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 replication set, comprising of 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 eQTM 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 replication 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.
Footnotes
Impact PDB associated differences in DNA methylation are reproducible and reflect key environmental modulators of bone homeostasis including viral processes, vitamin D metabolism as well as mechanical sheer load.
Competing interests Prof S H Ralston has received research funding from Amgen, Eli Lilly, Novartis, and Pfizer unrelated to the submitted work. The other authors have no conflicts of interest to declare
Funding This work was funded by a consolidator grant from the European Research Council to OMEA (311723-GENEPAD) and in part by an advanced investigator grant from the European Research Council to SHR (787270 - Paget-Advance). The PRISM trial was supported by grants from the Arthritis Research Campaign (13627) and the Paget’s Association.
Datasets Raw and processed methylation data generated in this study can be found at GEO under the accession GSE163970.
Ethics Statement The study was approved by the UK Multicenter Research Ethics Committee for Scotland (MREC01/0/53) and NHS Lothian, Edinburgh (08/S1104/8) ethics review committees. All participants provided written informed consent.