Clinical Implication of Smoking-Related Aryl-Hydrocarbon Receptor Repressor (AHRR) Hypomethylation in Japanese Adults

• Published in: Circulation Journal p. CJ-21-0958
• Main Authors: Takeuchi, Fumihiko, Takano, Kozue, Yamamoto, Masaya, Isono, Masato, Miyake, Wataru, Mori, Kotaro, Hara, Hisao, Hiroi, Yukio, Kato, Norihiro
• Format: Journal Article
• Language: English
• Published: The Japanese Circulation Society 01.06.2022
• Subjects: Coronary artery disease; Epigenome-wide association study; Smoking
• ISSN: 1346-9843; 1347-4820
• DOI: 10.1253/circj.CJ-21-0958

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 ascis-interaction of genetic variation. There was a significant inverse correlation (P=0.0005) between cg05575921 methylation extent andAHRRmRNA 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.