Heritable risk for severe anaphylaxis associated with increased ?-tryptase–encoding germline copy number at TPSAB1 - 04/02/21
, Jack Chovanec, BS a, Michael P. O’Connell, PhD a, Yihui Liu, PhD a, Julij Šelb, MD, PhD b, Roberta Zanotti, MD c, Yun Bai, PhD a, Jiwon Kim, BS a, Quang T. Le, PhD d, Tom DiMaggio, ADN a, Lawrence B. Schwartz, MD, PhD d, Hirsh D. Komarow, MD a, Matija Rijavec, PhD b, Melody C. Carter, MD a, Joshua D. Milner, MD e, ∗, Patrizia Bonadonna, MD f, ∗, Dean D. Metcalfe, MD a, ∗, Peter Korošec, PhD b, ∗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.
Le texte complet de cet article est disponible en PDF.Graphical abstract |
Key words : Mastocytosis, venom, hypersensitivity, idiopathic anaphylaxis, mast cell activation, hereditary α-tryptasemia
Abbreviations used : ADGRE2, BM, BST, ddPCR, EGM-2, HαT, HUVEC, HVA, IA, NIH, PAR, PAR-2, pNA, RR, SM, TPSAB1, TPSB2, TPSD1
Plan
| Supported by the Division of Intramural Research of the National Institute of Allergy and Infectious Diseases, National Institutes of Health. |
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| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 147 - N° 2
P. 622-632 - février 2021 Retour au numéro
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