C34-32 DNA Methylation at Birth Mediates the Association Between Maternal Allergic Disease and Childhood Atopy

Rationale

Allergic diseases commonly originate in early life, and maternal allergic disease is a recognized risk factor for offspring allergy. However, the biological mechanisms linking maternal allergic disease to offspring atopic status remain incompletely understood. Epigenetic modifications, such as DNA methylation (DNAm), may explain the association and help to understand the intergenerational transmission of atopy risk. This study investigates whether DNAm at birth mediates the association between maternal allergic disease and offspring atopy in childhood.

Methods

Maternal allergic disease was assessed at delivery in the Isle of Wight (IOW) birth cohort (F1) by questionnaire. Offspring atopic status was evaluated using Skin Prick Tests (SPT) at age 4 years for nine common indoor, outdoor, and food allergens. DNAm was measured at birth from Guthrie cards (n = 718) using Illumina Infinium MethylationEPIC BeadChips. After pre-processing and quality control, DNAm at 551,710 CpG sites was included in the analysis. A two-step analytic approach was applied: (1) epigenome-wide CpG screening using ttScreening in R, adjusting for cell type compositions, to identify CpGs associated with maternal atopy using linear regressions under a training and testing framework, and (2) path analysis in Mplus, adjusting for confounders (paternal atopy, maternal smoking, socioeconomic status, sex, and birth weight) to estimate the association of maternal allergic disease on offspring atopy through DNAm at birth at the CpGs that passed screening. Sex specific associations were evaluated by including the CpG×sex interaction term.

Results

In total, 118 CpGs passed screening and were further examined in path analyses. DNAm at cg08138900 (ZNF534) showed a positive indirect effect (indirect effect coefficient (IEC) = 0.103, p value = 0.031) with an indirect over direct effect ratio of 0.63. At the other two CpGs, cg09994527 [MIS18BP1] and cg22028137 [PDE7A], negative indirect effects were observed (IEC = -0.093, p value = 0.033; and IEC = -0.084, p value = 0.03, respectively) with indirect over direct effect ratios 0.27 and 0.24, respectively. Furthermore, the indirect effect of cg14452599 [NOS1] among girls was 0.156 lower compared to boys (p value = 0.037); a statistically significant negative indirect effect was observed in girls (IEC = -0.109, p value = 0.042) but not in boys (IEC = 0.047, p value = 0.318).

Conclusion

DNAm at birth showed mediation effects of maternal allergic disease on childhood atopy, supporting a potential role of perinatal epigenetic variation in childhood atopy.

This abstract is funded by: NIH