Abstract
Aims/hypothesisEpigenetic 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.MethodsWe 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.ResultsFrom 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/interpretationA 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.
Highlights
Introduction blood samples of100 diabetic and 100 control individuals selected from a Dutch population-based Lifelines study [11]
Our search strategy retrieved 19 epigenomewide association studies (EWASs) investigating DNA methylation associated with type 2 diabetes or glycaemic traits (Fig. 1), including 16 studies focusing on type 2 diabetes as outcome (Table 1) and four studies focusing on glycaemic traits (Table 2), with one study listed twice [25]
We found no significant association between the level of HbA1c and DNA methylation at any of the ten CpG sites (CpGs) identified in adipose tissue
Summary
Introduction blood samples of100 diabetic and 100 control individuals selected from a Dutch population-based Lifelines study [11]. Type 2 diabetes mellitus is a complex metabolic disease, of which the prevalence worldwide is growing rapidly. Globally 415 million people are estimated to have type 2 diabetes [1]. Hallmarks of type 2 diabetes include chronically elevated blood glucose levels due to decreased insulin secretion from pancreatic beta cells and insulin resistance in different tissues [2]. Genome-wide association studies (GWASs) have identified at least 75 loci associated with type 2 diabetes [6]. These genetic variants explain only 10–15% of disease heritability, suggesting a major role for environmental and lifestyle factors [6, 7]
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