Smoking elevating osteoarthritis risk: Insights from genetics, blood DNA methylations and proteome profiles

The relationship between smoking and osteoarthritis (OA) incidence remains unclear. This study aimed to explore the association of smoking behaviors and OA morbidity in the UK Biobank and further investigate the mediating role of DNA methylation and proteomics in the smoking-OA relationship through integrating multi-omics analyses, including genetic, epigenetic, and proteomic data. Our study revealed that smoking increased while ceasing smoking reduced OA risk, mediated by smoking-associated methylation modifications at 13 CpG sites, and proteomic signatures with consistent associations observed in prospective and Mendelian randomization (MR) studies. Genome-wide methylation analysis validated the findings of epigenetic MR. Smoking-associated methylation at cg03554335 (in gene C17ORF72) and cg06934523 (KIAA0247) demonstrated evidence of colocalization with OA susceptibility; methylation at cg21505886 (TACC3) and cg08867399 (HS6ST1) and downstream proteins alterations were associated with OA risk. Furthermore, smoking-associated protein signature mediated 72.8 % of the smoking-OA associations, involving the regulation of cytokine responses as well as the PI3K-Akt and MAPK signaling pathways. Besides, cessation-associated protein signature was also associated with OA risk. This study identified a significant association between smoking and morbidity of OA phenotypes, with underlying mechanism related to epigenetic modifications of CpG sites to expressions of located genes, and proteomic alterations. These findings provide evidence and mechanistic insights into the role of smoking cessation in reducing OA morbidity.