Causal effects of stimulus-induced blood cell phenotypes on the risk of primary knee osteoarthritis: A two-sample Mendelian randomization study

Primary knee osteoarthritis (PKOA) is a common degenerative joint disorder, where immune-mediated inflammation plays a key role in its onset and progression. However, the causal relationship between blood cell functional states under immune stimuli and PKOA risk has not been systematically evaluated. We conducted a 2-sample Mendelian randomization analysis to explore the causal effects of immune-related blood cell phenotypes on PKOA risk. Exposure data were derived from a GWAS by Homilius et al. (2024, Nature Genetics) involving 1312 European blood donors. Outcome data came from the PKOA GWAS in the FinnGen R12 cohort (23,582 cases and 438,992 controls). Causal estimates were calculated using inverse-variance weighted (IVW), Mendelian randomization-Egger regression, and the weighted median method. Four phenotypes were significantly associated with PKOA risk after correction for multiple testing: red blood cell membrane stability in response to rotenone, neutrophil volumetric and structural changes in response to Pam3CSK4, baseline morphological variations of an unclassified immune cell population, and structural remodeling of leukocytes in response to Pam3CSK4. Sensitivity analyses confirmed the robustness of these findings with no evidence of substantial pleiotropy or heterogeneity. This study is the first to explore causal links between immune-related blood cell phenotypes and PKOA risk. These findings suggest that immune functional phenotypes may serve as potential biomarkers for early detection and targeted intervention in PKOA, but further validation is required. Future research should include multi-ethnic validation and functional studies to confirm these biomarkers and assess their clinical applicability.