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

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.

Impact of naturally forming human α/β-tryptase heterotetramers in the pathogenesis of hereditary α-tryptasemia

“…Importantly, the portion of tryptase activity due to α/β-tryptase increases with the α-tryptase gene dosage. Consequently, an α-tryptase genedosage effect associated with a particular clinical phenotype, as shown in the current study for a cutaneous response to vibration or as reported for severe Dengue infection (Velasquez et al, 2015) or asthma (Abdelmotelb et al, 2014), might implicate involvement of α/β-tryptase. Also, as α-tryptase gene deficiency varies among individuals with Asian, European, and African backgrounds (Trivedi et al, 2009), affecting α/β-tryptase content, a role for these heterotetramers can now be considered in the context of natural selection.…”

Half-life of IgE in serum and skin: Consequences for anti-IgE therapy in patients with allergic disease

“…29–31 There is also some evidence that polymorphisms or copy number variations in other mast cell–derived proteases, including α-tryptase and chymase, are correlated with the serum IgE level. 32–34 However, in vivo human IgE has been postulated to associate with other plasma proteins, including α 1 -antitrypsin, to protect it from degradation. 30 …”

Mast cell proteases as pharmacological targets

“…Individuals with 4 active β genes lack α genes altogether, a situation that arises because α genes in most cases are alleles at a locus that also accepts β genes. Some individuals also may have duplicated loci containing α genes (Abdelmotelb et al, 2014). Among active β tryptases, one of the common variations is loss of an N-linked glycosylation site in βII tryptase, compared to the classical βI form, which may alter stability.…”