Infancy IgE methylation score and childhood wheezing and asthma: Multicohort study.

Abstract

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. We sought to establish and examine the residual effect of an epigenetic total IgE (DNAm-IgE) score on respiratory morbidity in a pediatric population. 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. 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], P_{heterogeneity} = .92), while 1 standard deviation of total IgE was associated with asthma (OR = 1.45 [95% confidence interval, 1.19, 1.76], P_{heterogeneity} = .29). All models were adjusted for sex, race/ethnicity, and birth weight. 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.