Causal Role of Oxidative Stress-Related Genes in Osteoarthritis

Background: Osteoarthritis (OA) is a common joint disease, primarily affecting the elderly. Oxidative stress (OS), resulting from an imbalance between oxidants and antioxidants, plays a significant role in OA progression. This study aimed to explore the causal relationship between OS-related genes and OA using summary-based Mendelian randomization (SMR). Methods: OS-related genes were selected from the GeneCards database with a relevance score ≥ 7. GWAS data for OA, including 24,955 cases and 378,169 controls, were retrieved from the IEU database. eQTL data were obtained from the eQTLGen Consortium. SMR analysis was conducted to assess the causal effects of gene expression on OA, with the HEIDI test used to confirm the absence of heterogeneity. Colocalization and enrichment analyses were performed, and regulatory networks for key genes were predicted. Results: SMR analysis identified 26 OS-related genes with causal links to OA. Seven genes were associated with an increased risk of OA, while 19 were protective. Enrichment analysis revealed pathways such as "response to oxidative stress" and "cellular oxidant detoxification." Colocalization analysis indicated LYRM4 and MAPK3 likely share causal variants with OA, and regulatory network predictions highlighted genes like NFS1 and ELK1 as potential regulators of LYRM4 and MAPK3. Conclusion: This study identified several OS-related genes potentially contributing to OA, with LYRM4 and MAPK3 as key candidates. These findings offer insights into OA pathogenesis, suggesting that mitochondrial dysfunction and inflammatory signaling play crucial roles. Further research is needed to validate these results and explore potential therapeutic strategies targeting these genes.