AHRR (cg05575921) hypomethylation marks smoking behaviour, morbidity and mortality
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AHRR (cg05575921) hypomethylation marks smoking behaviour, morbidity and mortality. / Bojesen, Stig E; Timpson, Nicholas; Relton, Caroline; Davey Smith, George; Nordestgaard, Børge G.
In: Thorax, Vol. 72, No. 7, 07.2017, p. 646-653.Research output: Contribution to journal › Journal article › Research › peer-review
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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 -
ID: 186865409