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

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

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‐κB 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.
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.
1599-1608
Barton, Sheila
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Ngo, Sherry
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Costello, Paula
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Garratt, Emma
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El-Heis, Sarah
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Antoun, Elie
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Clarke-Harris, Rebecca
7fc6eb8b-28cb-48cf-926f-84a9fd05b363
Murray, Robert
c3e973b5-525c-49b3-96ee-af60a666a0f4
Bhatt, Tejal
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Burdge, Graham
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Cooper, Cyrus
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Inskip, Hazel
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van der Beek, Eline M.
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Sheppard, Allan
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Godfrey, Keith
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Lillycrop, Karen
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EpiGen Consortium
Barton, Sheila
4f674382-ca0b-44ad-9670-e71a0b134ef0
Ngo, Sherry
19990b41-bd2f-45cb-bd34-ae1652d15b96
Costello, Paula
8fc5c643-2d38-4443-975a-8704af2fa755
Garratt, Emma
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El-Heis, Sarah
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Antoun, Elie
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Clarke-Harris, Rebecca
7fc6eb8b-28cb-48cf-926f-84a9fd05b363
Murray, Robert
c3e973b5-525c-49b3-96ee-af60a666a0f4
Bhatt, Tejal
574ea5bc-485f-48dd-a000-9cd1feebc8de
Burdge, Graham
09d60a07-8ca1-4351-9bf1-de6ffcfb2159
Cooper, Cyrus
e05f5612-b493-4273-9b71-9e0ce32bdad6
Inskip, Hazel
5fb4470a-9379-49b2-a533-9da8e61058b7
van der Beek, Eline M.
47fdbe30-a882-4ec4-b3f7-086dc3463e21
Sheppard, Allan
a6e27895-05ad-4b0b-98bb-4aa033b7182d
Godfrey, Keith
0931701e-fe2c-44b5-8f0d-ec5c7477a6fd
Lillycrop, Karen
eeaaa78d-0c4d-4033-a178-60ce7345a2cc

Barton, Sheila, Ngo, Sherry, Costello, Paula, Garratt, Emma, El-Heis, Sarah, Antoun, Elie, Clarke-Harris, Rebecca, Murray, Robert, Bhatt, Tejal, Burdge, Graham, Cooper, Cyrus, Inskip, Hazel, van der Beek, Eline M., Sheppard, Allan, Godfrey, Keith and Lillycrop, Karen , EpiGen Consortium (2017) DNA methylation of Th2 lineage determination genes at birth is associated with allergic outcomes in childhood. Clinical & Experimental Allergy, 47 (12), 1599-1608. (doi:10.1111/cea.12988).

Record type: Article

Abstract

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 (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.
Results

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‐κB 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.
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.

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GATA3 paper CEA.R2_clean - Accepted Manuscript
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More information

Accepted/In Press date: 12 July 2017
e-pub ahead of print date: 30 July 2017
Published date: December 2017

Identifiers

Local EPrints ID: 412217
URI: http://eprints.soton.ac.uk/id/eprint/412217
PURE UUID: f38dd909-6446-4024-8ca2-b3a75e7ca433
ORCID for Sheila Barton: ORCID iD orcid.org/0000-0003-4963-4242
ORCID for Emma Garratt: ORCID iD orcid.org/0000-0001-5268-4203
ORCID for Sarah El-Heis: ORCID iD orcid.org/0000-0003-4277-7187
ORCID for Rebecca Clarke-Harris: ORCID iD orcid.org/0000-0002-6888-9518
ORCID for Graham Burdge: ORCID iD orcid.org/0000-0002-7665-2967
ORCID for Cyrus Cooper: ORCID iD orcid.org/0000-0003-3510-0709
ORCID for Hazel Inskip: ORCID iD orcid.org/0000-0001-8897-1749
ORCID for Keith Godfrey: ORCID iD orcid.org/0000-0002-4643-0618
ORCID for Karen Lillycrop: ORCID iD orcid.org/0000-0001-7350-5489

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Date deposited: 14 Jul 2017 16:30
Last modified: 18 Mar 2024 05:09

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Contributors

Author: Sheila Barton ORCID iD
Author: Sherry Ngo
Author: Paula Costello
Author: Emma Garratt ORCID iD
Author: Sarah El-Heis ORCID iD
Author: Elie Antoun
Author: Rebecca Clarke-Harris ORCID iD
Author: Robert Murray
Author: Tejal Bhatt
Author: Graham Burdge ORCID iD
Author: Cyrus Cooper ORCID iD
Author: Hazel Inskip ORCID iD
Author: Eline M. van der Beek
Author: Allan Sheppard
Author: Keith Godfrey ORCID iD
Author: Karen Lillycrop ORCID iD
Corporate Author: EpiGen Consortium

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