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DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood.

ABSTRACT: There is now increasing evidence that asthma and atopy originate in part in utero, with disease risk being associated with the altered epigenetic regulation of genes.To determine the relationship between variations in DNA methylation at birth and the development of allergic disease, we examined the methylation status of CpG loci within the promoter regions of Th1/2 lineage commitment genes (GATA3, IL-4, IL-4R, STAT4 and TBET) in umbilical cord DNA at birth in a cohort of infants from the Southampton Women's Survey (n = 696) who were later assessed for asthma, atopic eczema and atopy.We found that higher methylation of GATA3 CpGs -2211/-2209 at birth was associated with a reduced risk of asthma at ages 3 (median ratio [median methylation in asthma group/median methylation in non-asthma group] = 0.74, P = .006) and 6-7 (median ratio 0.90, P = .048) years. Furthermore, we demonstrated that the GATA3 CpG loci associated with later risk of asthma lie within a NF-?B binding site and that methylation here blocks transcription factor binding to the GATA3 promoter in the human Jurkat T-cell line. Associations between umbilical cord methylation of CpG loci within IL-4R with atopic eczema at 12 months (median ratio 1.02, P = .028), and TBET with atopy (median ratio 0.98, P = .017) at 6-7 years of age were also observed.Our findings provide further evidence of a developmental contribution to the risk of later allergic disorders and suggest that involvement of epigenetic mechanisms in childhood asthma is already demonstrable at birth.

SUBMITTER: Barton SJ

PROVIDER: S-EPMC5681244 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood.

Barton S J SJ Ngo S S Costello P P Garratt E E El-Heis S S Antoun E E Clarke-Harris R R Murray R R Bhatt T T Burdge G G Cooper C C Inskip H H van der Beek E M EM Sheppard A A Godfrey K M KM Lillycrop K A KA

Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 20170831 12

<h4>Background</h4>There is now increasing evidence that asthma and atopy originate in part in utero, with disease risk being associated with the altered epigenetic regulation of genes.<h4>Objective and methods</h4>To determine the relationship between variations in DNA methylation at birth and the development of allergic disease, we examined the methylation status of CpG loci within the promoter regions of Th1/2 lineage commitment genes (GATA3, IL-4, IL-4R, STAT4 and TBET) in umbilical cord DNA ...[more]

PMID: 28756630

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Project description:BackgroundSeasonal variations in environmental exposures at birth or during gestation are associated with numerous adult traits and health outcomes later in life. Whether DNA methylation (DNAm) plays a role in the molecular mechanisms underlying the associations between birth season and lifelong phenotypes remains unclear.MethodsWe carried out epigenome-wide meta-analyses within the Pregnancy And Childhood Epigenetic Consortium to identify associations of DNAm with birth season, both at differentially methylated probes (DMPs) and regions (DMRs). Associations were examined at two time points: at birth (21 cohorts, N = 9358) and in children aged 1-11 years (12 cohorts, N = 3610). We conducted meta-analyses to assess the impact of latitude on birth season-specific associations at both time points.ResultsWe identified associations between birth season and DNAm (False Discovery Rate-adjusted p values < 0.05) at two CpGs at birth (winter-born) and four in the childhood (summer-born) analyses when compared to children born in autumn. Furthermore, we identified twenty-six differentially methylated regions (DMR) at birth (winter-born: 8, spring-born: 15, summer-born: 3) and thirty-two in childhood (winter-born: 12, spring and summer: 10 each) meta-analyses with few overlapping DMRs between the birth seasons or the two time points. The DMRs were associated with genes of known functions in tumorigenesis, psychiatric/neurological disorders, inflammation, or immunity, amongst others. Latitude-stratified meta-analyses [higher (≥ 50°N), lower (< 50°N, northern hemisphere only)] revealed differences in associations between birth season and DNAm by birth latitude. DMR analysis implicated genes with previously reported links to schizophrenia (LAX1), skin disorders (PSORS1C, LTB4R), and airway inflammation including asthma (LTB4R), present only at birth in the higher latitudes (≥ 50°N).ConclusionsIn this large epigenome-wide meta-analysis study, we provide evidence for (i) associations between DNAm and season of birth that are unique for the seasons of the year (temporal effect) and (ii) latitude-dependent variations in the seasonal associations (spatial effect). DNAm could play a role in the molecular mechanisms underlying the effect of birth season on adult health outcomes.

Dataset Information

DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood.

Publications

DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood.

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