Association and functional relevance of E237G, a polymorphism of the high-affinity immunoglobulin E-receptor beta chain gene, to airway hyper-responsiveness

Abstract

Background: The hyper-sensitivity reaction of IgE, with its high-affinity receptors (Fc epsilon RI), is central to the phenomenon of atopic diseases.

Objective: To evaluate the genetic effects of non-synonymous single-nucleotide polymorphisms (SNPs) of Fc epsilon RI on intermediate phenotypes of asthma, i.e. atopy and airway hyper-responsiveness (AHR), in the Korean general population.

Subjects and Methods: Atopy and AHR were evaluated in a cohort of 2055 subjects, aged 10-18 years, using skin prick tests (SPTs) for common aeroallergens and total serum IgE and methacholine bronchial provocation tests. All Fc epsilon RI-alpha, Fc epsilon RI-beta, and Fc epsilon RI-gamma gene exons of 24 healthy subjects were sequenced to locate informative non-synonymous SNPs (minor allele frequency > 2%). Informative SNPs were then scored, using the high-throughput single base extension method. Relative risk (RR) was determined by multiple logistic regression analysis, after adjusting for confounding factors. The functional relevance of non-synonymous SNPs was analysed using the sorting intolerant from tolerant (SIFT) program.

Results: The SNP search found only one informative non-synonymous SNP in Fc epsilon RI-beta: E237G (minor allele frequency=0.21). The positive rate of AHR was lower among subjects with the 237(*)E allele than among those with 237(*)G [RR (95% confidence interval)=0.41 (0.19-0.89); P=0.01]. However, the E237G substitution was not associated with either a positive SPT response or total serum IgE levels. Sequence evolution analysis predicted that the E237G variation is an intolerant amino acid substitution, with functional importance.

Conclusion: In the Korean general population, AHR is significantly associated with the E237G polymorphism of Fc epsilon RI-beta, which results in an intolerant amino acid substitution.