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Erik Melén,^1,2 Fredrik Nyberg,^1,3 Cecilia M. Lindgren,^4,5 Niklas Berglind,^1,6 Marco Zucchelli,^4,7 Emma Nordling,⁶ Jenny Hallberg,⁸ Magnus Svartengren,^6,8 Ralf Morgenstern,¹ Juha Kere,⁴ Tom Bellander,^1,6 Magnus Wickman,^1,9 and Göran Pershagen¹

¹Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; ²Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden; ³AstraZeneca R&D Mölndal, Mölndal, Sweden; ⁴Department of Biosciences at Novum, Karolinska Institutet, Stockholm, Sweden; ⁵Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom; ⁶Department of Occupational and Environmental Health, Stockholm County Council, Stockholm, Sweden; ⁷BEA Bioinformatics Core Facility at Novum, Karolinska Institutet, Stockholm, Sweden; ⁸Department of Public Health Sciences, Karolinska Institutet, Stockholm, Sweden; ⁹Sachs Children's Hospital, Stockholm, Sweden

Abstract
Background: Air pollutants may induce airway inflammation and sensitization due to generation of reactive oxygen species. The genetic background to these mechanisms could be important effect modifiers.

Objective: Our goal was to assess interactions between exposure to air pollution and single nucleotide polymorphisms (SNPs) in the β2-adrenergic receptor (ADRB2) , glutathione S-transferase P1 (GSTP1) , and tumor necrosis factor (TNF) genes for development of childhood allergic disease.

Methods: In a birth cohort originally of 4,089 children, we assessed air pollution from local traffic using nitrogen oxides (traffic NO_x) as an indicator based on emission databases and dispersion modeling and estimated individual exposure through geocoding of home addresses. We measured peak expiratory flow rates and specific IgE for inhalant and food allergens at 4 years of age, and selected children with asthma symptoms up to 4 years of age (n = 542) and controls (n = 542) for genotyping.

Results: Interaction effects on allergic sensitization were indicated between several GSTP1 SNPs and traffic NO_x exposure during the first year of life (p_nominal < 0.001–0.06) . Children with Ile105Val/Val105Val genotypes were at increased risk of sensitization to any allergen when exposed to elevated levels of traffic NO_x (for a difference between the 5th and 95th percentile of exposure: odds ratio = 2.4 ; 95% confidence interval, 1.0–5.3) . In children with TNF-308 GA/AA genotypes, the GSTP1–NO_x interaction effect was even more pronounced. We observed no conclusive interaction effects for ADRB2.

Conclusion: The effect of air pollution from traffic on childhood allergy appears to be modified by GSTP1 and TNF variants, supporting a role of genes controlling the antioxidative system and inflammatory response in allergy.

Key words: ADRB2, air pollution, allergy, asthma, genetics, GSTP1, interaction, nitrogen oxides, polymorphism, TNF. Environ Health Perspect 116:1077–1084 (2008) . doi:10.1289/ehp.11117 available via http://dx.doi.org/ [Online 25 March 2008]

Address correspondence to E. Melén, Astrid Lindgren Children's Hospital, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. Telephone: 468-517-700-00. Fax: 468-304-571. E-mail: erik.melen@ki.se

Supplemental Material is available online at http://www.ehponline.org/members/2008/11117/suppl.pdf

We thank all children and parents in the BAMSE (the Children, Allergy, Milieu, Stockholm, Epidemiological Survey) cohort, all nurses at the health care centers, and the BAMSE staff, especially S. Gustavsson and E. Hallner, at the Department of Occupational and Environmental Health, Stockholm County Council. We also thank A. Lindstedt and V. Mäkelä at the Clinical Research Centre, Karolinska University Hospital, for genotyping assistance and M. van Hage, Department of Medicine, Karolinska University Hospital, for IgE analyses.

This research was supported by the Swedish Environmental Protection Agency, Stockholm County Council, Swedish Asthma and Allergy Association, Swedish Foundation for Health Care Science and Allergy Research, Swedish Society of Medicine, Konsul Th.C. Bergh's Foundation, and Stiftelsen Frimurare Barnhuset i Stockholm.

F.N. 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. The other authors declare they have no competing financial interests.

Received 4 December 2007 ; accepted 21 March 2008.