Epigenome-wide mediation analysis identified Cytosine-phosphate-Guanine sites linking environmental factors with diabetes indicators

<h4>Aims</h4>Environmental factors can alter DNA methylation (DNAm) levels, influence gene expression, and then change fasting glucose (FG) or hemoglobin A1c (HbA1c).<h4>Methods</h4>Through analyzing DNAm data of 2366 Taiwan Biobank individuals aged between 30 and 70 years, I evaluated the role of DNAm in mediating the associations of seven non-genetic factors (BMI, chronological age, sex, smoking, drinking alcoholic beverages, education, and regular exercise) with FG and HbA1c.<h4>Results</h4>Among 846,232 Cytosine-phosphate-Guanine (CpG) sites, the single-mediator model explored that 21, 15, 10, 3, 3, and 1 CpGs significantly mediated (<i>p</i> < 6.6E-9) the BMI-HbA1c, BMI-FG, sex-FG, age-FG, age-HbA1c, and drinking-HbA1c associations, respectively. The multiple-mediator model considered all significant mediators and selected the model with the smallest Akaike Information Criterion, and identified 8 CpGs that linked exposures (BMI, sex, age, and drinking) to diabetes indicators. Seven out of the 8 CpGs have been reported to be associated with diabetes, FG, HbA1c, or insulin resistance in previous epigenome-wide association studies.<h4>Conclusion</h4>Four of the 8 CpGs (cg19693031, cg04816311, cg00574958, and cg11024682) were associated with the expression of genes implicated in diabetes and metabolism, including the <i>TXNIP</i>, <i>GPR146</i>, <i>CPT1A</i>, and <i>SREBF1</i> genes. These findings highlight the underlying epigenetic mechanism linking non-genetic factors with diabetes.