Resolving the genetics of human tryptases: implications for health, disease, and clinical use as a biomarker

Purpose of review To discuss our evolving understanding of the genetic variation in human tryptases and recent advances in associated clinical phenotypes. Recent findings Serum tryptase levels have long been used as biomarkers in clinical practice to diagnose mast cell-associated disorders and mast cell-mediated reactions but the contribution of specific secreted isoforms of human tryptases and their role(s) in health and disease has only recently begun to be illuminated. It is now recognized that hereditary alpha-tryptasemia (HαT) is a common genetic trait and the commonest cause for elevated basal serum tryptase (BST), where it can both contribute to mast cell-associated phenotypes, and potentially confound their correct diagnosis. Expression of different tryptase isoforms is now recognized to be associated with specific clinical phenotypes including clonal and nonclonal mast cell-associated disorders as well as certain asthma endotypes. These disparate impacts on clinical disorders may result from differences in enzymatic activities of mature α-tryptases and β-tryptases, and the unique substrate profile and stability of heterotetrameric mature α/β-tryptases recently described to naturally occur. Summary Variable copy number and isoform expression of tryptases differentially impact diseases and reactions associated with mast cells in humans. Recent advances in understanding of genetics governing BST levels have refined our understanding and the clinical use of this biomarker. In the future, incorporation of tryptase genotyping will likely be integral to the work-up and trial design of patients with phenotypes impacted by mast cells ranging from asthma to mastocytosis.