RESUMO
Sialic acid-binding immunoglobulin-like lectin-8 (Siglec-8) promotes the apoptosis of eosinophils and inhibits FcvarepsilonRI-dependent mediator release from mast cells. We investigated the genetic association between sequence variants in Siglec-8 and diagnosis of asthma, total levels of serum IgE (tIgE), and diagnosis of eosinophilic esophagitis (EE) in diverse populations. The effect of sequence variants on Siglec-8 glycan ligand-binding activity was also examined. Significant association with asthma was observed for SNP rs36498 (odds ratios (OR), 0.69, P=8.8 x 10(-5)) among African Americans and for SNP rs10409962 (Ser/Pro) in the Japanese population (OR, 0.69, P=0.019). Supporting this finding, we observed association between SNP rs36498 and current asthma among Brazilian families (P=0.013). Significant association with tIgE was observed for SNP rs6509541 among African Americans (P=0.016), and replicated among the Brazilian families (P=0.02). In contrast, no association was observed with EE in Caucasians. By using a synthetic polymer decorated with 6'-sulfo-sLe(x), a known Siglec-8 glycan ligand, we did not find any differences between the ligand-binding activity of HEK293 cells stably transfected with the rs10409962 risk allele or the WT allele. However, our association results suggest that the Siglec8 gene may be a susceptibility locus for asthma.
Assuntos
Antígenos CD/genética , Antígenos de Diferenciação de Linfócitos B/genética , Asma/genética , Predisposição Genética para Doença , Lectinas/genética , Polimorfismo de Nucleotídeo Único , Adolescente , Adulto , Negro ou Afro-Americano/genética , Povo Asiático/genética , Asma/etnologia , Brasil , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/fisiologia , População Branca/genética , Adulto JovemRESUMO
BACKGROUND: Asthma is a complex disease characterized by a high prevalence of allergic diathesis and the almost ubiquitous presence of upper airway disease (eg rhinitis). Previously, we observed linkage of asthma among Afro-Caribbean families to markers in chromosome 12q, which contains a number of genes encoding for products closely related to allergic airway inflammation and disease. OBJECTIVE: To identify susceptibility loci in chromosome 12q contributing to the genetics of upper and lower airway diseases and to expand the region to include genes encoding IFN- ã(IFNG) and one of the signal transducers and activators of transcription (STAT6), we conducted further linkage studies among 33 multiplex families. METHODS: We characterized 528 subjects from Barbados for asthma; 82 percent were characterized for allergic rhinitis. Two-point and multipoint linkage analysis of 22 microsatellite markers (spanning ~79 centimorgan) was performed. RESULTS: Affected sib-pair analysis revealed significant evidence for linkage to asthma over approximately 30 cM (P < .05 to .002), with the best evidence for linkage at a CA repeat polymorphism in the first intron of IFNG in 12q21.1 (P = .002). Evidence of linkage to allergic rhinitis was observed in the same region (D12S313, P = .006, and IFNGCA, P = .01. respectively). Multipoint linkage analysis also provided evidence for linkage to asthma, with the best nonparametric linkage analysis score at D12S326 (nonparametric linkage score = 3.8, P = .0008). Modest evidence for linkage to allergic rhinitis was observed next to D12S326 at D12S1052 (p = .036) CONCLUSIONS: Our findings suggest that (1) one or more loci in the chromosome 12q13.12-q23.3 region are contributing to the expresstion of the clinical phenotype asthma and the strongest evidence for linkage is in a region near the gene encoding IFNG and (2) a susceptibility locus for both asthma and allergic rhinitis maps to this region.