Abstract
BACKGROUND: Polycyclic aromatic hydrocarbon (PAH)-rich substances like cigarette smoke and PM(2.5) induce aryl hydrocarbon receptor (AHR)-mediated aryl hydrocarbon receptor repressor (AHRR) methylation. AHRR cg05575921 and coagulation factor II (thrombin) receptor-like 3 (F2RL3) cg03636183 methylation patterns are well-established biomarkers for smoking. Even though AHRR cg05575921 methylation has recently been associated with PM(2.5), the interaction between smoking and PM(2.5) on AHRR methylation is yet to be fully explored. We evaluated AHRR and F2RL3 CpG sites to identify potential significant markers in relation to PM(2.5) and smoking in Taiwanese adults. METHODS: DNA methylation and smoking data of 948 participants aged 30-70 years were obtained from the Taiwan Biobank Database (2008-2015), while PM(2.5) data were obtained from the Air Quality Monitoring Database (2006-2011). RESULTS: Smoking and PM(2.5) were independently associated with hypomethylation (lower levels) of AHRR cg05575921, AHRR cg23576855, F2RL3 cg03636183, and F2LR3 cg21911711 after multiple-comparison correction (Bonferroni P < 0.00028409). Cg05575921 was the most hypomethylated AHRR CpG site, while cg03636183 was the most hypomethylated F2RL3 CpG site. Overall, cg05575921 was the most hypomethylated CpG site: β = - 0.03909, P < 0.0001; - 0.17536, P < 0.0001 for former and current smoking, respectively (P-trend(smoking) < 0.0001) and - 0.00141, P < 0.0001 for PM(2.5). After adjusting for F2RL3 cg03636183, smoking and PM(2.5) remained significantly associated with cg05575921 hypomethylation: β - 0.02221, P < 0.0001; - 0.11578, P < 0.0001 for former and current smoking, respectively (P-trend(smoking) < 0.0001) and - 0.0070, P = 0.0120 for PM(2.5). After stratification by sex, smoking and PM(2.5) remained associated (P < 0.05) with cg05575921 hypomethylation in both men (β = - 0.04274, - 0.17700, and - 0.00163 for former smoking, current smoking, and PM(2.5), respectively) and women (β = - 0.01937, - 0.17255, and - 0.00105 for former smoking, current smoking, and PM(2.5), respectively). After stratification by residential area, former and current smoking remained associated (P < 0.05) with cg05575921 hypomethylation: β = - 0.03918 and - 0.17536, respectively (P-trend(smoking) < 0.0001). Living in the central and southern areas was also associated (P < 0.05) with cg05575921 hypomethylation: β = - 0.01356 and - 0.01970, respectively (P-trend(area) < 0.0001). CONCLUSION: Smoking and PM(2.5) were independently associated with hypomethylation of cg05575921, cg23576855, cg03636183, and cg21911711. The most hypomethylated CpG site was cg05575921 and its association with smoking and PM(2.5) was dose-dependent.