Therapeutic Potential of Downregulated Interleukin-6 Signaling for the Treatment of Chronic Pain: A Mendelian Randomization Study

Abstract

Introduction

While numerous studies have emphasized the pivotal involvement of the Interleukin 6 (IL-6) pathway in the development of chronic pain, the causal nature of this relationship remains uncertain.

Methods

In this study, we opted to include genetic variants situated within the locus of the IL-6 receptor (IL-6R) that exhibited associations with C-reactive protein (CRP) levels. CRP serves as a downstream effector in the IL-6 pathway. Utilizing these variants as genetic proxies, we aimed to modulate IL-6 signaling. Employing a two-sample Mendelian randomization (MR) approach, we investigated the potential link between the genetic proxy and seven distinct subtypes of chronic pain, categorized based on their corresponding body locations. Moreover, we examined the relationship between chronic pain and an alternative instrument of IL-6 signaling that was weighted based on s-IL-6R levels. Furthermore, we conducted exploratory analyses to estimate the plausible causal association between CRP, gp130, and the subtypes of chronic pain.

Results

Our analysis showed that genetic proxied downregulation of IL-6 signaling, weighted on CRP levels, was linked to a reduced risk of chronic back and knee pain. The sensitivity analyses across various MR methods confirmed the consistency of the findings and showed no evidence of horizontal pleiotropy or heterogeneity. Moreover, the results remained robust with different sets of instrument variables. A genetically increased level of s-IL-6R was also negatively associated with chronic back and knee pain. However, there was no causal relationship between CRP and gp130 with chronic pain.

Conclusion

Based on our findings, there is evidence to suggest a potential causal relationship between IL-6 signaling and chronic back and knee pain. Consequently, the downregulation of IL-6 signaling holds promise as a potential therapeutic target for addressing chronic back and knee pain.

Keywords:

• IL-6 signaling
• chronic pain
• Mendelian randomization

Data Sharing Statement

The original contributions presented in the study are included in the article, further inquiries can be directed to the corresponding authors.

Ethics Approval and Consent to Participate

As per the regulations outlined in People’s Republic of China’s “Notice on the Implementation of Ethical Review Measures for Life Science and Medical Research”, our study falls under the exemption criteria specified in Section 4 of the regulation. Therefore, ethics approval was not required for this research, as it met the following conditions:

1. Exemption Premise: The study exclusively utilized publicly available data, specifically summary-level data from GWAS, which does not involve sensitive personal information, pose harm to individuals, or compromise their privacy.

2. Exemption Provision: Our research adheres to the exemption circumstances outlined in Section 4 of the regulation:

- We utilized lawfully obtained publicly available data for our analysis.

- The data used in this study were fully anonymized, ensuring the privacy and confidentiality of individuals.

- Our research focuses on analyzing existing data and does not involve interventions, human biological samples, or activities related to reproductive cloning, genetic manipulation, or germ cells.

Due to the nature of our study and its compliance with the exemption criteria, we did not require explicit ethics approval. While informed consent was not obtained from individual participants since the study involved publicly available data, we ensured that all data accessed and analyzed were fully de-identified and complied with the terms of use and guidelines provided by the data source. We affirm that this research was conducted in accordance with the applicable laws, regulations, and ethical standards.

Acknowledgments

We gratefully acknowledge the authors and participants of all GWASs including UK Biobank, deCODE, CHARGE, and INTERVAL study from which we used summary statistics data.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.