Elsevier

Clinical Immunology

Volume 123, Issue 3, June 2007, Pages 268-271
Clinical Immunology

Tryptase haplotype in mastocytosis: Relationship to disease variant and diagnostic utility of total tryptase levels

https://doi.org/10.1016/j.clim.2007.02.007Get rights and content

Abstract

Serum mast cell tryptase levels are used as a diagnostic criterion and surrogate marker of disease severity in mastocytosis. Approximately 29% of the healthy population lacks α tryptase genes; however, it is not known whether lack of α tryptase genes leads to variability in tryptase levels or impacts on disease severity in mastocytosis. We have thus analyzed tryptase haplotype in patients with mastocytosis, computing correlations between haplotype and plasma total and mature tryptase levels; and disease category. We found: (1) the distribution of tryptase haplotype in patients with mastocytosis appeared consistent with Hardy–Weinberg equilibrium and the distribution in the general population; (2) the disease severity and plasma tryptase levels were not affected by the number of α or β tryptase alleles in this study; and (3) information about the tryptase haplotype did not provide any prognostic value about the severity of disease. Total and mature tryptase levels positively correlated with disease severity, as well as prothrombin time and partial thromboplastin time, and negatively correlated with the hemoglobin concentration.

Introduction

An elevated baseline total tryptase level is a minor diagnostic criterion for systemic mastocytosis according to World Health Organization criteria [1]. Tryptases are serine proteases produced by mast cells [2], [3]. Among members of the tryptase family in humans, including α, β, δ [4], ε [5] and γ (transmembrane) [6], [7], the two that are most abundantly expressed in and secreted by mast cells are α and β tryptases. Tryptases ε and γ are ≤ 50% identical to α and β tryptases, while δ-tryptase, though more closely related to α/β-tryptases, is truncated 40 amino acids shy of the C-terminus of α/β tryptases and appears to be less abundantly expressed [8], [9]. Human mature β tryptase is stored in mast cell granules and released upon activation while α tryptase is apparently processed only to the proenzyme stage and is constitutively secreted from mast cells along with β protryptase [10]. Therefore, serum or plasma levels of mature β tryptase are found transiently elevated after a mast cell degranulation event such as anaphylaxis, while the levels of the precursors of α/β tryptase are reported to reflect the total body mast cell burden; and to be elevated in patients with mastocytosis when compared to the general population [11], [12], [13].

The genes encoding α and β tryptases are located in 2 loci in close proximity to each other on chromosome 16p13.3 [4]. Mapping data suggests that α alleles compete with β alleles at one locus, while an adjacent locus contains β alleles exclusively (αβ versus ββ haplotype) [7]. Accordingly, it has been shown that 20–29% of the normal population lacks α tryptase and has a ββ:ββ genotype [10], [14], [15].

The αβ tryptase haploytpe and female gender are associated with a small but statistically significant elevation of circulating tryptase levels in healthy individuals [16]. It is, however, not known whether patients with mastocytosis have the same allelic distribution of α and β tryptase genes as the general population and whether those lacking the α tryptase gene have a corresponding decrease in circulating tryptase protein levels. The World Health Organization’s (WHO) diagnostic criteria for systemic mastocytosis do not take the α/β tryptase haplotype into account. Because of the potential impact of this haplotype on these criteria, we have examined the α/β tryptase genes in a cohort of patients with mastocytosis and evaluated the correlations of the α/β tryptase genotype with category of disease, serum tryptase levels and hematologic laboratory values.

Section snippets

Patients and methods

Thirty-one patients (13 males) with mastocytosis were examined after signing informed consent. All patients were diagnosed and classified into a disease category according to the World Health Organization’s criteria. The numbers of patients in each disease category in the order of increasing disease severity were as follows: 4 patients with pediatric-onset cutaneous mastocytosis (CM), 24 with indolent systemic mastocytosis (ISM) (9 with the subvariant smoldering systemic mastocytosis [SSM]), 2

Results

Seven of 31 (23%) patients with mastocytosis lacked the α tryptase gene while 8 (26%) patients had 2 α tryptase alleles. This distribution is similar to that of the general population and is consistent with a population in Hardy–Weinberg equilibrium. These results suggest that patients with mastocytosis do not have a skewed distribution of α tryptase alleles.

There was a strong correlation between the severity of mastocytosis category and plasma total, and mature tryptase levels (Spearman’s r

Discussion

Baseline total tryptase levels in mastocytosis are thought to reflect enzymatically inactive α and β protryptases that are constitutively secreted, even though a portion of β-protryptase undergoes intracellular processing to yield mature tryptase and is then stored in secretory granules [2]. Circulating protryptase levels thus appear to reflect the spontaneous secretion of both α and β protryptases, and possibly other tryptase precursors. Our results support the conclusion that while some

Acknowledgments

This work is supported by NIH grants HL024136 (G.H.C. and D.S.) and AI20487 (LBS), and the Division of Intramural Research, NIAID.

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1

Currently at the Division of Allergy and Immunology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.

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