BACKGROUND Experimental studies suggest that exposure to cadmium may alter DNA methylation (DNAm). In addition, DNAm status at several genomic sites has been associated with smoking in methylome-wide epidemiologic studies. Cadmium in cigarettes has been proposed as a causative agent for multiple health outcomes. The objective of this study was to investigate the mediator role of cadmium in the association between smoking and genomic DNAm profiles in 2325 Strong Heart Study participants. METHODS DNAm was measured in 860079 loci using the lllumina Infinium Human MethylationEPIC platform. Data were preprocessed, including correction for batch effect and cell heterogeneity. Cadmium concentrations in urine were determined by Inductively Coupled Plasma Mass Spectrometry, corrected by creatinine and log-transformed. Associations for active smoking on DNAm were estimated using linear regression models adjusted by age, body mass index, sex, with and without cadmium levels when required. We used the "difference of coefficients" method and the mediation R package to estimate the relative contribution of cadmium to smoking-associated DNAm. RESULTS 38.4 % of the participants were active smokers. Median urinary cadmium was 0.97 pg/g. At a Bonferroni significance level of 5.91e-08, we replicated well-known associations of active smoking with DNAm. Among the 1858 significant sites, the top 5 mediated effects (% of association attributed to cadmium) were observed for NFIB (cg03253449, 31.33 %), IFIH1 (cgl9965693, 28.9 %), CDC42BPB (cg02003183, 27.71 %), HSD17B12 (cgl4262884, 27.19 %) and AHRR (cg00731338, 21.37 %). CONCLUSIONS The association of active smoking and DNA methylation in well-established smoking associated DNAm sites was partially attributed to cadmium. Our results suggest that cadmium might be a partial mediator of the association between smoking and health outcomes through epigenetic mechanisms. These results need to be replicated in an independent study population.
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