Glycoprotein non-metastatic melanoma protein B is a biomarker of inflammation in individuals with Gaucher disease: relationship to clinico-pathological subtypes.

BACKGROUND: Gaucher disease (GD) is a lysosomal disease caused by mutations in the GBA1 gene, leading to glucosylceramide and glucosylsphingosine accumulation. GBA1 mutations are also the most common genetic risk factor for Parkinson's disease (PD). Increased expression of glycoprotein non-metastatic melanoma protein B (gpNMB), a potential biomarker of inflammation and neurodegeneration, has been reported in PD, GD and other LSDs. Plasma concentrations of gpNMB are correlated with the accumulation of bioactive lipid substrates in several chronic inflammatory diseases and gpNMB stimulates lipogenesis in white adipocytes. To explore its potential significance in GD we measured plasma gpNMB in patients with Gaucher Disease type 1 (GD1), Gaucher Disease Type 3 (GD3), GD1-PD, PD and GBA heterozygous PD and in different clinicopathological subtypes. RESULTS: The study enrolled participants the GAUCHERITE Cohort in the UK (172 GD1 and 20 GD3 patients) and the Biopark Cohort (72 IPD patients) in Sweden. Plasma concentrations of gpNMB were significantly higher in patients with Gaucher disease (mean: 200.9; range: 9.8-1643 ng/ml) compared with healthy controls (mean: 35.1; range.: 10.1- 125 ng/ml), including those receiving enzyme replacement therapy (ERT). Notably, gpNMB concentrations remained elevated in GD1 patients who had received ERT for more than 5 years. The biomarker was particularly elevated in patients who had been splenectomized, those with known pulmonary or liver disease, and those with monoclonal gammopathy, despite enzyme therapy. No statistical difference was found in plasma gpNMB concentrations between treated patients with GD1 and GD3. On average, there was no difference in plasma gpNMB concentrations between Gaucher patients with or without Pakinsonism. As expected however plasma gpNMB concentrations among patients with Parkinsonism were higher in those with type 1 Gaucher disease than either GBA1 heterozygotes or those with idiopathic PD (p=0.0001). CONCLUSION: Our findings indicate that the association of plasma gpNMB with liver cirrhosis, gammopathy and pulmonary disease in Gaucher disease warrants further investigation. Additionally, plasma gpNMB may serve as a supportive biomarker in the evaluation and clinical monitoring of residual disease activity. However, plasma gpNMB neither differentiated between the neuronopathic subtypes of Gaucher disease nor idiopathic Parkinson's disease.