<i>AHRR</i> (cg05575921) hypomethylation marks smoking behaviour, morbidity and mortality.

Abstract

Self-reported smoking underestimates disease risk. Smoking affects DNA methylation, in particular the cg05575921 site in the aryl hydrocarbon receptor repressor <i>(AHRR</i>) gene. We tested the hypothesis that <i>AHRR</i> cg05575921 hypomethylation is associated with risk of smoking-related morbidity and mortality. From the Copenhagen City Heart Study representing the Danish general population, we studied 9234 individuals. Using bisulphite treated leucocyte DNA, <i>AHRR</i> (cg05575921) methylation was measured. Rs1051730 (<i>CHRN3A</i>) genotype was used to evaluate smoking heaviness. Participants were followed for up to 22 years for exacerbations of 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 (PLCO_M2012). <i>AHRR</i> (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 <i>CHRN3A</i> genotype (-0.48% per T-allele, p=0.002). The multifactorially adjusted HRs for the lowest versus highest methylation quintiles were 4.58 (95% CI 2.83 to 7.42) for COPD exacerbations, 4.87 (2.31 to 10.3) for lung cancer and 1.67 (1.48 to 1.88) for all-cause 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 PLCO_M2012 6-year risks were similar (4.3% and 4.4%, p=0.77). <i>AHRR</i> (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality.