C-Reactive Protein and Risk of Low Back Pain: A Univariable and Multivariable Mendelian Randomization Study

To investigate the causal associations of genetically predicted C-reactive protein (CRP), major depressive disorder (MDD), body mass index (BMI), and smoking initiation with low back pain (LBP) using Mendelian randomization (MR).

Summary-level GWAS data for exposures and LBP (FinnGen R8) were obtained. Instrumental variables were selected at a strict genome-wide threshold (P < 5×10^-8) and harmonized. Two-sample univariable MR was performed primarily using random-effects inverse-variance weighted (IVW). Multivariable MR (MVMR) assessed independent effects adjusting for confounders, evaluated via conditional F-statistics. Sensitivity analyses included Cochran's Q, MR-Egger, and leave-one-out diagnostics.

Univariable MR showed that genetically predicted circulating CRP was associated with an increased risk of LBP (IVW: β = 0.100, 95% CI: 0.040 to 0.160, P = 0.001), corroborated by the weighted median estimator. Conversely, genetically predicted MDD showed no causal association with LBP (β = -0.039, P = 0.752). In MVMR, instrument strength was robust (conditional F: CRP = 61.37, BMI = 23.30, smoking = 14.39). Elevated CRP remained an independent risk factor for LBP (β = 0.093, 95% CI: 0.016 to 0.170, P = 0.018). Additionally, smoking initiation exhibited an independent causal effect (β = 0.268, 95% CI: 0.081 to 0.455, P = 0.005), while BMI showed no direct effect (β = 0.129, P = 0.128).

This study provides genetic evidence consistent with an independent causal association between elevated CRP levels and LBP risk, alongside smoking initiation. Genetically predicted MDD and BMI did not exhibit independent causal effects on LBP.