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Haplotypes of G Protein–coupled Receptor 154 Are Associated with Childhood Allergy and Asthma

Institute of Environmental Medicine, Centre for Allergy Research, and Department of Biosciences, Karolinska Institutet; Clinical Allergy Research Unit and Clinical Immunology and Allergy Unit, Department of Medicine, Karolinska Institutet and University Hospital; Department of Occupational and Environmental Health, Stockholm County Council, Stockholm; Clinical Research Centre, Karolinska University Hospital, Huddinge; AstraZeneca R&D Mölndal, Mölndal, Sweden; Institute for Risk Assessment Sciences, University of Utrecht, The Netherlands; University Children's Hospital, Ludwig Maximilian's University Munich, Munich, Germany; GeneOS Limited, Helsinki; Department of Medical Genetics, University of Helsinki, Helsinki, Finland; Division for Immunology, Zurich University Children's Hospital, Zurich, Switzerland; and Children's Hospital, Schwarzach, Austria

Correspondence and requests for reprints should be addressed to Fredrik Nyberg, Institute of Environmental Medicine, Karolinska Institutet, Box 210, Stockholm SE-171 77, Sweden. 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 G protein–coupled receptor for asthma susceptibility gene (GPR154; alias GPRA) 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 sensitization, asthma, and rhinoconjunctivitis, in study populations with diverse environmental backgrounds. Methods: We studied farm children, Steiner school children, and two reference groups from five Western European countries in the cross-sectional PARSIFAL (Prevention of Allergy Risk factors for Sensitization In children related to Farming and Anthroposophic Lifestyle) study and a sample of children from the Swedish birth cohort study BAMSE. DNA samples from 3,113 PARSIFAL and 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 sensitization (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 sensitization. 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 nonrisk (H1/H3) groups, a pattern supported by allelic association of single nucleotide polymorphisms (SNPs) rs324384 and rs324396. Conclusions: Our results indicate that polymorphisms and haplotypes in the haplotype block of GPR154 are associated with asthma, rhinoconjunctivitis, and sensitization in European children.

Key Words: asthma • children • genetic association • GPRA gene • IgE

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