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

Abstract

at many loci across the genome, 3 and that smoking-related changes in gene expression are epigenetically regulated. 4 Among EWAS-identified loci, the aryl-hydrocarbon receptor repressor (AHRR) gene has been noted as a promising candidate gene, with smoking-associated hypomethylation of AHRR CpG sites (e.g., cg05575921) detectable in DNA from peripheral lymphocytes and pulmonary macrophages. 5,6 AHRR encodes a transcription factor that can repress the aryl-hydrocarbon receptor pathway, which regulates the cytochrome P450 (CYP)-mediated catabolism of xenobiotics such as dioxin and polyaromatic hydrocarbons contained in tobacco smoke. 5 Although the exact relation-T obacco smoking is a leading preventable cause of morbidity and mortality in the world. Active smoking in adults increases the risk for a wide spectrum of chronic illness, such as cardiovascular and respiratory disease, and various forms of cancer. As self-reported smoking information is prone to inaccuracies due to recall bias and under-reporting, 1 an objective biomarker of longterm smoking behavior has been sought. Among current smokers, cotinine, a primary metabolite of nicotine, is a reliable measure of nicotine exposure, 2 but is not suited for the estimation of long-term smoking behavior due to its short half-life of 15-24 h.With the advent of epigenome-wide association studies (EWAS) in the last decade, it has become known that tobacco smoking has a broad effect on DNA methylation Editorial p ????

A validated restriction enzyme ddPCR cg05575921 (AHRR) assay to accurately assess smoking exposure

“…It has been previously demonstrated that a bisul te converted DNA ddPCR assay can accurately determine the CpG methylation status of cg05575921 within AHRR (3,4,13). Furthermore, strong concordance between BIS ddPCR and Illumina Epic array measures of cg05575921 have been reported (4,13).…”

Dysregulation of DNA Methylation in the Aryl-Hydrocarbon Receptor Repressor (<i>AHRR</i>) Gene

“…4 In this issue of the Journal, Takeuchi et al add more detailed evidence. 5 Through an EWAS in a Japanese population, they not only validated the association between AHRR cg05575921 demethylation and smoking status, but also showed that smoking-related AHRR cg05575921 hypomethylation remains for a long period of time, 20 years or more, even after smoking cessation. 5 They also reveal that AHRR cg05575921 hypomethylation appears to become evident from a relatively early stage of smoking (i.e., <10 years) among current smokers.…”

“…5 Through an EWAS in a Japanese population, they not only validated the association between AHRR cg05575921 demethylation and smoking status, but also showed that smoking-related AHRR cg05575921 hypomethylation remains for a long period of time, 20 years or more, even after smoking cessation. 5 They also reveal that AHRR cg05575921 hypomethylation appears to become evident from a relatively early stage of smoking (i.e., <10 years) among current smokers. These results suggest that AHRR cg05575921 hypomethylation is a quantifiable marker of smoking habits, including early stage or cessation stage of smoking.…”

From Differential DNA Methylation in COPD to Mitochondria: Regulation of AHRR Expression Affects Airway Epithelial Response to Cigarette Smoke

“…Here, we only observed a trend between AHRR methylation at cg21161138 and AHRR mRNA expression in epithelial cells, potentially because of the relatively lower power due to drop-outs. Nevertheless, previous studies have shown that smoking-related hypomethylation of AHRR is correlated with AHRR mRNA expression in blood, lung tissue and lung-derived macrophages [ 13 , 31 , 32 ], suggesting that the gene expression of AHRR is regulated by DNA methylation. Additionally, we observed a negative correlation between the expression of AHRR and AHR , which indicates that AHRR indeed regulates the expression of AHR in human airway epithelium.…”