Abstract
Paget's disease of bone (PDB) is characterized by focal increases in disorganized bone remodeling. This study aims to characterize PDB-associated changes in DNA methylation profiles in patients' blood. Meta-analysis of data from the discovery and cross-validation set, each comprising 116 PDB cases and 130 controls, revealed significant differences in DNA methylation at 14 CpG sites, 4 CpG islands, and 6 gene-body regions. These loci, including two characterized as functional through expression quantitative trait-methylation analysis, were associated with functions related to osteoclast differentiation, mechanical loading, immune function, and viral infection. A multivariate classifier based on discovery samples was found to discriminate PDB cases and controls from the cross-validation with a sensitivity of 0.84, specificity of 0.81, and an area under curve of 92.8%. In conclusion, this study has shown for the first time that epigenetic factors contribute to the pathogenesis of PDB and may offer diagnostic markers for prediction of the disease.
Highlights
Paget’s disease of bone (PDB) is characterized by increased but disorganized bone remodeling, which causes affected bones to enlarge, become weak and deform
Paget’s Disease of Bone (PDB) cases in the discovery set were slightly older and included more males compared to controls but no difference in age or gender distribution was found in the cross-validation set
To gain further insight into the pathology of PDB, we explored common methylation patterns amongst functional keywords identified as significantly over-represented amongst the Pooled sites
Summary
Paget’s disease of bone (PDB) is characterized by increased but disorganized bone remodeling, which causes affected bones to enlarge, become weak and deform. Paget’s disease is clinically silent until it has reached an advanced stage at which point irreversible damage to the skeleton has occurred (1). Bisphosphonates are an effective treatment (2) and can often improve bone pain but have a limited impact on other clinical outcomes in patients with advanced disease (3, 4). Mutations in SQSTM1 are the most common cause of PDB but other susceptibility genes and loci have been identified through genome wide association studies (7-9). These include genes that play an important role in osteoclast differentiation such as CSF1, TNFRSF11A and DCSTAMP.
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