Causal Relationship Between Systemic Circulatory Inflammatory Regulators and Intervertebral Disc Degeneration: A Bidirectional Two-Sample Mendelian Randomization Study

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Causal Relationship Between Systemic Circulatory Inflammatory Regulators and Intervertebral Disc Degeneration: A Bidirectional Two-Sample Mendelian Randomization Study

https://doi.org/10.21203/rs.3.rs-3619712/v1

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Background

In the context of the development of Intervertebral Disc Degeneration (IDD), inflammatory mediators play a pivotal role. Nevertheless, due to the influence of the inflammatory microenvironment, the causal relationship between specific inflammatory mediators and the development of IDD remains uncertain.

Methods

We utilized genetic data concerning systemic circulating inflammatory regulators obtained from a Genome-Wide Association Study (GWAS) analyzing 41 serum cytokines in a cohort of 8,293 individuals from Finland. The genetic data for IDD was derived from the most recent Genome-Wide Association Study summary statistics conducted within the FinnGen consortium, encompassing 37,636 IDD cases and 270,964 controls. Our analysis employed bidirectional two-sample Mendelian randomization (MR) techniques, which included several MR methods such as MR Egger, weighted median, inverse variance weighted (IVW), weighted mode, and simple mode. Additionally, the MR-PRESSO method was employed to identify horizontal pleiotropy, heterogeneity was quantified using the Cochran Q statistic, and MR Egger intercept analysis was performed to assess pleiotropy.

Results

We established causal relationships between three specific inflammatory factors and IDD. Elevated levels of MIP-1β [OR = 0.956, 95% CI: -0.08 to -0.006; P = 0.02] and IFN-G [OR = 0.915, 95% CI: -0.16 to -0.02; P = 0.01] expression were associated with a reduced risk of IDD. Conversely, genetic susceptibility to IDD was linked to a decrease in IL13 levels [OR = 0.967, 95% CI: -0.063 to -0.004; P = 0.03].

Conclusion

In this study, we have identified inflammatory factors that exhibit a causal relationship with the onset and progression of IDD, as supported by genetic predictions.

Health sciences/Medical research/Genetics research

Biological sciences/Genetics/Genetic interaction

Mendelian randomization

Intervertebral Disc Degeneration

Inflammatory Regulators

genetic relationships

infection susceptibility

Lower back pain (LBP) stands as the most prevalent musculoskeletal disorder, ranking first in terms of disability¹. Intervertebral Disc Degeneration (IDD) constitutes a significant cause of LBP, with approximately 40% of chronic lower back pain cases being associated with IDD². In recent years, degenerative spinal conditions have triggered severe lower back pain among middle-aged and even younger individuals, thus evolving into a public health concern. This phenomenon greatly impacts the quality of life and imposes a substantial economic burden on society. The global prevalence of lower back pain stands at 9.4%, and the associated healthcare costs have surged by 10% over the past 43 years³. Nevertheless, the pathogenic mechanisms of IDD remain unclear, and a deeper understanding of its etiology is paramount for the prevention and treatment of LBP.

Inflammatory environments are believed to play a pivotal role in the progression of IDD⁴, yet their mechanisms are complex and not entirely elucidated. In specific circumstances, the inflammatory microenvironment plays a crucial role in maintaining a stable environment within the intervertebral disc (IVD). For instance, there exists a delicate balance between IL-1β and its inhibitor, IL-1Ra, within the normal IVD to sustain the homeostasis of the extracellular matrix (ECM)⁵. Simultaneously, IL-1β and TNF-α, at particular concentrations, cooperatively uphold the equilibrium between synthesis and degradation of the extracellular matrix⁶. However, various factors can disrupt the biomechanical structure and cellular homeostasis within the normal IVD, stimulating the upregulation of multiple inflammatory factors, thus giving rise to an inflammatory microenvironment. Furthermore, the IVD's own inflammatory microenvironment recruits additional exogenous inflammatory cells, further exacerbating the severity of IDD⁷. These pieces of evidence suggest that inflammation serves as both a cause of IDD and a consequence of a vicious cycle following IDD's onset.

Nonetheless, current research faces various limitations: Replicating the complex inflammatory microenvironment within the IVD presents a significant challenge. It is difficult to eliminate the interplay between individual factors.Observing individual inflammatory factor levels at specific time points in clinical settings may not provide a comprehensive reflection of the overall inflammatory state during the disease process. Hence, there is an immediate need for an accurate assessment of the relationship between circulating inflammatory factors and the risk of IDD.

Mendelian Randomization (MR) leverages genetic variations as instrumental variables (IVs) to estimate causal relationships between exposures, intermediates, and outcomes, thereby mitigating biases stemming from residual confounding and reverse causality, which can be encountered by conventional epidemiological approaches⁸. Numerous prior investigations have successfully established causal links between circulating inflammatory factors and various elements^9,10,11.Consequently, in this two-sample Mendelian randomization analysis, conducted bidirectionally, our primary aim is to explore the causal connection between systemic circulatory inflammatory regulators and the development of IDD.

2.1 Study Design

The overall workflow of this study is depicted in the figure. Mendelian randomization (MR) analysis requires meeting three assumptions: (1) a strong association between instrumental variables (IVs) and exposure, (2) IVs independence from confounders, and (3) IVs relevance exclusively to the outcome through the exposure¹². This study utilizes bidirectional two-sample Mendelian Randomization (MR) analysis to thoroughly examine the causal relationship between systemic inflammatory regulators and IDD.Our research design is summarized in Fig. 1.

2.2 Data Sources

Both datasets employed in this MR analysis are extracted from summary data accessible to the public, originating from Genome-Wide Association Studies (GWAS). We obtained the most recent GWAS summary statistics for IDD from the FinnGen consortium R9 version (r9.finngen.fi), comprising 37,636 cases and 270,964 controls¹³. Data for 41 circulating inflammatory regulators were extracted from GWAS involving 8,293 individuals across three distinct cohorts¹⁴.

2.3 Single Nucleotide Polymorphism (SNP) Filtering

The core assumptions of MR necessitate that all SNPs serve as strong and independent predictors of the exposure with genome-wide statistical significance. When screening for SNPs to serve as instrumental variables for exposure in the context of 41 inflammatory factors and IDDs, We opted for a relatively lenient but still highly significant p-value of 5 × 10^− 6 because we discovered that a more stringent threshold of 5 × 10^− 8 would lead to the exclusion of a substantial number of SNPs, rendering the study unfeasible¹⁵.To eliminate linkage disequilibrium, we set R² < 0.001, kb = 10,000. Palindrome SNPs were removed from the analysis. Furthermore, we typically regard genetic variants with an F-value (calculated as F = β2 exposure/SE2 exposure) statistic lower than 10 as weak instrumental variables. Consequently, SNPs with F-values below 10 were eliminated. The steps taken in our study have fortified the association between instrumental variables and exposure factors, thereby enhancing the scientific validity and credibility of the subsequent MR analyses.

2.4 Bidirectional Mendelian Randomization Analysis

We employed five MR methods to calculate the relationship between the impact of SNPs on the outcome and their influence on exposure, consolidating the results obtained for each SNP to thoroughly evaluate the causal connection between exposure and outcome. The five MR methods include Inverse Variance Weighted (IVW), MR-Egger regression, Weighted Median method, Simple Mode, Weighted Mode. Among these, the results obtained through the IVW method serve as the primary reference in this study¹⁶, with P < 0.05 considered statistically significant evidence. We detected horizontal pleiotropy through a global test using the MR-PRESSO method and corrected potential pleiotropic outliers by removing SNP outliers when necessary¹⁷. Finally, we quantified heterogeneity through the Cochran Q statistic and conducted MR Egger intercept analysis to test for pleiotropy, with P > 0.05 serving as a reference value indicating no significant heterogeneity and pleiotropy^18,19.

MR analysis, including two-sample and multivariable MR, was performed using the TwoSampleMR package in R software (version 4.2.2).

3.1 Causal Effects of 41 Circulating Inflammatory Regulators on IDD

Out of the initial 41 systemic circulatory inflammatory regulators, a total of 428 SNPs were selected. The primary prediction method, IVW MR, demonstrated that increased expression levels of two inflammatory regulators, MIP-1β [OR = 0.956, CI: (-0.08)-(-0.006); P = 0.02] and IFN-G [OR = 0.915, CI: (-0.16)-(-0.02); P = 0.01], were associated with a decreased risk of IDD. Although not exhibiting statistical significance, the remaining four MR analysis methods provided some level of support for the aforementioned results (see Table S1, Fig. 2–6). The Cochran Q method did not detect heterogeneity (P > 0.05), and both MR-Egger and MR-PRESSO tests did not reveal horizontal pleiotropy (P > 0.05). The "leave-one-out" method involves systematically removing each SNP one at a time, calculating the combined effect of the remaining SNPs, and observing whether the results vary after each SNP is excluded. If significant changes in the results occur when a particular SNP is removed, it suggests that this specific SNP has a substantial impact on the overall findings. To ensure that the results are not unduly influenced by any single SNP, we conducted a "leave-one-out" sensitivity test. This analysis revealed that the overall results remained largely consistent after excluding each SNP, demonstrating the robustness and reliability of our findings.

3.2 Causal Effects of IDD on 41 Circulating Inflammatory Regulators

To assess the reverse causal effects, we extracted 135 SNPs associated with IDD, with significance levels at P < 5 × 10^− 6. As some SNPs were not applicable to certain cytokines, varying numbers of SNPs were used for different cytokines, which can be found in the supplementary table S2. Using the IVW method, We observed that an increased genetic predisposition to IDD correlated with a reduction in the levels of two factors: GROA [OR = 0.961, CI: (-0.071)-(-0.008); P = 0.02] and IL13 [OR = 0.967, CI: (-0.063)-(-0.004); P = 0.03]( Fig. 2–6). As the analysis using the simple mode in GROA yielded results contrary to the other four methods, we decided to exclude GROA. Sensitivity analysis was also performed, which did not detect heterogeneity or horizontal pleiotropy (P > 0.05), and the leave-one-out sensitivity test did not reveal variation in the overall outcome.

This study employed a two-sample MR analysis, utilizing data from the FinnGen project and GWAS data, to assess the causal association between 41 circulating inflammatory regulators and IDD. The study results indicated that higher levels of MIP-1β and IFN-γ were associated with a lower risk of IDD, while the reverse causal analysis revealed an association between genetic susceptibility to IDD and decreased levels of IL-13.

Inflammation consistently plays a significant role in the initiation and progression of IDD²⁰. Various factors both within and around the intervertebral disc can stimulate the formation of an inflammatory microenvironment, including microcrystals, ECM degradation products, mechanical loading, and immune cell infiltration. These factors can trigger the production of various inflammatory mediators by disc cells, such as cytokines, chemokines, NLRP3 inflammasomes, prostaglandin E2 (PGE2), and IFN-γ²¹. Inflammatory mediators have multifaceted pathogenic effects in IDD, including promoting the expression and activity of ECM-degrading enzymes, leading to structural and functional damage to the ECM²²; inducing senescence, apoptosis, and abnormal proliferation of disc cells⁷; increasing neurovascular generation and the production of pain-related factors, causing nerve fiber growth and innervation within the intervertebral disc²³. Thus, regulating the inflammatory microenvironment and restoring cytokine balance are effective strategies to control intervertebral disc degeneration.

Previous observational studies have indicated that the expression of inflammatory factors such as IL-1β and TNF-α significantly increases in IDD, and their expression levels are positively correlated with patient age and the severity of IDD^24,25,26. Furthermore, a higher expression of the NLRP3 inflammasome in IDD can mediate the production of various inflammatory cytokines, further promoting IDD development²⁵.

However, these observational studies might be subject to confounding factors or reverse causality that could distort the true causal relationship. For example, Weber et al²⁷. found that serum levels of IL-6 in IDD patients showed no significant association with the severity of intervertebral disc degeneration as indicated by MRI. These findings emphasize the complex relationship between inflammation and IDD.

MIP-1β, also known as CCL4, is a CC chemokine that plays a role in inflammation and host defense mechanisms by interacting with its specific receptor CCR5²⁸. Previous studies have suggested that MIP-1β expression levels are significantly elevated in severely degenerated NP tissue compared to mildly degenerated NP tissue^29,30. IFN-γ, also known as IFN-gamma, is one of the main inducers of M0 macrophage polarization³¹. Gorth et al.³²found that transgenic mice with overexpressed TNF-α exhibited early spontaneous IVD protrusion and elevated levels of IL-6, TNF-α, and IFN-γ upon NP exposure. Furthermore, research has shown that IFN-γ can increase the expression of TNF-α, IL-1β, COX-2, MMP-3, MMP-13, ADAMT-4, and ADAMT-5 in IVD cells³³. Interleukin-13 (IL-13) is an anti-inflammatory factor produced by Th2 cells, macrophages, and mast cells, and it participates in tissue remodeling and fibrosis through activation of the JAK/STAT signaling pathway³⁴. IL-13 receptors are expressed on macrophages and can inhibit M1 polarization while promoting M2 polarization, serving anti-inflammatory and tissue repair functions³⁵. Currently, there is limited research on the relationship between IL-13 and intervertebral disc degeneration.

In contrast to many previous observational studies, our study suggests that higher levels of IFN-γ and MIP-1β may lead to a decreased genetic risk for IDD, which could be attributed to the immunoregulation and tissue repair abilities of inflammatory factors on degenerated intervertebral discs. Yu et al.³⁶proposed that the loss of immune privilege caused by intervertebral disc lesions could be a significant factor in the development of IDD and sciatica. While the infiltration of inflammatory cells, growth factors, and cytokines may promote intervertebral disc degeneration, the functions of specific immune cells may aid in the regeneration of damaged disc tissues and the restoration of immune privilege. It has been reported that IFN-γ-induced inflammation of mesenchymal stem cells (MSCs) may improve their ability to suppress T-cell proliferation, serving an anti-inflammatory and tissue repair function³⁷. In the tumor microenvironment, IFN-γ and MIP-1β have shown dual roles in both anti-tumor and pro-tumor effects^38,39. Whether these roles are relevant to the process of intervertebral disc degeneration remains an avenue for further research. In the assessment of reverse causality, we found that the progression of IDD is associated with decreased levels of IL-13. We speculate that during the IDD process, the destabilization of the intracellular environment leads to increased expression of pro-inflammatory factors such as TNF-α and IL-1β, while concurrently resulting in a decrease in the expression of anti-inflammatory factors such as IL-13, ultimately creating an inflammatory microenvironment within the IVD. Therefore, activating the expression of anti-inflammatory factors like IL-13 within the IVD may be a strategy to slow the progression of intervertebral disc degeneration.

This study represents the first application of Mendelian randomization to examine the link between inflammation and IDD. This method helps overcome the problems of reverse causality bias that are common in traditional observational studies. Furthermore, we imposed strict study restrictions to reduce heterogeneity and pleiotropy in the outcome measures, providing reliable causal relationship estimates. Another notable aspect is the wide availability of serum samples in clinical studies, making our findings amenable to further validation and application.While the typical genome-wide significance P-value threshold is set at 5×10^− 8, our study used a relatively lenient threshold of 5×10^− 6 to explore more possibilities.

Lastly, it's important to acknowledge certain limitations of our study. Firstly, our genetic data originate from European populations, and their applicability to other ethnic groups requires further investigation.Therefore, careful consideration of its applicability is needed when applying the results to different population groups. Second, our study is more geared towards assessing the long-term effects of exposure on outcome measures, and the influence of exposure factors on outcome measures may vary across different age groups. Finally, While we made extensive efforts to exclude SNPs that might be associated with potential confounding factors and conducted a range of sensitivity analyses under varying assumptions, there is still the possibility of complex and multi-directional effects that were not fully detected.

In conclusion, this two-sample MR study suggests a causal relationship between inflammation and IDD. Higher levels of MIP-1β and IFN-γ appear to reduce the risk of IDD, and the progression of IDD is associated with a decrease in IL-13 levels. These findings provide new insights into strategies for preventing and delaying IDD progression.

Funding

This study was supported by the National Natural Science Foundation of China (82174399), Natural Science Foundation of Jiangsu Province(BK20211084), Science and Technology Development Program Project of Jiangsu Provincial Administration of Traditional Chinese Medicine(ZD202230), Construction Project of Key Laboratory of Traditional Chinese Medicine Orthopedics and Traumatology (JSDW202253, SZS2022019)

Author Contributions

ZXC: Writing–original draft. BX: Writing–review and editing. ZLH: Writing–review and editing. YJL: Writing–review and editing. XFS: Writing–review and editing. BJL: Writing–review and editing. JL: Writing–review and editing. XDZ: Writing–review and editing.YWL: Funding acquisition, Supervision, Writing–review and editing.

Data Availability Statement

The datasets analyzed for this study can be found in r9.finngen.fi and https://data.bris.ac.uk/data/dataset/3g3i5smgghp0s2uvm1doflkx9x.

Conflict of Interest

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.

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No competing interests reported.

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Causal Relationship Between Systemic Circulatory Inflammatory Regulators and Intervertebral Disc Degeneration: A Bidirectional Two-Sample Mendelian Randomization Study

Status:

Version 1

Abstract

Background

Methods

Results

Conclusion

Figures

1. Introduction

2. Materials and methods

2.1 Study Design

2.2 Data Sources

2.3 Single Nucleotide Polymorphism (SNP) Filtering

2.4 Bidirectional Mendelian Randomization Analysis

3. Results

3.1 Causal Effects of 41 Circulating Inflammatory Regulators on IDD

3.2 Causal Effects of IDD on 41 Circulating Inflammatory Regulators

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Version 1