Alpha‐tryptase gene variation is associated with levels of circulating IgE and lung function in asthma

A M Abdelmotelb,M J Rose‐Zerilli,S T Holgate,J W Holloway,A F Walls,S J Barton

doi:10.1111/cea.12259

A M Abdelmotelb, M J Rose‐Zerilli + Show 4 more

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https://doi.org/10.1111/cea.12259

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Abstract

summaryBackgroundTryptase, a major secretory product of human mast cells has been implicated as a key mediator of allergic inflammation. Genetic variation in the tryptases is extensive, and α-tryptase, an allelic variant of the more extensively studied β-tryptase, is absent in substantial numbers of the general population. The degree to which α-tryptase expression may be associated with asthma has not been studied. We have investigated the α-tryptase gene copy number variation and its potential associations with phenotypes of asthma.ObjectivesCaucasian families (n = 341) with at least two asthmatic siblings (n = 1350) were genotyped for the α-tryptase alleles, using high-resolution melting assays. Standards for the possible α-/β-tryptase ratios were constructed by cloning α-and β-tryptase PCR products to generate artificial templates. Association analysis of asthma affection status and related phenotypes [total and allergen-specific serum IgE, bronchial hyperresponsiveness to methacholine, forced expiratory volume in 1s (FEV1) and atopy and asthma severity scores] was undertaken using family-based association tests (FBAT).ResultsFour consistent melting patterns for the α-tryptase genotype were identified with alleles carrying null, one or two copies of the α-tryptase allele. Possessing one copy of α-tryptase was significantly associated with lower serum levels of total and dust mite-specific IgE levels and higher FEV1 measurements, while two copies were related to higher serum concentrations of total and dust mite-specific IgE and greater atopy severity scores.Conclusions and Clinical RelevanceAssociations of α-tryptase copy number with serum IgE levels, atopy scores and bronchial function may reflect roles for tryptases in regulating IgE production and other processes in asthma.

Highlights

The serine protease tryptase has the potential to act as a key mediator in asthma and allergy, and increased levels have been detected in the airways of asthmatics [reviewed in Ref. 1]
The digest method allowed the presence or absence of the a-tryptase allele to be detected in an individual, but did not permit quantification of copy number
When an optimized capillary electrophoresis technique was applied to samples, no a-tryptase alleles not containing the 10- to 11-bp deletion were detected in 96 samples, suggesting the frequency of any such allele was < 0.5% in our population

Summary

Introduction

The serine protease tryptase has the potential to act as a key mediator in asthma and allergy, and increased levels have been detected in the airways of asthmatics [reviewed in Ref. 1]. A range of functions found for b-tryptase would be consistent with this serine protease contributing to inflammation and tissue remodelling. It can interact with various cell types, stimulate cytokine release from epithelial [2], endothelial [3, 4] and airway smooth muscle cells [5], provoke mast cell degranulation [6, 7], induce collagen secretion by fibroblasts [8] and act as a growth factor for fibroblasts [8], airway smooth muscle [5, 9] and epithelial cells [2]. Little is known of the extent of copy number variation and the potential association with asthma or other conditions

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