DNA methylation of blood cells is associated with prevalent type 2 diabetes in a meta-analysis of four European cohorts

Abstract

Background Type 2 diabetes (T2D) is a heterogeneous disease with well-known genetic and environmental risk factors contributing to its prevalence. Epigenetic mechanisms related to changes in DNA methylation (DNAm), may also contribute to T2D risk, but larger studies are required to discover novel markers, and to confirm existing ones. Results We performed a large meta-analysis of individual epigenome-wide association studies (EWAS) of prevalent T2D conducted in four European studies using peripheral blood DNAm. Analysis of differentially methylated regions (DMR) was also undertaken, based on the meta-analysis results. We found three novel CpGs associated with prevalent T2D in Europeans at cg00144180 (HDAC4), cg16765088 (near SYNM) and cg24704287 (near MIR23A) and confirmed three CpGs previously identified (mapping to TXNIP, ABCG1 and CPT1A). We also identified 77 T2D associated DMRs, most of them hypomethylated in T2D cases versus controls. In adjusted regressions among diabetic-free participants in ALSPAC, we found that all six CpGs identified in the meta-EWAS were associated with white cell-types. We estimated that these six CpGs captured 11% of the variation in T2D, which was similar to the variation explained by the model including only the common risk factors of BMI, sex, age and smoking (R2 = 10.6%). Conclusions This study identifies novel loci associated with T2D in Europeans. We also demonstrate associations of the same loci with other traits. Future studies should investigate if our findings are generalizable in non-European populations, and potential roles of these epigenetic markers in T2D etiology or in determining long term consequences of T2D.

Adipose Tissue Epigenetic Profile in Obesity-Related Dysglycemia - A Systematic Review

“…To identify the extent to which the DMRs are specific to AT, on a second stage we then performed a non-systematic search in PubMed for papers describing DNA methylation in WB of subjects with MUHO (39,40,46,61,62,69,(119)(120)(121)(122)(123)(124)(125)(126)(127)(128). 27 genes associating methylation changes above 5% in AT were also found to carry DMRs in WB, with 8 common CpGs, each located in a single gene, showing concordant methylation patterns in WB and AT: hypermethylation in subjects with MUHO at cg14642338 (PAMR1), cg09419670 (PSMD5), cg21053323 (SUMO3) and cg17878506 (TBC1D4); hypomethylation at cg02707176 (PCDHGA1/PCDHGA4), cg20050113 (SLC9A2), cg19693031 (TXNIP) and cg00117018 (ZNF251), with an overall correlation coefficient R 2 = 0.88 (Supplementary Table 8).…”

Connecting the epigenome, metabolome and proteome for a deeper understanding of disease

“…Four of the seven CpG sites (CPT1A, ABCG1, DHCR24 and MYO5C) were also associated with BMI [57] and four (CPT1A, ABCG1, DHCR24 and TXNIP) with serum triglycerides [105,108]. A recent meta-analysis of EWAS with diabetes also identified TXNIP, ABCG1 and CPT1A [20]. Taken together, it appears that this early EWAS with metabolomics had anticipated the implication of TXNIP, ABCG1 and CPT1A methylation in diabetes and obesity-related phenotypes [109].…”

“…For example, an EWAS with serum immunoglobulin E (IgE) levels found that three loci accounted for 13% of IgE variation, explaining a 10-fold higher variance of the trait than currently explained by GWAS [81]. A recent meta-analysis of EWAS with type 2 diabetes found that the six top CpGs accounted for 11% of the trait variation, which was similar to the variation that could be explained by the common risk factors of BMI, sex, age and smoking [20]. Likewise, in a study for 13 clinical traits in adipose tissue, methylation of the FASN locus alone could account for 16% of the variation in BMI [82].…”

Cohort profile: Epigenetics in Pregnancy (EPIPREG) – population-based sample of European and South Asian pregnant women with epigenome-wide DNA methylation (850k) in peripheral blood leukocytes

“…One of the most studied epigenetic mechanisms is DNA methylation, which plays an important role in normal development, chromatin organization and gene expression [3]. Several studies have indicated that DNA methylation is associated with cardiovascular risk factors such as body mass index (BMI) [4][5][6][7], gestational diabetes (GDM) [8], type 2 diabetes (T2D) [9][10][11][12][13], lipid levels [14,15], hypertension [16,17], smoking [18][19][20][21][22] and alcohol intake [23][24][25], suggesting that cardiometabolic diseases have an epigenetic component.…”