Clinical & Experimental Allergy

Methylation of IL-2 promoter at birth alters the risk of asthma exacerbations during childhood

Authors

  • J. A. Curtin,

    1. The University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
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    • Equal contributors
  • A. Simpson,

    1. The University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
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    • Equal contributors
  • D. Belgrave,

    1. The University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
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  • A. Semic-Jusufagic,

    1. The University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
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  • A. Custovic,

    Corresponding author
    • The University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK
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    • Joint last authorship.
  • F. D. Martinez

    1. Arizona Respiratory Center, Tucson, AZ, USA
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    • Joint last authorship.

Correspondence:

Professor Adnan Custovic, School of Translational Medicine, 2nd Floor ERC, UHSM, Manchester, M23 9LT, UK. E-mail: adnan.custovic@manchester.ac.uk

Summary

Background

Epigenetic modifications may have a role in asthma susceptibility.

Objective

To investigate whether epigenetic modification at birth of a CpG site necessary for the regulation of IL-2 transcription (IL-2 Site1) is associated with the development of asthma during childhood.

Methods

Methylation of IL-2 Site1 was assessed in cord blood from 303 children (225 with atopic mothers); as controls, we measured methylation of a site not important in the transcription of IL-2 (IL-2 Site7) and methylation of the LINE-1 repetitive element. Children were followed to the age of 8 years. Information on severe asthma exacerbations and hospital admissions was collected from child's primary care medical record. To account for potential confounding by bronchiolitis, we used exacerbations/hospitalizations after age 1 year as primary outcomes.

Results

There were 49 severe exacerbations amongst 33 children, and 22 hospital admissions amongst 11 children. The risk of asthma exacerbation increased 1.07-fold (95% CI 1.01–1.14, = 0.03) and the risk of hospital admission increased 1.12-fold (95% CI 1.04–1.20, = 0.002) for each one per cent increase in IL-2 Site1 methylation. Children who were admitted to hospital at any time-point had significantly higher IL-2 Site1 methylation than children not admitted to hospital (= 0.007). There was a significant interaction between age at exacerbation (= 0.03) or hospital admission (P = 0.02) and methylation, with the effect of methylation increasing with increasing age. Methylation of the control IL-2 Site7 or LINE-1 was not a significant predictor of asthma exacerbations/hospital admission, and we found no association between IL-2 Site1 methylation and hospital admissions for other reasons (0.99 [0.92–1.06]). Cord blood mononuclear cell phytohemagglutinin-stimulated lymphoproliferative responses decreased significantly with increasing IL-2 Site1 methylation (P < 0.001).

Conclusions

Increasing methylation in cord blood of a functional CpG site in the IL-2 promoter is associated with increased likelihood of severe asthma exacerbations and hospital admissions for asthma/wheeze between ages of 2 and 8 years.

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