Mendelian randomization and transcriptome analysis identified immune-related biomarkers for osteoarthritis.

ABSTRACT

Background: The immune microenvironment assumes a significant role in the pathogenesis of osteoarthritis (OA). However, the current biomarkers for the diagnosis and treatment of OA are not satisfactory. Our study aims to identify new OA immune-related biomarkers to direct the prevention and treatment of OA using multi-omics data. Methods: The discovery dataset integrated the GSE89408 and GSE143514 datasets to identify biomarkers that were significantly associated with the OA immune microenvironment through multiple machine learning methods and weighted gene co-expression network analysis (WGCNA). The identified signature genes were confirmed using two independent validation datasets. We also performed a two-sample mendelian randomization (MR) study to generate causal relationships between biomarkers and OA using OA genome-wide association study (GWAS) summary data (cases n = 24,955, controls n = 378,169). Inverse-variance weighting (IVW) method was used as the main method of causal estimates. Sensitivity analyses were performed to assess the robustness and reliability of the IVW results. Results: Three signature genes (FCER1G, HLA-DMB, and HHLA-DPA1) associated with the OA immune microenvironment were identified as having good diagnostic performances, which can be used as biomarkers. MR results showed increased levels of FCER1G (OR = 1.118, 95% CI 1.031-1.212, P = 0.041), HLA-DMB (OR = 1.057, 95% CI 1.045 -1.069, P = 1.11E-21) and HLA-DPA1 (OR = 1.030, 95% CI 1.005-1.056, P = 0.017) were causally and positively associated with the risk of developing OA. Conclusion: The present study identified the 3 potential immune-related biomarkers for OA, providing new perspectives for the prevention and treatment of OA. The MR study provides genetic support for the causal effects of the 3 biomarkers with OA and may provide new insights into the molecular mechanisms leading to the development of OA.