AHRR (cg05575921) Hypomethylation Marks Smoking Behavior, Morbidity And Mortality

Stig BOJESEN, Copenhagen University Hospital, Denmark
TIMPSON N. 4 , RELTON C. 4 , DAVEY SMITH G. 4 , NORDESTGAARD B. 1,2,3

1 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
2 Faculty of Health and Medical Sciences, University of Copenhagen, Denmark
3 The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark
4 MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, UK

Background
Self-reported smoking produces underestimated disease risk estimates. Smoking affects DNA methylation, in particular the cg05575921 site in the AHRR gene. We tested the hypothesis that AHRR cg05575921 hypomethylation is associated with smoking behavior, 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) DNA methylation was measured. Genotype for rs1051730 (CHRN3A) was used to evaluate smoking heaviness and methylation. Participants were followed for up to 22 years for events of chronic obstructive pulmonary disease (COPD), 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).
Results
AHRR (cg05575921) hypomethylation was associated with smoking status, daily and cumulative smoking, and time since smoking cessation (all p-values<3*10-49), and the smoking-related CHRN3A genotype (p=0.003, trend test). The multifactorially adjusted hazard ratios for the lowest versus highest methylation quintiles were 2.91(95% confidence interval, 2.23-3.80) for COPD, 4.87(2.31-10.3) for lung cancer, and 1.67(1.48-1.88) for all-cause mortality. Finally, among 2576 high-risk smokers eligible for lung cancer screening by CT, the 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 the predicted PLCOM2012 6-year risks were similar (4.3% and 4.4%, p=0.77).
Conclusion
AHRR (cg05575921) hypomethylation is a marker of past and current smoking behavior and provides potentially clinical relevant risk predictions of future smoking related morbidity and mortality.