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The protective effect of farm animal exposure on childhood allergy is modified by NPSR1 polymorphisms
  1. S Bruce1,2,
  2. F Nyberg3,4,
  3. E Melén4,5,
  4. A James6,7,
  5. V Pulkkinen2,
  6. C Orsmark-Pietras1,
  7. A Bergström4,
  8. B Dahlén6,7,
  9. M Wickman4,8,
  10. E von Mutius9,
  11. G Doekes10,
  12. R Lauener11,
  13. J Riedler12,
  14. W Eder9,13,
  15. M van Hage14,
  16. G Pershagen4,15,
  17. A Scheynius16,
  18. J Kere1,2,17
  1. 1
    Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden
  2. 2
    Department of Medical Genetics, University of Helsinki, Helsinki, Finland
  3. 3
    Astra Zeneca R&D Mölndal, Mölndal, Sweden
  4. 4
    Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
  5. 5
    Astrid Lindgren Children’s Hospital, Karolinska University Hospital Solna, Sweden
  6. 6
    Department of Medicine, Division of Respiratory Medicine and Allergy, Karolinska University Hospital, Huddinge, Sweden
  7. 7
    Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden
  8. 8
    Sachs Children’s Hospital, Stockholm, Sweden
  9. 9
    University Children’s Hospital, Ludwig Maximilians University Munich, Munich, Germany
  10. 10
    Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
  11. 11
    Children’s Hospital, Zurich University, Zurich, Switzerland
  12. 12
    Children’s Hospital Schwarzach, Schwarzach, Austria
  13. 13
    Children’s Hospital, Paracelsus Medical University, Salzburg, Austria
  14. 14
    Clinical Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institutet and University Hospital, Solna, Sweden
  15. 15
    Department of Occupational and Environmental Health, Stockholm County Council, Stockholm, Sweden
  16. 16
    Clinical Allergy Research Unit, Department of Medicine Solna, Karolinska Institutet and University Hospital, Solna, Sweden
  17. 17
    Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden
  1. S Bruce, Department of Biosciences and Nutrition, Hälsovägen 7-9, 14157 Huddinge, Sweden; sara.bruce{at}biosci.ki.se

Abstract

Background: Little is known about the asthma candidate gene neuropeptide S receptor 1 (NPSR1) in relation to environmental exposures, but recent evidences suggest its role as an effect modifier.

Objectives: To explore the interaction between NPSR1 polymorphisms and environmental exposures related to farming lifestyle and to study the in vitro effects of lipopolysaccharide (LPS) stimulation on NPSR1 expression levels.

Methods: We studied 3113 children from PARSIFAL, a European cross-sectional study on environmental/lifestyle factors and childhood allergy, partly focused on children brought up on a farm. Information on exposures and outcomes was primarily obtained from parental questionnaires. Seven tagging polymorphisms were analysed in a conserved haplotype block of NPSR1. Multivariate logistic regression was used to evaluate a multiplicative model of interaction. NPSR1 protein and messenger RNA (mRNA) levels in monocytes were measured after LPS stimulation by fluorescence activated cell sorting (FACS) and quantitative real-time polymerase chain reaction (PCR).

Results: A strong interaction was seen between current regular contact to farm animals and several NPSR1 polymorphisms, particularly rs323922 and rs324377 (p<0.005), with respect to allergic symptoms. Considering the timing of initiation of such current regular farm animal contact, significant interactions with these and two additional polymorphisms (SNP546333, rs740347) were revealed. In response to LPS, NPSR1-A protein levels in monocytes were upregulated (p = 0.002), as were NPSR1-A mRNA levels (p = 0.02).

Conclusions: The effect of farm animal contact on the development of allergic symptoms in children is modified by NPSR1 genetic background.

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Footnotes

  • Competing interests: SB, EM, AJ, COP, AB, BD, MW, EvM, GD, RL, JR, WE, and MvH declare no competing interests; AS was appointed to a full-time professorship in Clinical Allergy Research by Karolinska Institutet of Stockholm, Sweden in November 1995; this was a donation given at one occasion for 15 million SEK from Kabi Pharmacia, Uppsala, Sweden and the annual proceeds cover the salary for AS and the salary for one administrative assistant/research assistant until retirement and AS has no obligation to the donor; JK and VP are co-inventors on patents related to the discovery of GPRA as an asthma susceptibility gene; GP received $38 000 in 2002 and $10 000 in 2003 from AstraZeneca as research grants for epidemiological registry studies of comorbidities in lung cancer patients; FN is employed by AstraZeneca (AZ), holds some shares and AZ also supports his academic part-time adjunct position at Karolinska Institutet.

  • Funding: This study was supported by the Stockholm County Council, the Swedish Foundation for Health Care Science and Allergy Research, the Swedish Society of Medicine, Konsul Th. C. Bergh’s Foundation, the Swedish Environmental Protection Agency, the European Union QLRT 1999-01391, the Kuehne Foundation, the Swedish Foundation for Health Care Science and Allergy Research, the Swedish Asthma and Allergy Association’s Research Foundation, the Swedish Research Council, the Swedish Heart and Lung Foundation, Sigrid Jusélius Foundation, Päivikki and Sakari Sohlberg Foundation, the Academy of Finland and the Swiss National Research Foundation.

  • Patient consent: Obtained

  • ▸ Additional tables and figure are published online only at http://jmg.bmj.com/content/vol46/issue3

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