Investigating the Causal Role of Neurotrophic Factors in Low Back Pain and Sciatica: A Mendelian Randomization Study.

Background: Low back pain (LBP) and sciatica are among the most prevalent musculoskeletal disorders, leading to significant disability and an economic burden. Neurotrophic factors, including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-derived neurotrophic factor (GDNF), play critical roles in pain modulation and neuronal function. While NGF-targeting monoclonal antibodies have shown potential in treating chronic pain, their efficacy and safety remain under debate. This study employs Mendelian Randomization (MR) to assess the causal relationships between NGF, BDNF, GDNF, and the risk of LBP and sciatica.

Methods: We conducted a two-sample MR analysis using genetic instruments for NGF, BDNF, and GDNF. LBP and sciatica data were obtained from FinnGen. The inverse variance weighted (IVW) method was applied as the primary causal estimation, with the weighted median (WM) and MR-Egger regression used for sensitivity analyses. Reverse MR was performed to evaluate bidirectional causality. Furthermore, we used expression quantitative trait loci (eQTLs) within 50 kb of each gene locus as genetic instruments for NGF regulation, ensuring that the genetic variants used directly influence neurotrophic factor expression.

Results: MR analysis revealed a significant causal association between NGF and an increased risk of LBP (OR = 1.121, 95% CI 1.021-1.230, p = 0.016) and sciatica (OR = 1.158, 95% CI 1.034-1.296, p = 0.010), while BDNF and GDNF showed no significant associations with pain outcomes. Sensitivity analyses confirmed the robustness of the NGF findings, with no evidence of horizontal pleiotropy or heterogeneity. Reverse MR analysis showed no significant causal effect of LBP or sciatica on NGF levels (p > 0.05), ruling out reverse causality. Additionally, we investigated the NGF-eQTL, which captures genetically regulated NGF expression, and found a significant association between the NGF-eQTL and LBP (OR = 1.040, 95% CI 1.010-1.070, p = 0.007). Unlike external NGF measurements, the NGF-eQTL minimizes environmental confounding and reverse causation, providing stronger genetic evidence supporting NGF as a therapeutic target for LBP.

Conclusion: This study provides genetic evidence that NGF plays a causal role in LBP and sciatica, reinforcing its potential as a therapeutic target. However, BDNF and GDNF were not significantly associated with pain outcomes, suggesting distinct mechanisms of pain modulation. While clinical trials of anti-NGF monoclonal antibodies have demonstrated efficacy in pain reduction, concerns about adverse effects, such as joint degeneration, habe limited their widespread clinical use. Future research should explore genetic predictors of anti-NGF therapy response to optimize treatment strategies for LBP and related musculoskeletal pain disorders.