TY - JOUR

T1 - AHRR (cg05575921) hypomethylation marks smoking behaviour, morbidity and mortality

AU - Bojesen, Stig E

AU - Timpson, Nicholas

AU - Relton, Caroline

AU - Davey Smith, George

AU - Nordestgaard, Børge G

N1 - Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

PY - 2017/7

Y1 - 2017/7

N2 - 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.

AB - 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.

KW - Aged

KW - Basic Helix-Loop-Helix Transcription Factors

KW - Biomarkers

KW - Cause of Death

KW - DNA Methylation

KW - Denmark

KW - Disease Progression

KW - Female

KW - Genotype

KW - Humans

KW - Lung Neoplasms

KW - Male

KW - Middle Aged

KW - Pulmonary Disease, Chronic Obstructive

KW - Receptors, Nicotinic

KW - Repressor Proteins

KW - Risk Assessment

KW - Risk-Taking

KW - Smoking

KW - Journal Article

U2 - 10.1136/thoraxjnl-2016-208789

DO - 10.1136/thoraxjnl-2016-208789

M3 - Journal article

C2 - 28100713

VL - 72

SP - 646

EP - 653

JO - Thorax

JF - Thorax

SN - 0040-6376

IS - 7

ER -