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DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood
Author(s) -
Barton S. J.,
Ngo S.,
Costello P.,
Garratt E.,
ElHeis S.,
Antoun E.,
ClarkeHarris R.,
Murray R.,
Bhatt T.,
Burdge G.,
Cooper C.,
Inskip H.,
van der Beek E. M.,
Sheppard A.,
Godfrey K. M.,
Lillycrop K. A.
Publication year - 2017
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12988
Subject(s) - dna methylation , epigenetics , atopy , asthma , methylation , allergy , cpg site , immunology , medicine , gata3 , odds ratio , biology , genetics , gene , transcription factor , gene expression
Summary Background 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. Objective and Methods 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 ( GATA 3, IL ‐4, IL ‐4R, STAT 4 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. Results We found that higher methylation of GATA 3 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 GATA 3 CpG loci associated with later risk of asthma lie within a NF ‐κB binding site and that methylation here blocks transcription factor binding to the GATA 3 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. Conclusions and Clinical Relevance 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.