AHRR (cg05575921) hypomethylation marks smoking behaviour, morbidity and mortality

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Stig E Bojesen, Nicholas Timpson, Caroline Relton, George Davey Smith, Børge G Nordestgaard

RATIONALE AND OBJECTIVES: Self-reported smoking underestimates disease risk. Smoking affects DNA methylation, in particular the cg05575921 site in the aryl hydrocarbon receptor repressor (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 leucocyte 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 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 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 PLCOM2012 6-year risks were similar (4.3% and 4.4%, p=0.77).

CONCLUSION: AHRR (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality.

Original languageEnglish
JournalThorax
Volume72
Issue number7
Pages (from-to)646-653
Number of pages8
ISSN0040-6376
DOIs
Publication statusPublished - Jul 2017

    Research areas

  • Aged, Basic Helix-Loop-Helix Transcription Factors, Biomarkers, Cause of Death, DNA Methylation, Denmark, Disease Progression, Female, Genotype, Humans, Lung Neoplasms, Male, Middle Aged, Pulmonary Disease, Chronic Obstructive, Receptors, Nicotinic, Repressor Proteins, Risk Assessment, Risk-Taking, Smoking, Journal Article

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