Methylation of IL-2 promoter at birth alters the risk of asthma exacerbations during childhood

Background Epigenetic modifications may have a role in asthma susceptibility. Objective To investigate whether epigenetic modification at birth of a CpG site necessary for the regulation of IL-2 transcription (IL-2 Site1) is associated with the development of asthma during childhood. Methods Methylation of IL-2 Site1 was assessed in cord blood from 303 children (225 with atopic mothers); as controls, we measured methylation of a site not important in the transcription of IL-2 (IL-2 Site7) and methylation of the LINE-1 repetitive element. Children were followed to the age of 8years. Information on severe asthma exacerbations and hospital admissions was collected from child's primary care medical record. To account for potential confounding by bronchiolitis, we used exacerbations/hospitalizations after age 1year as primary outcomes. Results There were 49 severe exacerbations amongst 33 children, and 22 hospital admissions amongst 11 children. The risk of asthma exacerbation increased 1.07-fold (95% CI 1.011.14, P=0.03) and the risk of hospital admission increased 1.12-fold (95% CI 1.041.20, P=0.002) for each one per cent increase in IL-2 Site1 methylation. Children who were admitted to hospital at any time-point had significantly higher IL-2 Site1 methylation than children not admitted to hospital (P=0.007). There was a significant interaction between age at exacerbation (P=0.03) or hospital admission (P=0.02) and methylation, with the effect of methylation increasing with increasing age. Methylation of the control IL-2 Site7 or LINE-1 was not a significant predictor of asthma exacerbations/hospital admission, and we found no association between IL-2 Site1 methylation and hospital admissions for other reasons (0.99 [0.921.06]). Cord blood mononuclear cell phytohemagglutinin-stimulated lymphoproliferative responses decreased significantly with increasing IL-2 Site1 methylation (P<0.001). Conclusions Increasing methylation in cord blood of a functional CpG site in the IL-2 promoter is associated with increased likelihood of severe asthma exacerbations and hospital admissions for asthma/wheeze between ages of 2 and 8years.