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Rationale and objectives Self-reported smoking underestimates disease risk. Smoking affects DNA methylation, in particular the cg05575921 site in the AHRR gene. We tested the hypothesis that AHRR cg05575921 hypomethylation is associated with risk of smoking related morbidity and mortality. Methods From the Copenhagen City Heart Study representing the Danish general population, we studied 9234 individuals. Using bisulphite treated leukocyte DNA, AHRR (cg05575921) methylation was measured. Rs1051730 (CHRN3A) genotype was used to evaluate smoking heaviness. Participants were followed for up to 22 years for exacerbations of chronic obstructive pulmonary disease (COPD), event of lung cancer, and all-cause mortality. Six-year lung cancer risk was calculated according to the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCOM2012). Measurements and main results AHRR (cg05575921) hypomethylation was associated with former and current smoking status, high daily and cumulative smoking, short time since smoking cessation (all p-values<7*10-31), and the smoking-related CHRN3A genotype (-0.48% per T-allele, p=0.002). The multifactorially adjusted hazard ratios for the lowest versus highest methylation quintiles were 4.58(95% confidence interval, 2.83-7.42) for COPD exacerbations, 4.87(2.31-10.3) for lung cancer, and 1.67(1.48-1.88) for allcause mortality. Finally, among 2576 high-risk smokers eligible for lung cancer screening by CT, observed cumulative incidences of lung cancer after 6 years for individuals in the lowest and highest methylation quintiles were 3.7% and 0.0% (p=2*10-7 ), whereas predicted PLCOM2012 6-year risks were similar (4.3% and 4.4%, p=0.77). Conclusions AHRR (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking related morbidity and mortality.