Abstract
Gaucher disease, the most common lysosomal storage disorder, is caused by β-glucocerebrosidase deficiency. Bone complications are the major cause of morbidity in patients with type 1 Gaucher disease (GD1). Genetic components strongly influence bone remodelling. In addition, chronic inflammation produced by Gaucher cells induces the production of several cytokines, which leads to direct changes in the bone remodelling process and can also affect the process indirectly through other immune cells. In this study, we analysed the association between bone mineral density (BMD), bone marrow burden score, and relevant genetic polymorphisms related to bone metabolism, as well as profiles of proinflammatory cytokines in a GD1 cohort. This study included 83 patients distributed according to bone status. BMD was measured with DXA and broadband ultrasound attenuation; bone marrow involvement was evaluated using MRI. We also analysed 26 SNPs located in 14 genes related to bone metabolism. To assess proinflammatory status, we analysed IL-4, IL-6, IL-7, IL-10, IL-13, MIP-1α, MIP-1β, and TNFα in plasma samples from 71 control participants and GD1 patients. SNP genotype proportions and BMD differed significantly between ESRI c.453-397T>C and VDR c.1024+283G>A variants. We also observed significant associations between GD1 genotypes and bone affectation. When patients were stratified by spleen status, we observed significant correlations between non-/splenectomized groups and Spanish MRI (S-MRI) score. Across genotype proportions of non-/splenectomized patients and S-MRI, we observed significant differences in ESRI c.453-397T>C, VDR c.-83-25988G>A, and TNFRSF11B c.9C>G polymorphisms. We observed different significant proinflammatory profiles between control participants, treatment-naïve patients, and patients on enzyme replacement therapy (ERT); between non-/splenectomized patients (between untreated and ERT-treated patients) and among those with differing GBA genotypes. The data suggest that patients with GD1 have increased susceptibility to developing bone disease owing to the coexistence of genetic variants, and that genetic background in GD1 is fundamental to regulate the impact of proinflammatory status on the development of bone disease.
Highlights
Gaucher disease (GD) (OMIM#230800), the most common lysosomal disease, is an autosomal recessive disorder caused by a deficiency of the enzyme β-glucocerebrosidase (EC 3.2.1.45)
In the study reported here, we analyzed the association between bone mineral density (BMD), the bone marrow burden Spanish MRI (S-MRI) score, and relevant genetic polymorphisms related to bone metabolism in a cohort of GD1 patients
To study the genetic background of the study participants, we analyzed 26 single-nucleotide polymorphisms (SNPs) located in 14 genes related to bone metabolism that had been associated with BMD loss in previous studies [5, 22,23,24,25]
Summary
Gaucher disease (GD) (OMIM#230800), the most common lysosomal disease, is an autosomal recessive disorder caused by a deficiency of the enzyme β-glucocerebrosidase (EC 3.2.1.45). This disease is characterized by spleen and liver enlargement, cytopenias, and bone marrow infiltration[1]. More than 80% of GD1 patients have bone involvement [2]. Bone remodeling takes place throughout the entire skeleton, and it has been calculated that approximately 20% of trabecular bones and 10% of compact bones are involved in this process [4]. The most important factors that influence bone remodeling are genetic components, which may explain between 65% and 90% of bone mass variability [5]
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