Alpha‐tryptase gene variation is associated with levels of circulating IgE 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 ?-tryptase, an allelic variant of the more extensively studied ?-tryptase, is absent in substantial numbers of the general population. The degree to which ?-tryptase expression may be associated with asthma has not been studied. We have investigated the ?-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 ?-tryptase alleles, using high resolution melting assays. Standards for the possible ?-/?-tryptase ratios were constructed by cloning ?-and ?-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, FEV1, and atopy and asthma severity scores) were undertaken using family based association tests (FBAT). Results Four consistent melting patterns for the ?-tryptase genotype were identified with alleles carrying null, one or two copies of the ?-tryptase allele. Possessing one copy of ?-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 Relevance Associations of ?-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.