Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Vascular Disease
Clinical Implication of Smoking-Related Aryl-Hydrocarbon Receptor Repressor (AHRR) Hypomethylation in Japanese Adults
Fumihiko TakeuchiKozue TakanoMasaya YamamotoMasato IsonoWataru MiyakeKotaro MoriHisao HaraYukio HiroiNorihiro Kato
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Supplementary material

2022 Volume 86 Issue 6 Pages 986-992


Background: Tobacco smoking is a leading preventable cause of morbidity and mortality worldwide; still, the success rate of smoking cessation is low in general. From the viewpoint of public health and clinical care, an objective biomarker of long-term smoking behavior is sought.

Methods and Results: This study assessed DNA methylation as a biomarker of smoking in a hospital setting through a combination of molecular approaches including genetic, DNA methylation and mRNA expression analyses. First, in an epigenome-wide association study involving Japanese individuals with chronic cardiovascular disease (n=94), genome-wide significant smoking association was identified at 2 CpG sites on chromosome 5, with the strongest signal at cg05575921 located in intron 3 of the aryl-hydrocarbon receptor repressor (AHRR) gene. Highly significant (P<1×10−27) smoking–cg05575921 association was validated in 2 additional panels (n=339 and n=300). For the relationship of cg05575921 methylation extent with time after smoking cessation and cumulative cigarette consumption among former smokers, smoking-related hypomethylation was found to remain for ≥20 years after smoking cessation and to be affected by multiple factors, such as cis-interaction of genetic variation. There was a significant inverse correlation (P=0.0005) between cg05575921 methylation extent and AHRR mRNA expression.

Conclusions: The present study results support that reversion of AHRR hypomethylation can be a quantifiable biomarker for progress in and observance of smoking cessation, although some methodological points need to be considered.

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