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Cited by 231Mast cells and histamineFood Allergy and Anaphylaxis ResearchDrug-Induced Adverse Reactions

The DOI matches its Crossref record; 33 of the 33 references it cites were found in a registry or an index.

Heritable risk for severe anaphylaxis associated with increased α-tryptase–encoding germline copy number at TPSAB1

Lyons, Jonathan J., Chovanec, Jack, O’Connell, Michael P., Liu, Yihui, Šelb, Julij, Zanotti, Roberta, Bai, Yun, Kim, Jiwon, Le, Quang T., DiMaggio, Tom, Schwartz, Lawrence B., Komarow, Hirsh D., Rijavec, Matija, Carter, Melody C., Milner, Joshua D., Bonadonna, Patrizia, Metcalfe, Dean D., Korošec, Peter·2021·Journal of Allergy and Clinical Immunology
DOI 10.1016/j.jaci.2020.06.035
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Abstract

Background An elevated basal serum tryptase level is associated with severe systemic anaphylaxis, most notably caused by Hymenoptera envenomation. Although clonal mast cell disease is the culprit in some individuals, it does not fully explain this clinical association.Objective Our aim was to determine the prevalence and associated impact of tryptase genotypes on anaphylaxis in humans.Methods Cohorts with systemic mastocytosis (SM) and venom as well as idiopathic anaphylaxis from referral centers in Italy, Slovenia, and the United States, underwent tryptase genotyping by droplet digital PCR. Associated anaphylaxis severity (Mueller scale) was subsequently examined. Healthy volunteers and controls with nonatopic disease were recruited and tryptase was genotyped by droplet digital PCR and in silico analysis of genome sequence, respectively. The effects of pooled and recombinant human tryptases, protease activated receptor 2 agonist and antagonist peptides, and a tryptase-neutralizing mAb on human umbilical vein endothelial cell permeability were assayed using a Transwell system.Results Hereditary α-tryptasemia (HαT)-a genetic trait caused by increased α-tryptase-encoding Tryptase-α/β1 (TPSAB1) copy number resulting in elevated BST level-was common in healthy individuals (5.6% [n = 7 of 125]) and controls with nonatopic disease (5.3% [n = 21 of 398]). HαT was associated with grade IV venom anaphylaxis (relative risk = 2.0; P < .05) and more prevalent in both idiopathic anaphylaxis (n = 8 of 47; [17%; P = .006]) and SM (n = 10 of 82 [12.2%; P = .03]) relative to the controls. Among patients with SM, concomitant HαT was associated with increased risk for systemic anaphylaxis (relative risk = 9.5; P = .007). In vitro, protease-activated receptor-2-dependent vascular permeability was induced by pooled mature tryptases but not α- or β-tryptase homotetramers.Conclusions Risk for severe anaphylaxis in humans is associated with inherited differences in α-tryptase-encoding copies at TPSAB1.

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Metadata

Authors
Lyons, J. J., Chovanec, J., O’Connell, M. P., Liu, Y., Šelb, J., Zanotti, R., Bai, Y., Kim, J., Le, Q. T., DiMaggio, T., Schwartz, L. B., Komarow, H. D., Rijavec, M., Carter, M. C., Milner, J. D., Bonadonna, P., Metcalfe, D. D., & Korošec, P.
Affiliations
  • National Institutes of Health (US)
  • University Clinic of Pulmonary and Allergic Diseases Golnik (SI)
  • University of Verona (IT)
  • Virginia Commonwealth University (US)
  • Columbia University (US)
  • Azienda Ospedaliera Universitaria Integrata Verona (IT)
Corresponding author
Lyons, Jonathan J.
ORCID
Venue
Journal of Allergy and Clinical Immunology
Publisher
Elsevier BV
Published
2021-02
Volume
147
Issue
2
Pages
622-632
ISSN
0091-6749 (ISSN-L)
DOI
10.1016/j.jaci.2020.06.035
OpenAlex
W3044735023
Cited by
230
References
33
Citations by year
2026: 27 · 2025: 31 · 2024: 36 · 2023: 35 · 2022: 43 · 2021: 51
FWCI
11.80
Type
journal article
Language
en
Open access
closed
Licence
Locations
  • Journal of Allergy and Clinical Immunology (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Institute of Allergy and Infectious Diseases
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
  • Health Sciences › Medicine › Immunology and Allergy › Food Allergy and Anaphylaxis Research
  • Health Sciences › Medicine › Pharmacology (medical) › Drug-Induced Adverse Reactions
Keywords
hereditary alpha-tryptasemia, TPSAB1, copy number variation, systemic anaphylaxis, idiopathic anaphylaxis, systemic mastocytosis, hymenoptera venom allergy, protease-activated receptor 2, vascular permeability, droplet digital PCR
MeSH terms
Adolescent, Adult, Aged, Anaphylaxis, Arthropod Venoms, Child, Female, Genotype, Humans, Male, Middle Aged, Genetic Predisposition to Disease, Mastocytosis, Systemic, Tryptases, Young Adult, DNA Copy Number Variations

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