title: The influence of genetic variability and proinflammatory status on the development of bone disease in patients with Gaucher disease.
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.
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain; Translational Research Unit, Miguel Servet University Hospital, Zaragoza, Spain; Spanish Gaucher Disease Foundation (FEETEG), Zaragoza, Spain; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Gervas-Arruga
authors.affiliation: Spanish Gaucher Disease Foundation (FEETEG), Zaragoza, Spain; Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Jorge Javier
authors.initials: JJ
authors.lastname: Cebolla
authors.affiliation: Unidad de Patología Infecciosa y Epidemiología, Facultad de Veterinaria, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: de Blas
authors.affiliation: Spanish Gaucher Disease Foundation (FEETEG), Zaragoza, Spain; International Skeletal Society-Radiodiagnostic Center, Zaragoza, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Roca
authors.affiliation: Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain; Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Pocovi
authors.affiliation: Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Zaragoza, Spain; Translational Research Unit, Miguel Servet University Hospital, Zaragoza, Spain; Spanish Gaucher Disease Foundation (FEETEG), Zaragoza, Spain; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Giraldo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001847:Bone Diseases / Q000209:etiology / Q000235:genetics*; D054405:Chemokine CCL3 / Q000097:blood; D054407:Chemokine CCL4 / Q000097:blood; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000097:blood; D005260:Female; D005776:Gaucher Disease / Q000150:complications / Q000235:genetics*; D014644:Genetic Variation; D060005:Genotyping Techniques; D006801:Humans; D007249:Inflammation / Q000150:complications; D007378:Interleukins / Q000097:blood; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D055815:Young Adult
chemical_list: C515429:CCL3 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha