Disclosure(s): No financial relationships with ineligible companies to disclose
Background/Purpose: Lipoprotein subclasses play diverse roles in health and disease. Although lipoproteins have been implicated in knee osteoarthritis (KOA), the relationship between lipoprotein subclasses and KOA remains unexplored. Methods: We conducted a cohort study of 115,237 participants from the UK Biobank to examine the associations of 85 plasma lipoprotein subclasses, defined by combinations of density (high, low, intermediate, very-low), size (extremely-large, very-large, large, medium, small, very-small), and composition (triglyceride, free cholesterol, cholesteryl ester, phospholipid), with incident KOA in the metabolome-wide analysis (Figure 1A). Data were analyzed using Cox proportional hazards models, correcting for multiple tests (0.05/9). We conducted the analyses using two models. Model 1 adjusted for age, sex, Townsend Deprivation Index score, body mass index (BMI; as a categorical variable), drinking status, smoking status, fasting time, lipid-lowering medication, and history of knee joint injury. Model 2 included the same covariates as Model 1, except that BMI was adjusted as a continuous variable. We subsequently conducted targeted analyses to examine the association between the key lipoprotein subclasses, which consistently showed significant associations with KOA across both models, and knee replacement, as the outcome may reflect severe OA (Figure 1B). Results: During a median follow-up period of 12.8 years, 6,782 incident cases of KOA were identified. A total of 38 lipoprotein subclasses were statistically significantly associated with incident KOA (Figure 2). Specifically, higher concentrations of very-large and large high-density lipoproteins (HDL), excluding triglyceride, were associated with a lower risk of incident KOA (hazard ratios [HRs] range 0.87-0.94). Conversely, higher concentrations of small HDL, irrespective of composition, were associated with a higher risk of incident KOA (HRs range 1.04-1.09). Extremely-large very-low-density lipoprotein (VLDL) across all compositions, very-large VLDL excluding cholesteryl ester, and large VLDL excluding cholesteryl ester showed positive associations with incident KOA (HRs range 1.05-1.10). Additionally, medium, small, and very-small VLDL, and intermediate-density lipoprotein, as well as large, medium and small low-density lipoprotein, combined with triglyceride, were consistently positively associated with incident KOA (HRs range 1.04-1.06). After adjusting for BMI as a continuous variable, differential effects among HDL subclasses remained evident, except for the association between large HDL and KOA. Conversely, the associations between other lipoprotein subclasses and KOA become non-statistically significant. Similar findings were observed for the associations between HDL subclasses and the risk of knee replacement in the targeted analysis (Figure 3). Conclusion: We provided novel evidence of diverse associations between lipoprotein subclasses and incident KOA, indicating the distinct effects of HDL subclasses.
