Association of season of birth with DNA methylation and allergic disease.

BACKGROUND: Season of birth influences allergy risk; however, the biological mechanisms underlying this observation are unclear. The environment affects DNA methylation, with potentially long-lasting effects on gene expression and disease. This study examined whether DNA methylation could underlie the association between season of birth and allergy. METHODS: In a subset of 18-year-old participants from the Isle of Wight (IoW) birth cohort (n = 367), the risks of birth season on allergic outcomes were estimated. Whole blood epigenome-wide DNA methylation was measured, and season-associated CpGs detected using a training-and-testing-based technique. Validation method examined the 8-year-old Prevention and Incidence of Asthma and Mite Allergy (PIAMA) cohort. The relationships between DNA methylation, season of birth and allergy were examined. CpGs were analysed in IoW third-generation cohort newborns. RESULTS: Autumn birth increased risk of eczema, relative to spring birth. Methylation at 92 CpGs showed association with season of birth in the epigenome-wide association study. In validation, significantly more CpGs had the same directionality than expected by chance, and four were statistically significant. Season-associated methylation was enriched among networks relating to development, the cell cycle and apoptosis. Twenty CpGs were nominally associated with allergic outcomes. Two CpGs were marginally on the causal pathway to allergy. Season-associated methylation was largely absent in newborns, suggesting it arises post-natally. CONCLUSIONS: This study demonstrates that DNA methylation in adulthood is associated with season of birth, supporting the hypothesis that DNA methylation could mechanistically underlie the effect of season of birth on allergy, although other mechanisms are also likely to be involved.

Identifying CpG sites associated with eczema via random forest screening of epigenome-scale DNA methylation.

BACKGROUND: The prevalence of eczema is increasing in industrialized nations. Limited evidence has shown the association of DNA methylation (DNA-M) with eczema. We explored this association at the epigenome-scale to better understand the role of DNA-M. Data from the first generation (F1) of the Isle of Wight (IoW) birth cohort participants and the second generation (F2) were examined in our study. Epigenome-scale DNA methylation of F1 at age 18 years and F2 in cord blood was measured using the Illumina Infinium HumanMethylation450 Beadchip. A total of 307,357 cytosine-phosphate-guanine sites (CpGs) in the F1 generation were screened via recursive random forest (RF) for their potential association with eczema at age 18. Functional enrichment and pathway analysis of resulting genes were carried out using DAVID gene functional classification tool. Log-linear models were performed in F1 to corroborate the identified CpGs. Findings in F1 were further replicated in F2. RESULTS: The recursive RF yielded 140 CpGs, 88 of which showed statistically significant associations with eczema at age 18, corroborated by log-linear models after controlling for false discovery rate (FDR) of 0.05. These CpGs were enriched among many biological pathways, including pathways related to creating transcriptional variety and pathways mechanistically linked to eczema such as cadherins, cell adhesion, gap junctions, tight junctions, melanogenesis, and apoptosis. In the F2 generation, about half of the 83 CpGs identified in F1 showed the same direction of association with eczema risk as in F1, of which two CpGs were significantly associated with eczema risk, cg04850479 of the PROZ gene (risk ratio (RR) = 15.1 in F1, 95 % confidence interval (CI) 1.71, 79.5; RR = 6.82 in F2, 95 % CI 1.52, 30.62) and cg01427769 of the NEU1 gene (RR = 0.13 in F1, 95 % CI 0.03, 0.46; RR = 0.09 in F2, 95 % CI 0.03, 0.36). CONCLUSIONS: Via epigenome-scaled analyses using recursive RF followed by log-linear models, we identified 88 CpGs associated with eczema in F1, of which 41 were replicated in F2. Several identified CpGs are located within genes in biological pathways relating to skin barrier integrity, which is central to the pathogenesis of eczema. Novel genes associated with eczema risk were identified (e.g., the PROZ and NEU1 genes).