Deciphering the Relationship Between Circulating Metabolites and Osteoarthritis: A Comprehensive Genetic Correlation and Mendelian Randomization Studies.

Abstract

The causal impact of blood metabolites on OA has yet to be definitively established, further studies are needed to explore the specific roles of metabolites in OA. This is a genetic correlation and two-sample bidirectional mendelian randomization study. GWAS summary data of metabolites and OA were extracted from large-scale GWAS study based on Europeans and Asians. LDSC was conducted to estimate the genetic correlations between 233 circulating metabolites and 11 OA phenotypes, MR was then performed to explore the casual association. 41.20% of the metabolic traits showed genetic correlation with All OA, 15.88% with Knee/Hip OA, 51.50% with Knee OA, and 52.79% with Spine OA. No significant genetic correlations were detected between the metabolic traits and other OA phenotypes. Lactate levels was associated with increased odds of All OA (OR: 1.1558, P<0.001), Hip OA (OR: 1.1446, P=0.004), Knee/Hip OA (OR: 1.1820, P<0.001), Knee OA (OR: 1.1375, P=0.001), Spine OA (OR: 1.3179, P<0.001), THR (OR: 1.5290, P<0.001), and TJR (OR: 1.2827, P<0.001), except for Thumb OA (OR: 0.9429, P<0.001). Ratio of conjugated linoleic acid to total fatty acids was associated 6 OA phenotypes: Hip OA (OR: 0.9522, P=0.035), Knee/Hip OA (OR: 1.0890, P<0.001), Knee OA (OR: 1.1429, P<0.001), THR (OR: 1.3800, P<0.001), TJR (OR: 1.3102, P<0.001), and TKR (OR: 1.2555, P<0.001). Glycerol levels exhibited significant MR associations with four OA phenotypes: Finger OA (OR: 0.6669, P<0.001), Hand OA (OR: 0.8682, P=0.011), Hip OA (OR: 0.9395, P<0.001), and Knee OA (OR: 1.1409, P=0.036). This study underscores genetic and causal connections between specific metabolites and OA. These findings could inform future therapeutic metabolic pathways involved in OA.