Chitotriosidase variants in patients with Gaucher disease. Implications for diagnosis and therapeutic monitoring.

Objective: Human plasma chitotriosidase (ChT) activity, a biomarker for evaluating and monitoring Gaucher disease (GD), varies in the general population owing to variants in the CHIT1 gene. Our aim is to determine the frequency of the c.1049_1072dup24 (dup24) and p.G102S polymorphisms, their influence on plasma ChT activity, and its change with enzyme replacement therapy (ERT).

Methods: The study included 269 type1 GD patients. Genomic DNA was genotyped using PCR, restriction isotyping and agarose gel electrophoresis. ChT activity was measured with the 4-methylumbelliferyl-β-D-N,N',N″triacetylchitotrioside substrate at non-saturating concentrations at diagnosis, before beginning therapy and after one year on ERT.

Results: Allele frequencies for dup24 and p.G102S were 0.22 and 0.27, respectively. Four percent of patients were homozygous and 37% heterozygous for dup24, and 9% homozygous and 37% heterozygous for p.G102S. The presence of dup24 and p.G102S polymorphisms in the CHIT1 gene significantly reduced plasma ChT activity in naïve patients. By contrast, the percentage of ChT activity decrease after one year of ERT was independent of the presence of these genetic variants.

Conclusions: This study indicates that genotyping for c.1049_1072dup24 and p.G102S polymorphisms will improve the interpretation of plasma chitotriosidase activity at diagnosis but, this is not mandatory for monitoring of enzyme replacement therapy.