The integrative analysis of DNA methylation and mRNA expression profiles confirmed the role of selenocompound metabolism pathway in Kashin-Beck disease.

Kashin-Beck disease (KBD) is an endemic chronic osteochondropathy. The etiology of KBD remains unknown. In this study, we conducted an integrative analysis of genome-wide DNA methylation and mRNA expression profiles between KBD and normal controls to identify novel candidate genes and pathways for KBD. Articular cartilage samples from 17 grade III KBD patients and 17 healthy controls were used in this study. DNA methylation profiling of knee cartilage and mRNA expression profile data were obtained from our previous studies. InCroMAP was performed to integrative analysis of genome-wide DNA methylation profiles and mRNA expression profiles. Gene ontology (GO) enrichment analysis was conducted by online DAVID 6.7. The quantitative real-time polymerase chain reaction (qPCR), Western blot, immunohistochemistry (IHC), and lentiviral vector transfection were used to validate one of the identified pathways. We identified 298 common genes (such as COL4A1, HOXA13, TNFAIP6 and TGFBI), 36 GO terms (including collagen function, skeletal system development, growth factor), and 32 KEGG pathways associated with KBD (including Selenocompound metabolism pathway, PI3K-Akt signaling pathway, and TGF-beta signaling pathway). Our results suggest the dysfunction of many genes and pathways implicated in the pathogenesis of KBD, most importantly, both the integrative analysis and in vitro study in KBD cartilage highlighted the importance of selenocompound metabolism pathway in the pathogenesis of KBD for the first time.