medRxiv : the preprint server for health sciences · 2024
Genetic contributions to epigenetic-defined endotypes of allergic phenotypes in children.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
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Thompson Emma E, Zhong Xiaoyuan, Carbonetto Peter, Morin Andréanne, Willwerscheid Jason, Visness Cynthia M, Bacharier Leonard B, Kattan Meyer, O'Connor George T, Rivera-Spoljaric Katherine, Wood Robert A, Gold Diane R, Hershey Gurjit K Khurana, Johnson Christine C, Miller Rachel L, Seroogy Christine M, Zoratti Edward M, Gergen Peter J, Levin Albert M, Altman Matthew C, Hartert Tina, Stephens Matthew, Jackson Daniel J, Gern James E, McKennan Christopher G, Ober Carole
Аннотация
BACKGROUND: Asthma is the most common chronic respiratory disease in children, but little is known about genetic contributions to its underlying endotypes. To address this gap, we studied the methylome, transcriptome, and genome from children with extensive phenotyping from birth.
METHODS: We performed DNA methylation (DNAm) studies using the Asthma&Allergy array and RNA-sequencing in nasal mucosal cells from 284 children (age 11 years) in the Urban Environment and Childhood Asthma (URECA) birth cohort with genotypes from whole-genome sequencing. Using empirical Bayes matrix factorization on all CpGs on the array, we derived 16 DNAm signatures and tested for associations between phenotypes and gene expression. We then replicated results in two additional cohorts and estimated the heritability of phenotype-associated signatures using single-nucleotide polymorphisms (SNPs) associated with an allergic disease, and with CpGs and genes associated with the signatures.
FINDINGS: Three DNAm signatures were associated with at least one phenotype: allergic asthma, allergic rhinitis, allergic sensitization (atopy), total IgE, exhaled nitric oxide, or blood eosinophils. The genes correlated with each of the three signatures were enriched in networks reflecting inhibited immune response to microbes, impaired epithelial barrier integrity, and activated T2 immune pathways. We replicated the signature-phenotype associations in two additional birth cohorts. The estimated joint SNP heritabilities of the signatures were 0.17 (p=0.0027), 0.30 (p=9.3×10-7), and 0.16 (p=9.0×10-7), respectively.
INTERPRETATION: We identified three significantly heritable DNAm signatures defining asthma and allergy endotypes across diverse populations. Our study demonstrated that epigenetic patterning in airway mucosal cells reflects perturbations in underlying biological processes related to the development of asthma and allergic diseases in childhood.
FUNDING: National Institute of Allergy and Infectious Diseases and the National Institutes of Health, Office of the Director.
METHODS: We performed DNA methylation (DNAm) studies using the Asthma&Allergy array and RNA-sequencing in nasal mucosal cells from 284 children (age 11 years) in the Urban Environment and Childhood Asthma (URECA) birth cohort with genotypes from whole-genome sequencing. Using empirical Bayes matrix factorization on all CpGs on the array, we derived 16 DNAm signatures and tested for associations between phenotypes and gene expression. We then replicated results in two additional cohorts and estimated the heritability of phenotype-associated signatures using single-nucleotide polymorphisms (SNPs) associated with an allergic disease, and with CpGs and genes associated with the signatures.
FINDINGS: Three DNAm signatures were associated with at least one phenotype: allergic asthma, allergic rhinitis, allergic sensitization (atopy), total IgE, exhaled nitric oxide, or blood eosinophils. The genes correlated with each of the three signatures were enriched in networks reflecting inhibited immune response to microbes, impaired epithelial barrier integrity, and activated T2 immune pathways. We replicated the signature-phenotype associations in two additional birth cohorts. The estimated joint SNP heritabilities of the signatures were 0.17 (p=0.0027), 0.30 (p=9.3×10-7), and 0.16 (p=9.0×10-7), respectively.
INTERPRETATION: We identified three significantly heritable DNAm signatures defining asthma and allergy endotypes across diverse populations. Our study demonstrated that epigenetic patterning in airway mucosal cells reflects perturbations in underlying biological processes related to the development of asthma and allergic diseases in childhood.
FUNDING: National Institute of Allergy and Infectious Diseases and the National Institutes of Health, Office of the Director.