Alpha-tryptase gene variation is associated with levels of circulating Ig E and lung function in asthma.

Background Tryptase, 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. Objectives Caucasian 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 Ig E, bronchial hyperresponsiveness to methacholine, forced expiratory volume in 1s ( FEV₁) and atopy and asthma severity scores] was undertaken using family-based association tests ( FBAT). Results Four 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 Ig E levels and higher FEV₁ measurements, while two copies were related to higher serum concentrations of total and dust mite-specific Ig E and greater atopy severity scores. Conclusions and Clinical Relevance Associations of α-tryptase copy number with serum Ig E levels, atopy scores and bronchial function may reflect roles for tryptases in regulating Ig E production and other processes in asthma. [ABSTRACT FROM AUTHOR]