Mendelian randomization study of diabetes, blood lipids, and the risk of knee and hip osteoarthritis

Osteoarthritis (OA), particularly knee and hip osteoarthritis (KOA and HOA), is a leading cause of disability. Although diabetes-related factors and lipid abnormalities have been implicated in OA development, the causal nature of these associations remains unclear.

This study investigates the relationships between diabetes-related factors (type 2 diabetes (T2D), fasting insulin and glycated hemoglobin (HbA1c)), blood lipid risk factors (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides), and OA using Mendelian randomization (MR) analysis.

A bidirectional MR design was applied, using genetic data from publicly available genome-wide association studies (GWAS) that included 403,124 KOA cases and 393,873 HOA cases, along with datasets on diabetes-related and blood lipid risk factors. Genetic variants were used as instrumental variables, and causal relationships were assessed using the TwoSampleMR (v. 0.5.7) package in R. The primary analytical methods included inverse-variance weighted (IVW) analysis, weighted median (WM) analysis, and MR-Egger regression.

The forward MR analysis did not identify a causal relationship between diabetes-related factors or blood lipid markers and OA. However, this does not exclude the possibility of indirect pathways or small effects that may not have been detected. In the reverse MR analysis, fasting insulin demonstrated a potential causal relationship with HOA (odds ratio (OR) = 2.568, 95% confidence interval (95% CI): 1.192-5.536, p = 0.016). Additionally, HbA1c (OR = 1.675, 95% CI: 1.254-2.238, p < 0.01), T2D (OR = 1.082, 95% CI: 1.008-1.162, p = 0.03), and LDL-C (OR = 0.799, 95% CI: 0.688-0.928, p < 0.01) were associated with KOA. Glycated hemoglobin and T2D appeared to be potential risk factors for KOA, whereas LDL-C showed a protective association.

This study provides evidence supporting causal associations between diabetes-related factors, blood lipid levels, and the risk of KOA and HOA. These findings suggest that effective blood glucose control and lipid management may help prevent or slow the progression of OA.