Abstract: BACKGROUND: In recent years, epidemiological studies have shown that obesity is a risk factor for knee osteoarthritis, and fatty acid intake, metabolism and biosynthesis are closely related to the development of obesity. However, the causal relationship between fatty acids and osteoarthritis is still unknown.
OBJECTIVE: Using the Mendelian randomization analysis to investigate the causal relationship between five fatty acid phenotypes and knee osteoarthritis.
METHODS: The genome-wide association study data on fatty acid ratios from the UK Biobank (met-D) and genome-wide association study data on knee osteoarthritis from the EBI-A database were pooled together. Single nucleotide polymorphisms were used as instrumental variables and sensitive single nucleotide polymorphisms were selected for analysis. Two-sample Mendelian randomization analysis was conducted to evaluate the causal relationship between fatty acids and knee osteoarthritis outcome risk. We used inverse variance weighting method, MR-Egger regression method, weighted median method, weighted model method, and simple model method to study the causal relationship between fatty acids and knee osteoarthritis. Further inverse Mendelian randomization analysis was performed in the same way to ensure the validity of the results.
RESULTS AND CONCLUSION: The forward analysis and inverse variance weighting method showed a causal relationship between three types of fatty acid phenotypes and knee osteoarthritis. Among them, the proportion of saturated fatty acids to total fatty acids was positively correlated with the risk of knee osteoarthritis (odds ratio [OR]=1.825, 95% confidence interval (CI): 1.230, 2.706, P=0.003), the proportion of omega 3 polyunsaturated fatty acids to total fatty acids was negatively correlated with the risk of knee osteoarthritis (OR=0.822, 95% CI: 0.688 8, 0.981, P=0.03), and the proportion of omega 6 polyunsaturated fatty acids to total fatty acids was positively correlated with the risk of knee osteoarthritis (OR=1.268, 95% CI: 1.079, 1.491, P=0.004). There were two types of fatty acid phenotypes that do not have a causal relationship with knee osteoarthritis, including total fatty acids (OR=0.925, 95% CI: 0.804-1.066, P=0.283) and the proportion of monounsaturated fatty acids to total fatty acids (OR=0.877, 95% CI: 0.756-1.018, P=0.084). The reverse analysis results indicated that when knee osteoarthritis was used as exposure data, there was no significant causal relationship with the phenotype of fatty acids. The sensitivity analysis results showed that the P-values of the bidirectional Mendelian randomization Cochran’s Q-test and MR Egger regression were both greater than 0.05, indicating that there was no significant heterogeneity or pleiotropy in the causal effect analysis between fatty acid phenotype and knee osteoarthritis. To conclude, reducing the content of saturated fatty acids and omega 6 polyunsaturated fatty acids and increasing the content of omega 3 polyunsaturated fatty acids can reduce the risk of knee osteoarthritis. This provides valuable clues for studying the biological mechanisms of knee osteoarthritis and exploring the early prevention and treatment of knee osteoarthritis, as well as providing new directions for the development of interventional drugs.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Key words: knee osteoarthritis, Mendelian randomization, causal relationship, sensitivity analysis, inverse variance weighting method, saturated fatty acids, polyunsaturated fatty acids, pro-inflammatory cytokines, lipid metabolism, knee joint adduction torque