Infancy IgE methylation score and childhood wheezing and asthma: Multicohort study.
BACKGROUND: Early-life epigenetic programming may mediate gene-environment interactions underlying recurrent wheezing and asthma. Multi-CpG methylation scores can summarize the epigenetic potential for high IgE beyond what is captured by observed IgE levels. OBJECTIVE: We sought to establish and examine the residual effect of an epigenetic total IgE (DNAm-IgE) score on respiratory morbidity in a pediatric population. METHODS: We used data from the 35th Multicenter Airway Research Collaboration (MARC-35; n = 560), the 43rd Multicenter Airway Research Collaboration (MARC-43; n = 177), and the Boston Birth Cohort (BBC; n = 80). DNA methylation (Illumina EPIC array) was measured in blood during infancy (MARC-35, MARC-43) and in cord blood at birth (BBC). Total IgE was assessed in blood at infancy, recurrent wheezing at age 3 years, and asthma at age 6 years for all cohorts. RESULTS: MARC-35 data were used to train and evaluate a DNAm-IgE score (R = 0.502 vs total IgE). MARC-43 and BBC data were used to validate the score (R = 0.309 and R = 0.132). In meta-analyses of the 3 cohorts, 1 standard deviation of DNAm-IgE score residuals (DNAm-IgE score regressed on total IgE) was associated with recurrent wheezing (OR = 1.33 [95% confidence interval, 1.11, 1.60], Pheterogeneity = .92), while 1 standard deviation of total IgE was associated with asthma (OR = 1.45 [95% confidence interval, 1.19, 1.76], Pheterogeneity = .29). All models were adjusted for sex, race/ethnicity, and birth weight. CONCLUSION: Early-life epigenetic patterns related to total IgE may contribute to subsequent respiratory morbidity beyond measured IgE levels. The DNAm-IgE score and its residual component should be viewed as exploratory tools that require further validation and mechanistic study.