DNA methylation of the allergy regulatory gene interferon gamma varies by age, sex, and tissue type in asthmatics

Background: Asthma is associated with allergic sensitization in about half of all cases, and asthma phenotypes can vary by age and sex. DNA methylation in the promoter of the allergy regulatory gene interferon gamma (IFN gamma) has been linked to the maintenance of allergic immune function in human cell and mouse models. We hypothesized that IFN gamma promoter methylation at two well-studied, key cytosine phosphate guanine (CpG) sites (-186 and -54), may differ by age, sex, and airway versus systemic tissue in a cohort of 74 allergic asthmatics. Results: After sampling buccal cells, a surrogate for airway epithelial cells, and CD4+ lymphocytes, we found that CD4+ lymphocyte methylation was significantly higher in children compared to adults at both CpG sites (P < 0.01). Buccal cell methylation was significantly higher in children at CpG -186 (P = 0.03) but not CpG -54 (P = 0.66). Methylation was higher in males compared to females at both CpG sites in CD4+ lymphocytes (-186: P < 0.01, -54: P = 0.02) but not buccal cells (-186: P = 0.14, -54: P = 0.60). In addition, methylation was lower in CD4+ lymphocytes compared to buccal cells (P < 0.01) and neighboring CpG sites were strongly correlated in CD4+ lymphocytes (r = 0.84, P < 0.01) and weakly correlated in buccal cells (r = 0.24, P= 0.04). At CpG -186, there was significant correlation between CD4+ lymphocytes and buccal cells (r = 0.24, P = 0.04) but not at CpG -54 (r = -0.03, P = 0.78). Conclusions: These findings highlight significant age, sex, and tissue-related differences in IFN gamma promoter methylation that further our understanding of methylation in the allergic asthma pathway and in the application of biomarkers in clinical research.