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

Abstract

Rationale and objectivesSelf-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.MethodsFrom 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 resultsAHRR (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).ConclusionAHRR (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality.

Prediction models for endometrial cancer for the general population or symptomatic women: A systematic review

“…The change in DNA methylation predicted the risk of developing type 2 diabetes (Wahl et al, 2017). In addition, the hypomethylation of the aryl hydrocarbon receptor repressor (AHRR) gene holds information on former smoking status, which might contribute to risk predictions of lung cancer (Bojesen et al, 2017). Further, the methylation of peripheral blood cell DNA can serve as a predictor for the risk of developing breast cancer (Widschwendter et al, 2008).…”

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers

“…All regions corresponding to the CpG sites significant in this analysis, and all CpG sites themselves, have previously been identified as being associated with smoking [8,12,[33][34][35][36], and discussed with regard to their biological implications in a number of publications, in particular 2q37.1 [8,13,37], AHRR [7,38,39], GFI1 [40], MYO1G [41] and F2RL3 [7,42]. Further, most of these loci have been identified as associated with conditions or diseases also related to smoking.…”

Translating genomics into risk prediction

“…However, several steps remain to be taken before we can truly translate these findings into clinical practice. First, validation and generalisability of the findings reported by Bojesen et al 15 in independent cohorts should be demonstrated. The population studied in this manuscript, though large, is relatively isolated and genetically homogeneous.…”

“…In Thorax , Bojesen et al 15 examine the associations between methylation at the AHRR and morbidity and mortality associated with smoking-related diseases in a large cohort with extended longitudinal follow-up (median 19 years). The authors begin by assessing the performance of a targeted, PCR-based assay for methylation at cg05575921 in blood.…”