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
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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In the citing paper
“Further, H a T may be associated with an increased severity of anaphylactic reactions and other mediator-induced symptoms in patients with mastocytosis and venom allergy. 25,129”
From Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review (2021) · cites this paper as [129]
In the citing paper
“in patients with SM, where it can reach up to 12%–20% (17, 19, 22, 23).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [17]
In the citing paper
“severe episodes were twice more frequent in individuals with both SM and HαT than in those with SM but without HαT (17, 18).”
From Defining “Normal” basal serum tryptase levels: a context-dependent approach to improve diagnostics in systemic mastocytosis (2025) · cites this paper as [17]
In the citing paper
“There is a consensus that HαT is a risk modifier of severe anaphylaxis [21,48,49,50,51,52,53].”
From Diagnostic Significance of Tryptase for Suspected Mast Cell Disorders (2023) · cites this paper as [48]
In the citing paper
“A recent description of a / b -tryptase heterotetrameric tryptases, which have expanded biologic functions relative to mature b -tryptases, may offer a possible mechanism explaining MCA in these individuals. 128,129”
From Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review (2021) · cites this paper as [129]
In the citing paper
“However, an approximately two to three times higher prevalence of H a T has been reported in two large cohorts of SM patients 25,129 ; also, H a T concurrently occurring with MCAS has been reported. 130,131”
From Selecting the Right Criteria and Proper Classification to Diagnose Mast Cell Activation Syndromes: A Critical Review (2021) · cites this paper as [129]
In the citing paper
“HαT is enriched in patients with SM,42,43 in Hymenoptera-allergic patients with severe anaphylaxis,44,45 and in patients with idiopathic anaphylaxis.42,43,45,46”
From Mast cell activation syndrome: Current understanding and research needs (2024) · cites this paper as [45]
In the citing paper
“because HaT has been shown to be an independent heritable genetic risk factor of severe anaphylaxis.23”
From Low Prevalence of Idiopathic Mast Cell Activation Syndrome Among 703 Patients With Suspected Mast Cell Disorders (2024) · cites this paper as [23]
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Self-citation
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)
- 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
- 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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