetes in the EWAS literature were replicated in blood and show promise for clinical use as disease biomarkers. However, more prospective studies are needed to support the robustness of these findings.

Keywords: DNA methylation; Epigenome-wide association studies; Glucose; Glycated haemoglobin; Systematic review; Type 2 diabetes.

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Conflict of interest statement

Data availability

Data are available upon request from the authors.

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

JVvVO and EW designed and implemented the study and drafted the manuscript. HS, ML and AMWS contributed significantly to study design. EW and MJB analysed the data. JVvVO, HLL and BHRW were involved in data acquisition. EW, JVvVO, ML, AMWS, HS and MJB contributed to the interpretation of the data. ML, AMWS and HS critically reviewed the manuscript for important intellectual content. All authors reviewed and approved the final manuscript. EW and JVvVO are the guarantors of the study.

Figures

Fig. 1
Fig. 1
PRISMA 2009 flow chart of the literature search performed up to 26 April 2017
See this image and copyright information in PMC

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