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Published ahead of print on February 11, 2005, doi:10.1164/rccm.200410-1317OC

Am. J. Respir. Crit. Care Med., Volume 171, Number 10, May 2005, 1089-1095

A more recent version of this article appeared on May 15, 2005
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Submitted on October 13, 2004
Accepted on January 21, 2005

Haplotypes of G-protein-coupled Receptor 154 are Associated with Childhood Allergy and Asthma

Erik Melen1, Sara Bruce2, Gert Doekes3, Michael Kabesch4, Tarja Laitinen5, Roger Lauener6, Cecilia M Lindgren7, Josef Riedler8, Annika Scheynius9, Marianne van Hage-Hamsten10, Juha Kere11, Goran Pershagen12, Magnus Wickman12, Fredrik Nyberg13*, and PARSIFAL Genetics Study Group14

1 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allergy Research, Karolinska Institutet, Stockholm, Sweden, 2 Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden; Department of Biosciences, Karolinska Institutet, Stockholm, Sweden; Clinical Allergy Research Unit, Department of Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden, 3 Institute for Risk Assessment Sciences, University of Utrecht, Utrecht, The Netherlands, 4 University Children's Hospital, Ludwig Maximilian's University Munich, Munich, Germany, 5 GeneOS Limited, Helsinki, Finland; Department of Medical Genetics, University of Helsinki, Helsinki, Finland, 6 Division for Immunology, Zurich University Children's Hospital, Zurich, Switzerland, 7 Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden; Department of Biosciences, Karolinska Institutet, Stockholm, Sweden, 8 Children's Hospital Schwarzach, Schwarzach, Austria, 9 Clinical Allergy Research Unit, Department of Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden, 10 Department of Medicine, Clinical Immunology and Allergy Unit, Karolinska Institutet and University Hospital, Stockholm, Sweden, 11 Clinical Research Centre, Karolinska University Hospital, Huddinge, Sweden; Department of Biosciences, Karolinska Institutet, Stockholm, Sweden; GeneOS Limited, Helsinki, Finland, 12 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; Department of Occupational and Environmental Health, Stockholm County Council, Stockholm, Sweden, 13 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden; AstraZeneca R and D Molndal, Molndal, Sweden, 14 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden

* To whom correspondence should be addressed. E-mail: Fredrik.Nyberg{at}imm.ki.se.

Rationale: Allergic diseases are influenced by both genes and environment. A 70-kb haplotype-block in the GPR154 gene (alias GPRA; G-protein-coupled receptor for asthma susceptibility) on chromosome 7p was recently identified to influence susceptibility to asthma and elevated total serum IgE levels in adults. Objectives: To assess the impact of GPR154 on childhood allergic disease, including allergic sensitisation, asthma and rhinoconjunctivitis, in study populations with diverse environmental backgrounds. Methods: We studied farm children, Steiner school children and two reference groups from 5 Western European countries in the cross-sectional PARSIFAL study and a sample of children from the Swedish birth cohort study BAMSE. DNA samples from 3,113 (PARSIFAL) + 800 (BAMSE) children were genotyped for 7 GPR154 polymorphisms and haplotypes were inferred. The proportions of alleles and haplotypes (H1-H7) were compared in affected children with their healthy counterparts. Results: Data indicate a global association of the haplotype-block to sensitisation (allergen-specific serum IgE ≥0.35 kU/L, p=0.022), with significant haplotype-specific associations for H1, H5 and H6. Haplotypes H1 and H5 were also significantly associated with childhood allergic asthma (p=0.045 and p=0.023, respectively), and H5 to asthma regardless of sensitisation. A broader involvement of GPR154 in allergic diseases was further supported in allergic rhinoconjunctivitis (H3: p=0.046). The associated haplotypes could be allocated into risk (H5/H6) and non-risk (H1/H3) groups, a pattern supported by allelic association of SNPs rs324384 and rs324396. Conclusions: Our results indicate that polymorphisms and haplotypes in the haplotype block of GPR154 are associated with asthma, rhinoconjunctivitis and sensitisation in European children.
Key words: Asthma, children, genetic association, GPRA gene, IgE




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