Levels of the biomarkers cathepsin D, cathepsin S, YKL-40, and progranulin are not accurate enough to measure disease activity in Gaucher disease patients, but might inform the severity of disease-related manifestations such as skeletal disease and splenomegaly, a new study shows.
The study, “Aberrant progranulin, YKL-40, cathepsin D and cathepsin S in Gaucher disease,” was published in the journal Molecular Genetics and Metabolism.
Gaucher disease develops as a result of a deficiency in the enzyme glucocerebrosidase, a lack of which causes deposition of the large lipid (fat) molecule glucocerebroside into macrophages and monocytes (two types of immune cells), producing what are known as Gaucher cells.
A biomarker is a measurable substance in an organism whose presence is indicative of disease. Biomarkers are frequently used to diagnose a disease, measure its severity, and monitor response to treatment.
To date, several macrophage-specific biomarkers have been identified and used for Gaucher disease.
However, Gaucher disease is more complex and involves the immune system beyond just the macrophages, and researchers have been investigating the presence of other potential biomarkers.
Scientists have found that the expression of the proteins cathepsin D and S, YKL-40, and progranulin were altered in the serum (a component of blood) of a mouse model of Gaucher disease.
Thus, researchers at Yale and University College Dublin set out to investigate the levels of these potential biomarkers in patients with Gaucher disease, and to compare their accuracy to the currently established biomarkers chitotriosidase and chemokine ligand 18 (CCL18), which are used as indicators of disease severity and response to therapy.
First, researchers showed that the average YKL-40 and cathepsin D and S levels were significantly higher in Gaucher disease patients compared to healthy controls.
In contrast, the average progranulin levels were significantly lower in Gaucher disease patients compared to healthy controls.
Enzyme replacement therapy — the standard of care for patients with Gaucher disease — led to a normalization in the levels of cathepsin D and S. However, there were no changes in levels of progranulin and YKL-40.
Next, researchers sought to determine the levels of these biomarkers in patients with different manifestations of the disease.
Patients with persistent splenomegaly (enlargement of the spleen) after long-term enzyme replacement therapy had significantly higher serum YKL-40 compared to patients with smaller spleens.
Interestingly, serum YKL-40 levels were also higher in patients with severe bone involvement compared to those with milder bone involvement.
When comparing levels of these biomarkers with currently established ones, YKL-40 was only weakly associated with chitotriosidase and CCL18, while cathepsin S was moderately associated with chitotriosidase and CCL18.
Progranulin, on the other hand, was not significantly associated with either chitotriosidase or CCL18.
Taken together, “while these biomarkers do not meet robust properties of established macrophage-specific biomarkers, they may inform severity of skeletal disease, contribution of fibrosis to residual splenomegaly, and other disease manifestations,” the investigators concluded.