Haplotypes of G protein-coupled receptor 154 are associated with childhood allergy and asthma.

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 > or = 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.

[1]  S. Weiland,et al.  G-Protein-coupled receptor polymorphisms are associated with asthma in a large German population. , 2005, American journal of respiratory and critical care medicine.

[2]  J. Kere,et al.  Sex specific protective effects of interleukin-9 receptor haplotypes on childhood wheezing and sensitisation , 2004, Journal of Medical Genetics.

[3]  J. Kere,et al.  Positionally cloned susceptibility genes in allergy and asthma. , 2004, Current opinion in immunology.

[4]  H. Shin,et al.  Lack of association of GPRA (G protein-coupled receptor for asthma susceptibility) haplotypes with high serum IgE or asthma in a Korean population. , 2004, The Journal of allergy and clinical immunology.

[5]  J. Kere,et al.  Influence of male sex and parental allergic disease on childhood wheezing: role of interactions , 2004, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[6]  Ian Purvis,et al.  Detection of genotyping errors by Hardy–Weinberg equilibrium testing , 2004, European Journal of Human Genetics.

[7]  Thomas J. Hudson,et al.  Characterization of a Common Susceptibility Locus for Asthma-Related Traits , 2004, Science.

[8]  B. Raby,et al.  Asthma genetics 2003. , 2004, Human molecular genetics.

[9]  Gonçalo Abecasis,et al.  Positional cloning of a novel gene influencing asthma from Chromosome 2q14 , 2003, Nature Genetics.

[10]  E. Gelfand,et al.  A comparison of the clinical characteristics of children and adults with severe asthma. , 2003, Chest.

[11]  G. Abecasis,et al.  Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma , 2003, Nature Genetics.

[12]  Steuart Rorke,et al.  Association of the ADAM33 gene with asthma and bronchial hyperresponsiveness , 2002, Nature.

[13]  J. Celedón,et al.  Lack of association between antibiotic use in the first year of life and asthma, allergic rhinitis, or eczema at age 5 years. , 2002, American journal of respiratory and critical care medicine.

[14]  M. Wickman,et al.  Environmental risk factors for allergy and socioeconomic status in a birth cohort (BAMSE) , 2002, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[15]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[16]  D. Schaid,et al.  Score tests for association between traits and haplotypes when linkage phase is ambiguous. , 2002, American journal of human genetics.

[17]  J. Ioannidis,et al.  Replication validity of genetic association studies , 2001, Nature Genetics.

[18]  Dennis Nowak,et al.  Exposure to farming in early life and development of asthma and allergy: a cross-sectional survey , 2001, The Lancet.

[19]  M. Daly,et al.  High-resolution haplotype structure in the human genome , 2001, Nature Genetics.

[20]  J. Bousquet,et al.  A revised nomenclature for allergy: An EAACI position statement from the EAACI nomenclature task force , 2001, Allergy.

[21]  Pardis C Sabeti,et al.  Linkage disequilibrium in the human genome , 2001, Nature.

[22]  Eric S. Lander,et al.  The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes , 2000, Nature Genetics.

[23]  N. Rothman,et al.  Population stratification in epidemiologic studies of common genetic variants and cancer: quantification of bias. , 2000, Journal of the National Cancer Institute.

[24]  P. Gustafsson,et al.  Asthma from childhood to adulthood: asthma severity, allergies, sensitization, living conditions, gender influence and social consequences. , 2000, Respiratory medicine.

[25]  E. Mutius,et al.  Reduced risk of hay fever and asthma among children of farmers , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[26]  G. Pershagen,et al.  Atopy in children of families with an anthroposophic lifestyle , 1999, The Lancet.

[27]  R. Barbee,et al.  The natural history of asthma. , 1998, The Journal of allergy and clinical immunology.

[28]  M. Rijn,et al.  A murine model of allergic rhinitis: studies on the role of IgE in pathogenesis and analysis of the eosinophil influx elicited by allergen and eotaxin. , 1998, The Journal of allergy and clinical immunology.

[29]  J. Soriano,et al.  Total serum IgE is associated with asthma independently of specific IgE levels. The Spanish Group of the European Study of Asthma. , 1996, The European respiratory journal.

[30]  L. Excoffier,et al.  Maximum-likelihood estimation of molecular haplotype frequencies in a diploid population. , 1995, Molecular biology and evolution.

[31]  D. Strachan,et al.  International Study of Asthma and Allergies in Childhood (ISAAC): rationale and methods. , 1995, The European respiratory journal.

[32]  P. Demoly,et al.  [A revised nomenclature for allergy]. , 2004, Archives de pediatrie : organe officiel de la Societe francaise de pediatrie.

[33]  A. Bush,et al.  Early thickening of the reticular basement membrane in children with difficult asthma. , 2003, American journal of respiratory and critical care medicine.