Tobacco use has been reported to be the main cause of 90% of male and 80% of female lung cancers, as well as a relevant risk factor for other cancers such as oropharynx, larynx, esophagus, stomach, liver, pancreas, kidney, bladder, and colorectum. Smoking directly affects DNA methylation and although several genes have been reported to be differentially methylated in smokers, gender differences and population-specific differences remain to be further investigated. Our aim was to undertake global and sex-specific genome-wide epigenomic studies (EWAS) in a Mediterranean population to identify the main smoking DNA-methylated genes.
We analyzed 88 participants in the PREDIMED PLUS-Valencia study paired by age and sex (44 males and 44 females). We included current smokers, former and non-smokers according to the WHO classification. We performed genome-wide DNA methylation using Illumina 850K methylation EPIC arrays. Differential methylation (M-values) was statistically analyzed with Partek, including multivariate adjustement.
In the whole sample, the top-ranked differentially methylated CpG sites (blood) were: cg05575921 in the AHRR (aryl hydrocarbon receptor repressor) gene (P = 2.73E-14), cg21566642 (P = 1.51E-12); cg01940273 (P = 2.10E-10); cg03636183 in the F2RL3 (coagulation factor II thrombin receptor-like 3) gene (P = 6.90E-09); cg23576855 in the AHRR (9.05E-08); and cg17739917 in the RARA (retinoic acid receptor, alpha) gene (P = 1.90E-07), replicating previous finding of the hypomethylation in the AHRR and F2RL3 sites in smokers. In the sex-specific analyses, we detected for both men and women similar hypomethylation in the cg05575921-AHRR site, but some heterogeneity for other loci including the BRCA1 gene.
Smoking has consistent effect of on the methylation of the AHRR gene, but some gender differences for other genes have been detected. This may be related with further gender-smoking differences for some cancers.
2011-005398-22.
Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia, Innovación y Universidades.
Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia, Innovación y Universidades.
All authors have declared no conflicts of interest.