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Sex specific protective effects of interleukin-9 receptor haplotypes on childhood wheezing and sensitisation
  1. E Melén1,2,*,
  2. H Gullstén3,4,*,
  3. M Zucchelli5,
  4. A Lindstedt3,
  5. F Nyberg1,6,
  6. M Wickman1,7,
  7. G Pershagen1,
  8. J Kere3,4,5
  1. 1Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  2. 2Centre for Allergy Research, Karolinska Institutet, Sweden
  3. 3Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden
  4. 4Department of Medical Genetics, University of Helsinki, Finland
  5. 5Department of Biosciences, Karolinska Institutet, Sweden
  6. 6AstraZeneca R&D Mölndal, Mölndal, Sweden
  7. 7Department of Occupational and Environmental Health, Stockholm County Council, Stockholm, Sweden
  1. Correspondence to:
 Dr Erik Melén
 Department of Occupational and Environmental Health, Norrbacka, Karolinska University Hospital, SE-171 76 Stockholm, Sweden;

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Asthma and wheezing are characterised by airway inflammation and reversible airflow obstruction, and seem to have multiple phenotypes that may differ on the basis of age of onset.1 Boys are more prone to develop wheezing and asthma in the early years, whereas girls are more susceptible later in life.2–4 Whether this difference is due to genetic, hormonal, or environmental factors is unclear. We have previously reported an increased risk of wheezing and sensitisation in boys, in agreement with other studies, but could also demonstrate an interaction exceeding additivity between male sex and parental allergic disease, particularly in children with persistent wheezing.5 This finding raised the hypothesis of a sex specific genetic influence on childhood wheezing.

The interleukin-9 receptor gene (IL9R), located on the pseudoautosomal region of X and Y chromosomes (Xq28 and Yq126,7), has previously been associated with asthma in two separate family based data sets.8,9 Haplotype analyses of polymorphic microsatellite markers in one of the studies9 revealed significant associations, predominantly in females, which suggest that the influence may be sex specific. However, to our knowledge no study on associations between IL9R single nucleotide polymorphisms (SNPs) and asthma and allergy has yet been reported.

The IL9 receptor belongs to the haematopoietin receptor superfamily10 and is expressed on T cells, mast cells, macrophages, eosinophils, and neutrophils.11,12 The receptor consists of a specific IL9Rα unit and the common γc subunit, which forms a heteromer upon IL9 binding and activates Janus kinases and STAT factors.10,13 Signals from the IL9 receptor have been shown to be crucial for immunologic processes such as T cell development14 and prevention of apoptosis.13,15 More specifically, IL9 may stimulate release of chemotactic factors from bronchial epithelial cells and smooth muscle cells. …

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  • * These authors have contributed equally to this study.

  • Fredrik Nyberg is employed by AstraZeneca and AstraZeneca also supports his part time adjunct position as Lecturer in Molecular Epidemiology at Karolinska Institutet. AstraZeneca has not contributed any direct financing to this study. Sources of research support: Stockholm County Council, The Swedish Asthma and Allergy Association, The Swedish Foundation for Health Care Science and Allergy Research, The Swedish Society of Medicine, Konsul Th.C. Bergh’s Foundation and The Swedish Environmental Protection Agency.

  • Conflict of interest: none declared.

  • Ethics approval: the study was approved by the ethical committee of Karolinska Institutet, Stockholm.