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Abstract
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.
- Tobacco and the lung
- Lung Cancer
- COPD epidemiology
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Footnotes
Contributors Conception and design: SEB, NT, CR, GDS, BGN. Administrative support: SEB, BGN. Provision of study materials or participants: SEB, BGN. Collection and assembly of data: SEB. Data base assembly and control: SEB. Data analysis and interpretation: SEB, NT, BGN. Writing of first draft: SEB. Manuscript writing: SEB, NT, CR, GDS, BGN. Final approval of manuscript: SEB, NT, CR, GDS, BGN.
Funding The Capital Region of Denmark, Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University hospital. GDS and CLR are partially supported by the ESRC (RES-060-23-0011) “The biosocial archive: transforming lifecourse social research through the incorporation of epigenetic measures”. GDS, CLR and NJT are supported by the UK Medical Research Council Integrative Epidemiology Unit and the University of Bristol (MC_UU_12013_1, MC_UU_12013_2 and MC_UU_12013_3) and the Cancer Research UK Integrative Cancer Epidemiology Programme (C18281/A19169). Role of the Funding organisations: The funding organisations had no role in design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript and decision to submit the manuscript for publication.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Danish Ethics Committee.
Provenance and peer review Not commissioned; externally peer reviewed.