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

Abstract

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, = 0.016) and sciatica (OR = 1.158, 95% CI 1.034-1.296, = 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 ( > 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, = 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.

Discussion

Our findings provide strong genetic evidence that nerve growth factor (NGF) plays a causal role in the development of low back pain and sciatica, supporting NGF inhibition as a promising therapeutic strategy. These results align with clinical observations where anti-NGF monoclonal antibodies demonstrated pain-relieving effects, though safety concerns remain. In contrast, no causal associations were observed for BDNF or GDNF, underscoring the specificity of NGF in peripheral pain sensitization. The study demonstrates the value of Mendelian Randomization in minimizing confounding and reverse causation, thereby strengthening causal inference. Future work should focus on pharmacogenomic predictors to identify patients most likely to benefit from NGF-targeted interventions while minimizing adverse effects.

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.

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2025-08-12
2025-11-04

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Investigating the Causal Role of Neurotrophic Factors in Low Back Pain and Sciatica: A Mendelian Randomization Study
Bentham Science Publishers ; https://doi.org/10.2174/0109298673358689250711005445
/content/journals/cmc/10.2174/0109298673358689250711005445
/content/journals/cmc/10.2174/0109298673358689250711005445
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  • Article Type:     Research Article
Keywords: mendelian randomization ; Low back pain ; pain management ; BDNF ; neurotrophic factors ; nerve growth factor

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