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BACKGROUND: Current evidence suggests an increased risk for cancer mortality in those with low aryl hydrocarbon receptor repressor (AHRR) DNA methylation (DNAm) levels. Therefore, AHRR DNAm could identify a more "fragile" group at risk for cancer mortality than questionnaire-based evaluations. Given this, the aim was to identify "fragile" groups at risk of cancer mortality by integrating questionnaire-based smoking indices and leukocyte AHRR DNAm levels in the Japanese population. METHODS: The target population was 795 participants without a clinical history who underwent a health checkup in 1990. They were followed for up to 30 years for mortality. The AHRR DNAm levels in leukocytes were measured by the pyrosequencing method. HRs for cancer mortality were calculated using a Cox proportional hazards model. RESULTS: Significantly higher HRs for all-cancer mortality were observed in low AHRR DNAm groups regardless of smoking intensity [pack-years <20: 3.69 (1.46-9.37); pack-years ≥20: 2.13 (1.11-4.09)]. Compared with current smokers, significantly lower HRs for all-cancer mortality were observed in the group with high AHRR DNAm regardless of years since quitting [YSQ ≤10: 0.13 (0.02-0.96); YSQ >10: 0.28 (0.08-0.98)]. Even for YSQ greater than 10, there was no significant mortality risk reduction in the low AHRR DNAm group. CONCLUSIONS: The population with low AHRR DNAm levels had a higher risk of cancer mortality even with low smoking exposure. Furthermore, no significant risk reduction was observed in former smokers with low AHRR DNAm levels. IMPACT: AHRR DNAm levels in leukocytes may help identify groups at risk for cancer mortality overlooked by questionnaire-based smoking indices.

Thioredoxin-interacting protein (TXNIP) plays an important role in glucose metabolism, and its expression is regulated by DNA methylation (DNAm). Although the association between TXNIP DNAm and type 2 diabetes mellitus has been demonstrated in studies with a cross-sectional design, prospective studies are needed. We therefore examined the association between TXNIP DNAm levels and longitudinal changes in glycemic traits by conducting a longitudinal study involving 169 subjects who underwent two health checkups in 2015 and 2019. We used a pyrosequencing assay to determine TXNIP DNAm levels in leukocytes (cg19693031). Logistic regression analyses were performed to assess the associations between dichotomized TXNIP DNAm levels and marked increases in glycemic traits. At four years, the TXNIP DNA hypomethylation group had a higher percentage of changes in fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) compared to those in the hypermethylation group. The adjusted odds ratios for FPG and HbA1c levels were significantly higher in the TXNIP DNA hypomethylation group than in the hypermethylation group. We found that TXNIP DNA hypomethylation at baseline was associated with a marked increase in glycemic traits. Leukocyte TXNIP DNAm status could potentially be used as an early biomarker for impaired glucose homeostasis.

DNA methylation can be affected by numerous lifestyle factors, including diet. Tobacco smoking induces aryl hydrocarbon receptor repressor (AHRR) DNA hypomethylation, which increases the risk of lung and other cancers. However, no lifestyle habits that might increase or restore percentage of AHRR DNA methylation have been identified. We hypothesized that dietary intakes of vegetables/fruits and serum carotenoid concentrations are related to AHRR DNA methylation. A total of 813 individuals participated in this cross-sectional study. A food frequency questionnaire was used to assess dietary intake of vegetables and fruits. AHRR DNA methylation in peripheral blood mononuclear cells were measured using pyrosequencing method. In men, dietary fruit intake was significantly and positively associated with AHRR DNA methylation among current smokers (P for trend = .034). A significant positive association of serum provitamin A with AHRR DNA methylation was observed among current smokers (men: standardized β = 0.141 [0.045 to 0.237], women: standardized β = 0.570 [0.153 to 0.990]). However, compared with never smokers with low provitamin A concentrations, percentages of AHRR DNA methylation were much lower among current smokers, even those with high provitamin A concentrations (men: β = -19.1% [-33.8 to -19.8], women: β = -6.0% [-10.2 to -1.7]). Dietary intake of vegetables and fruits rich in provitamin A may increase percentage of AHRR DNA methylation in current smokers. However, although we found a beneficial effect of provitamin A on AHRR DNA methylation, this beneficial effect could not completely remove the effect of smoking on AHRR DNA demethylation.