The Journal of Allergy and Clinical Immunology
Volume 120, Issue 6 , Pages 1308-1315, December 2007

A polymorphism in CD14 modifies the effect of farm milk consumption on allergic diseases and CD14 gene expression

  • Christian Bieli, MD

      Affiliations

    • Institute of Social and Preventive Medicine, University of Basel, Basel, Switzerland
    • Corresponding Author InformationReprint requests: Christian Bieli, MD, Institute of Social and Preventive Medicine, University of Basel, Steinengraben 49, 4051 Basel, Switzerland.
    • These authors contributed equally to this work.
    • ,
  • Waltraud Eder, MD

      Affiliations

    • Arizona Respiratory Center, University of Arizona, Tucson, Ariz
    • University Children's Hospital Munich, Munich, Germany
    • These authors contributed equally to this work.
    • ,
  • Remo Frei, MSc

      Affiliations

    • Zurich University Children's Hospital, Zurich, Switzerland
    • ,
  • Charlotte Braun-Fahrländer, MD

      Affiliations

    • Institute of Social and Preventive Medicine, University of Basel, Basel, Switzerland
    • ,
  • Walt Klimecki, PhD

      Affiliations

    • Arizona Respiratory Center, University of Arizona, Tucson, Ariz
    • ,
  • Marco Waser, PhD

      Affiliations

    • Institute of Social and Preventive Medicine, University of Basel, Basel, Switzerland
    • ,
  • Josef Riedler, MD

      Affiliations

    • Children's Hospital Schwarzach, Schwarzach, Austria
    • ,
  • Erika von Mutius, MD, MSc

      Affiliations

    • University Children's Hospital Munich, Munich, Germany
    • ,
  • Annika Scheynius, MD, PhD

      Affiliations

    • Department of Medicine, Clinical Allergy Research Unit, Karolinska Institutet and University Hospital, Solna, Stockholm, Sweden
    • ,
  • Göran Pershagen, MD, PhD

      Affiliations

    • Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden
    • ,
  • Gert Doekes, PhD

      Affiliations

    • Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands
    • ,
  • Roger Lauener, MD

      Affiliations

    • Zurich University Children's Hospital, Zurich, Switzerland
    • ,
  • Fernando D. Martinez, MD

      Affiliations

    • Arizona Respiratory Center, University of Arizona, Tucson, Ariz
    • ,
  • PARSIFAL study group

      Affiliations

    • The Prevention of Allergy – Risk Factors for Sensitisation in Children Related to Farming and Anthroposophic Lifestyle study group: Tobias Alfvén, Johan Alm, Anna Bergström, Lars Engstrand, Helen Flöistrup, Marianne van Hage, Niclas Håkansson, Gunnar Lilja, Fredrik Nyberg, Jackie Swartz, and Magnus Wickman (Sweden); Felix Sennhauser, Johannes Wildhaber, and Alex Möller (Switzerland); Bert Brunekreef, Dieneke Schram-Bijkerk, Mirian Boeve, Jeroen Douwes, Machteld Huber, and Mirjam Matze (The Netherlands); Marcus R. Benz, Jörg Budde, and Markus Ege (Germany); Ellen Üblagger, Gertraud Weiss, and Mynda Schreuer (Austria); and Karin B. Michels (United States).

Received 20 December 2006; received in revised form 5 June 2007; accepted 19 July 2007. published online 08 October 2007.

Background

Consumption of farm milk in early life is associated with less asthma and allergies.

Objective

We hypothesized that genetic variation in the innate immunity receptor CD14 might modify the association between farm milk consumption and asthma and atopy.

Methods

Questionnaire data, serum IgE levels, and genotypes for 4 single nucleotide polymorphisms in CD14 were assessed in farmers' and nonfarmers' children from 2 European populations (Allergy and Endotoxin study, n = 576; Prevention of Allergy Risk factors for Sensitization in children related to Farming and Anthroposophic Lifestyle study, n = 1539). In a subsample (n = 222) CD14 gene expression was measured in peripheral blood leukocytes. The effects of farm milk and CD14 genotypes on asthma, allergies, and CD14 expression and their interactions were investigated.

Results

We found a significant interaction between genetic variation in CD14/−1721 and farm milk consumption. Adjusted odds ratios for the association between farm milk and asthma varied between the genotypes: AA, 0.18 (95% CI, 0.07-0.47); AG, 0.47 (95% CI, 0.26-0.86); and GG, 0.98 (95% CI, 0.46-2.08). Similar patterns were observed for symptoms of allergic rhinoconjunctivitis and pollen sensitization. CD14/−1721 also modified the association between farm milk and CD14 gene expression (adjusted geometric means ratios: AA, 1.61 (95% CI, 0.98-2.66); AG, 1.11 (95% CI, 0.71-1.72); and GG, 0.76 (95% CI, 0.39-1.48).

Conclusion

The protective effect of farm milk consumption on allergic diseases is stronger in children carrying the A allele in CD14/−1721 than in children homozygous for the G allele. This might be mediated through farm milk–induced upregulated CD14 gene expression.

Clinical implications

Our results support the hypothesis that the inverse association between farm milk consumption and allergic diseases is mediated by CD14-activated innate immune mechanisms.

Key words: Allergy, asthma, CD14, gene-environment interaction, gene expression, farming, epidemiology

Abbreviations used: ALEX, Allergy and Endotoxin, OR, Odds ratio, PARSIFAL, Prevention of Allergy – Risk Factors for Sensitisation in Children Related to Farming and Anthroposophic Lifestyle, PBLC, Peripheral blood leukocyte, SNP, Single nucleotide polymorphism

 

 The Prevention of Allergy – Risk Factors for Sensitisation in Children Related to Farming and Anthroposophic Lifestyle study was supported by a research grant from the European Union (QLRT 1999-01391) and by funding from the Swedish Foundation for Health Care Science and Allergy Research; the Swiss National Foundation (grant no. 32-100324); the National Heart, Lung, and Blood Institute (grant nos. HL66800, HL66806, and HL67672); and the Kühne Foundation. The Allergy and Endotoxin study was supported by the Austrian FWF (grant 14015-Med); Propter Hominis (Liechtenstein); the Zurich Lung Association; UBS, Switzerland; the Bavarian Ministry for the Environment; and the National Heart, Lung, and Blood Institute (grant nos. HL66800, HL66806, and HL67672).

 Disclosure of potential conflict of interest: F. D. Martinez has consulting arrangements with Pfizer and Genentech, has patent licensing arrangements with the CARE Network, and has received lecture fees from Merck. The rest of the authors have declared that they have no conflict of interest.

PII: S0091-6749(07)01432-7

doi:10.1016/j.jaci.2007.07.034

The Journal of Allergy and Clinical Immunology
Volume 120, Issue 6 , Pages 1308-1315, December 2007

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