D1.309 - The complexity of basal serum tryptase levels: Genotyping tryptase genes is not enough

Basal serum tryptase (BST) levels, which reflect constitutive release of the α- and β-tryptase, are commonly used as biomarkers for allergic reactions and mast cell disorders. Hereditary α-tryptasemia (HαT), an autosomal dominant trait found in about 6% of the general Western population, involves extra copies of the TPSAB1 gene encoding α-tryptase associated with elevated BST. However, additional factors beyond genetic copy number may also influence BST levels.

Here, we present the genotypes of patients undergoing digital PCR (dPCR)-based copy number (CN) analysis of TPSAB1 and TPSB2, the gene encoding β-tryptase, along with their associated BST and renal function.

Forty-five consenting patients were included, grouped according to BST as elevated (>11.4 ng/mL, n=26), normal (≥1 to ≤11.4 ng/mL, n=13), and low (<1 ng/mL, n=6). DNA extracted from peripheral blood samples was digested with BamHI and subjected to two duplex dPCR assays targeting α- and β-tryptase sequences, separately, and a reference gene with conserved CN. BST was measured using the ImmunoCAP immunoassay, and glomerular filtration rate (GFR) was estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation.

Eleven different tryptase genotypes were identified, six non-HαT (0α/3β, 0α/4β, 1α/2β, 1α/3β, 1α/4β, and 2α/2β) and five HαT-associated (2α/3β, 3α/2β, 3α/3β, 4α/2β, and 5α/1β) (Table 1). No additional copies of α-tryptase copies were detected in patients with BST ≤11.4 ng/mL. In contrast, HαT genotypes were detected in 21 of 26 (80.8%) patients with elevated BST and most commonly reported anaphylaxis or allergy.

Five non-HαT patients with elevated BST showed diminished GFR (<90 mL/min/1.73 m²), with two patients having chronic kidney disease (stages 4 and 3b), and one patient testing positive for KITp.D816V in peripheral blood. Patients with diminished GFR had higher BST levels than those with the same genotype and preserved renal function (Table 1). Also, there was significant variability in BST in patients with identical genotypes.

Our data confirm a positive correlation between increased CN of the α-tryptase gene and elevated BST levels. However, the HαT genotype cannot explain all increased BST levels. Assessment of kidney function can help guide the accurate differential diagnosis of patients with unexplained BST elevation.