Mediation by DNA methylation on the association of BMI and serum uric acid in Chinese monozygotic twins

Obesity is an established risk factor for hyperuricemia, but the mechanisms are only partially understood. We examined whether BMI-related DNA methylation (DNAm) variation would mediate the association of BMI with serum uric acid (SUA). We first conducted an epigenome-wide association analysis (EWAS) in 64 monozygotic twin pairs to detect BMI-related DNAm variation and then evaluated the mediated effect of DNAm using mediation analysis. Ontology enrichments analysis was performed for CpGs using GREAT tool. The genes where the candidate CpG mediators mapped were validated using gene expression data. BMI was positively associated with log10 transformed SUA level (β = 0.01, P < 0.001). The association between BMI and DNAm of 138 CpGs reached P < 1 × 10-4 level. Twenty BMI-related differentially methylated regions within MAP2K2, POU4F2, AGAP2, MRGPRE, ADM5, and NKX1-1 were found. Of the 138 CpGs, 4 within VENTX (involved in cellular responses to stress pathway), SMOC2 (enable calcium ion binding), and FSCN2 (a member of fascin protein family) mediated the association between BMI and SUA, with a mediating effect of 0.002-μmol/L lower log10 transformed SUA levels and a proportion of 18.89 %-24.92 % negative mediating effect. BMI × DNAm interactions on SUA were observed for 2 CpGs within VENTX. The gene expression level of VENTX was also negatively associated with SUA level. BMI-related DNAm variation may partially mediate the association of BMI with SUA.