Molecular networks in atopic mothers impact the risk of infant atopy

• Published in: Allergy (Copenhagen) Vol. 78; no. 1; pp. 244 - 257
• Main Authors: Schedel, Michaela, Leach, Sonia M., Strand, Matthew J., Danhorn, Thomas, MacBeth, Morgan, Faino, Anna V., Lynch, Anne M., Winn, Virginia D., Munoz, Lindsay L., Forsberg, Shannon M., Schwartz, David A., Gelfand, Erwin W., Hauk, Pia J.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.01.2023
• Subjects: Atopic dermatitis; Child; Child, Preschool; Children; Cord blood; Dermatitis; Dermatitis, Atopic - epidemiology; Dermatitis, Atopic - genetics; differentially expressed gene; differentially methylated region; DNA methylation; Eczema; Epigenetics; Family; Female; Gene expression; Genomic analysis; Humans; Infant; Infants; Interferon; maternal atopy; Myxovirus resistance proteins; Pregnancy; Principal components analysis; Prospective Studies; Risk Factors; Signal transduction; Transcription factors; Transcriptome; Transcriptomics; atopic dermatitis; differentially expressed gene; cord blood; differentially methylated region; maternal atopy
• ISSN: 0105-4538; 1398-9995
• DOI: 10.1111/all.15490

Background The prevalence of atopic diseases has increased with atopic dermatitis (AD) as the earliest manifestation. We assessed if molecular risk factors in atopic mothers influence their infants' susceptibility to an atopic disease. Methods Pregnant women and their infants with (n = 174, high‐risk) or without (n = 126, low‐risk) parental atopy were enrolled in a prospective birth cohort. Global differentially methylated regions (DMRs) were determined in atopic (n = 92) and non‐atopic (n = 82) mothers. Principal component analysis was used to predict atopy risk in children dependent on maternal atopy. Genome‐wide transcriptomic analyses were performed in paired atopic (n = 20) and non‐atopic (n = 15) mothers and cord blood. Integrative genomic analyses were conducted to define methylation–gene expression relationships. Results Atopic dermatitis was more prevalent in high‐risk compared to low‐risk children by age 2. Differential methylation analyses identified 165 DMRs distinguishing atopic from non‐atopic mothers. Inclusion of DMRs in addition to maternal atopy significantly increased the odds ratio to develop AD in children from 2.56 to 4.26. In atopic compared to non‐atopic mothers, 139 differentially expressed genes (DEGs) were identified significantly enriched of genes within the interferon signaling pathway. Expression quantitative trait methylation analyses dependent on maternal atopy identified 29 DEGs controlled by 136 trans‐acting methylation marks, some located near transcription factors. Differential expression for the same nine genes, including MX1 and IFI6 within the interferon pathway, was identified in atopic and non‐atopic mothers and high‐risk and low‐risk children. Conclusion These data suggest that in utero epigenetic and transcriptomic mechanisms predominantly involving the interferon pathway may impact and predict the development of infant atopy. This study assessed the influence of molecular risk factors in atopic mothers influence on their infants' susceptibility to an atopic disease. DMRs distinguished atopic from non‐atopic mothers. Inclusion of maternal DMRs further increased the risk in the offspring to develop AD conferred by maternal atopy alone. Transcriptomic analyses identified DEGs in atopic compared with non‐atopic mothers with shared DEGs in high‐risk relative to low‐risk children.Abbreviations: DEG, differentially expressed gene; DMR, differentially methylated region; HELZ2, helicase with zinc finger 2; HERC5, HECT and RLD domain containing E3 ubiquitin protein ligase 5; IFI6, interferon α inducible protein 6; IFI44L, interferon induced protein 44 like; IFIT3, interferon‐induced protein with tetratricopeptide repeats 3; IMPAC, Impact of Parental risk factors on Atopy in Children; MX1, MX dynamin like GTPase 1; REC8, REC8 meiotic recombination protein; SIGLEC1, sialic acid binding Ig like lectin 1; XAF1, XIAP associated factor 1