Tryptase loss-of-function mutations reduce tryptase expression and predict asthmatic response to anti-IgE therapy

Background: Tryptase is a major mast cell product implicated in asthma by promoting bronchoconstriction and stromal cell hyperplasia. Loss-of-function mutations in genes TPSAB1 and TPSB2 encoding tryptases are common in ethnically diverse populations. We hypothesized that these mutations decrease tryptase activity and predict asthmatic clinical response to anti-IgE therapy. Objective: To understand the relationship of tryptase loss-of-function mutations with mast cell tryptase activity ex vivo, circulating tryptase levels, and clinical response to anti-IgE therapy. Methods: Active tryptase allele count was determined by direct sequencing of TPSAB1 and TPSB2 genes and counting functional alleles. Tryptase activity was measured by enzymatic assay in human foreskin mast cell lysates. Total tryptase in serum/plasma was assessed by ELISA. Post hoc pharmacogenetic analysis was conducted of the EXTRA study (NCT00314574), a double-blind placebo controlled study of allergic moderate to severe asthmatics treated with Xolair (anti-IgE). Results: Active tryptase allele count correlated with 1) tryptase activity in primary mast cells (P<0.05, N=101 donors), 2) circulating tryptase levels in two studies of severe asthma (P<0.001, N=105 and N=36), and 3) FEV1% improvement in asthmatics treated with Xolair when comparing subjects with 1 or 2 versus 3 or 4 active alleles (P<0.05 interaction test, N=309, FEV1% improvement 11.3[3,19.6]% and -0.7[-7.1,5.7]% respectively). Conclusion: Active tryptase allele count determines expression of functional tryptase and may predict clinical outcomes for therapeutic strategies for asthma directed at mast cells.