Investigating Causal Associations Between Circulating Cytokines and Vestibular Disorders Using Mendelian Randomization: Insights from Large-Scale Genome-Wide Association Studies Data in European Populations

Abstract

The presence of circulating cytokines has a significant impact on the development and progression of vestibular disorders. However, further investigation is needed to determine the direction of causation and causal effects. By applying two-sample Mendelian randomization (MR), we analyzed the potential causal connection between 41 circulating cytokines and vestibular disorders using the integrated data from genome-wide association studies (GWAS). The major analysis utilized for MR was inverse variance weighted (IVW). To examine reverse causation, we conducted reverse MR analysis. In addition, we assessed the robustness of the findings by performing pleiotropy and heterogeneity tests. Our results demonstrated that two circulating cytokines were significantly correlated with vestibular disorders risk. More specifically, vascular endothelial growth factor [IVW, odds ratio (OR) = 0.999, 95% confidence interval (CI) = 0.999–1.000, P = 0.046] and interleukin-7 (IVW, OR = 0.999, 95% CI = 0.998–1.000, P = 0.033) were negatively correlated with vestibular disorders risks, respectively. No evidence was identified to support associations between the remaining 39 circulating cytokines and vestibular disorders. These findings reveal a distinct correlation between circulating cytokines and vestibular diseases, providing a novel perspective and potential biological target for future clinical interventions for vestibular disorders.

Introduction

As the core neural structure that maintains spatial positioning and balance regulation, the vestibular system is anatomically divided into peripheral and central parts. Its peripheral part is composed of the vestibular organ of the inner ear (including the mechanosensitive hair cells of the semicircular canal, elliptical sac, and balloon) and its vestibular nerve (CN VIII branch), which is responsible for transmitting peripheral signals to the center. The central part includes the brain stem vestibular nucleus group (including four subnuclei), the vestibular-central projection pathway (up to the parapal cortex, the transmedial longitudinal bundle to regulate the oculomotor nucleus, the anterior horn of the spinal cord), and the regulatory network to coordinate spatial positioning and balance regulation (Cullen, 2019). Pathological damage of the vestibular system will cause a series of syndromes or pathological states, collectively known as vestibular disease (Bisdorff et al., 2015; Strupp et al., 2020). Typical clinical manifestations of such diseases include postrelated visual oscillation (positional oscillopsia), vestibular visual impairment (vestibulo-ocular dysfunction), and the balance imbalance caused by sensory conflict, with vertigo (vertigo) and dizziness (dizziness) as the core clinical syndrome (Bisdorff et al., 2015). Vertigo, a sense of self-motion or a distortion of self-motion during otherwise normal head movements (Salmito et al., 2020), is clinically very common. Epidemiological studies have shown that ∼15%–35% of the adult population experience clinically meaningful vertigo episodes at least once in their lifetime (Karatas, 2008; Pothier et al., 2018). A recent cross-sectional study of 70 million European populations further revealed the age–sex distribution of vestibular dysfunction: its prevalence increased with age after childhood, peaked between 74 and 94 years with significantly higher incidence in women (n = 2,973,323; 65.4%) than in men (n = 1,570,240; 34.6%; P < 0.001) (Hülse et al., 2019). However, due to the complexity and diversity of their pathogenesis, effective treatments for these vestibular disorders remain limited. As a result, it is imperative to identify their etiology.

The immune system is a crucial determinant in the pathogenesis and development of vestibular disorders (Akdal et al., 2018). Immune factors could be a contributing factor in the pathogenesis of these disorders (Andrianov et al., 2007; Song et al., 2024). It was Lehnhardt who initially proposed, in 1958, that the presence of anti-cochlear antibodies might be associated with abrupt bilateral hearing loss (Lehnhardt, 1958). Concerning the experimental guinea pig cochlea, the data collected by Beickert, along with Yoshihiko and Yukihiro, offered evidence in favor of the autoimmune hypothesis (Beickert, 1961; Yoshihiko and Yukihiro, 1964). The vestibular extracellular matrix and inner cochlea are largely dependent on the cochlea. In view of the autoimmune inner ear disease, the cochlea was revealed as a potential antigen, given its link to the release of inflammatory cytokines and inner ear immunity (Baruah, 2014; Jung et al., 2019). A number of clinical trials have indicated that changes in the levels of cytokines in circulation arise from vestibular disorders. Evidence from a specific clinical investigation substantiated that ∼60% of Meniere’s disease (MD) patients possess antibodies, specifically Ikβ α (Inhibitor of Nuclear Factor Kappa-B Alpha), NF-kβ (Nuclear Factor Kappa-B) P50 and P65, TNF-α (Tumor Necrosis Factor-Alpha), and IL-1α (Tumor Necrosis Factor-Alpha). These act against the cytokines within the cochlea and inner ear proteins in their serum (Adams et al., 2009). A separate cohort study suggested that patients diagnosed with idiopathic sensorineural deafness displayed elevated levels of serum neutrophils and IL-6, with decreased levels of natural killer cells (Masuda et al., 2012). Circulating cytokine levels, as vital inflammatory regulatory molecules, significantly impact neurological disorders. Nevertheless, the connection between these inflammatory markers and vestibular disorders, as well as the former’s link to the pathophysiology of the latter, remains uncertain in terms of causality. Hence, development of potential avenues for treatment, prediction, and prevention could be facilitated by gaining a clear understanding of the precise involvement of circulating cytokines and associated risk factors in vestibular disorders.

In examining causality involving exposures and outcomes of interest, the use of Mendelian randomization (MR) is prevalent. Also known as the random pairing of parental alleles in every offspring, this approach applies the fundamental concept of Mendelian law. In the context of randomized clinical trials, it is comparable with the randomization of participating individuals (Bowden and Holmes, 2019; Luo et al., 2023). As a result, MR has become an essential instrument for delving into the causal links between phenotypes, illnesses, and complex traits (Xiao et al., 2022). In this MR study, we leveraged genome-wide association study (GWAS) data to systematically investigate the causal interplay between 41 circulating cytokines and vestibular disorders. Using genetic variants robustly associated with cytokine levels (P < 5 × 10⁻⁶) as instrumental variables (IVs), we employed bidirectional two-sample MR analyses to delineate direction-specific causal effects while circumventing limitations inherent to observational designs, including residual confounding and reverse causation. Our research could shed light on such a link, identify potential targets for pharmacotherapy, and introduce novel diagnostic biomarkers.

Materials and Methodology

Study design

The utilization of genetic variants in MR analysis necessitates the fulfillment of three assumptions (Burgess et al., 2013). First, a strong correlation between genetic variants and exposure must be demonstrated. In this case, exposure is also known as the circulating cytokines. Second, there are no confounding factors connected to the IVs. Finally, instead of other pathways, the outcome is solely linked to exposure to IVs. The former, in this regard, is also known as vestibular disorders. The full study design is illustrated in Figure 1.

FIG. 1.

The process of present MR analyses is shown in a flow chart. (A) Principle diagram of MR study. (B) Diagrammatic illustration of the complete MR analysis process. Assumption 1: The IVs selected for this study should demonstrate a significant association with circulating cytokines. Assumption 2: The IVs chosen for present study are required to have no significant associations with other potential confounding factors. Assumption 3: The IVs utilized in present study do not have any independent causal pathways leading to the outcome (vestibular disorders) other than through circulating cytokines. IVs, instrumental variables; LD, linkage disequilibrium; MR, Mendelian randomization; SNPs, single nucleotide polymorphisms.

Sample selection criteria

The sample selection criteria were meticulously designed to align with the study’s objectives and ensure validity. First, the focus was on individuals of European descent, who constituted the majority of participants. This choice facilitated greater genetic homogeneity and reduced population stratification and confounding effects, thereby enhancing the robustness of the MR analyses. Second, publicly available datasets with high-quality phenotypic and genotypic data were selected due to their extensive coverage and adequate sample sizes, ensuring both statistical power and precision. Third, harmonized GWAS outcome data further supported consistency, replicability, and practical feasibility. Collectively, this rigorous approach underscores the study’s depth in exploring causal relationships between circulating cytokines and the risk of vestibular disorders within a scientifically robust and ethically sound framework.

Data sources

MR analysis was performed utilizing two datasets, both sourced from publicly available GWAS data (Supplementary Table S1). We obtained data on exposure and outcomes solely from individuals of European descent in order to minimize possible population biases.

In light of the 41 systemic inflammatory regulators, the GWAS data featured in a comprehensive study served as the source of the datasets concerning circulating cytokines (Ahola-Olli et al., 2017). The study comprised 8,293 participants from three separate Finnish cohorts: the Young Finns Cardiovascular Risk Study (YFS), and FINRISK 2002 and 1997. The FINRISK survey had participants with an average age of 60 years while that of the YFS cohort was 37 years (Kalaoja et al., 2021). Among the YFS and FINRISK 2002 cohort participants, the study measured the serum cytokines and heparin plasma. Meanwhile, for the FINRISK 1997 cohort participants, the measurement of their growth factors and cytokines were done using their plasma. Standard deviations were used to indicate circulating cytokine levels. The website was used to collect complete GWAS summary statistics (https://www.ebi.ac.uk/gwas/downloads/summary-statistics).

Vestibular disorders were extracted from a separate, unaffiliated study—in terms of the GWAS outcome dataset. The UK Biobank provided the dataset, which consisted of 458,921 control subjects of European descent and 4,012 cases (https://gwas.mrcieu.ac.uk/datasets/ukb-b-5188/). Along with biological samples and phenotypic data, detailed data were collected from every participant through oral interviews and questionnaires (Sudlow et al., 2015). To assess vestibular disorders visits, a consent form was electronically signed, a touchscreen questionnaire was completed, and a short computer-assisted interview was conducted.

Selection of IVs

In this MR study, the selection of single nucleotide polymorphisms (SNPs) was stratified using a two-tiered approach to optimize instrument validity. Initially, SNPs were filtered at the genome-wide significance threshold P < 5 × 10⁻⁸, a stringent criterion widely adopted in genetic epidemiology to minimize false-positive associations and prioritize robust genetic proxies for circulating cytokines. However, for >50% of exposures exhibiting limited genome-wide significant SNPs, the threshold was pragmatically relaxed to P < 5 × 10⁻⁶ to ensure sufficient IV availability, a critical prerequisite for maintaining statistical power in MR and the reliability of causal inference. This calibrated relaxation balanced two methodological imperatives: (i) mitigating weak instrument bias by retaining SNPs with meaningful exposure associations P < 5 × 10⁻⁶ and (ii) preserving statistical precision through linkage disequilibrium (LD) score regression to exclude pleiotropic outliers. Such a hierarchical SNP selection strategy aligns with consensus MR guidelines, demonstrating rigorous adherence to the trade-off between instrument strength and analytical robustness in exposure–outcome causal estimation.

To ensure independence among SNPs, we applied a clumping process using a physical distance threshold of 10,000 kb and a LD threshold of R ² < 0.001 (Myers et al., 2020). This approach is based on the following rationale: (1) Avoiding multicollinearity: High LD among SNPs can lead to excessive correlation, introducing multicollinearity issues that reduce the precision of causal inference and bias effect estimates. (2) Enhancing instrument independence: Independent SNPs capture distinct genetic regulatory pathways of the exposure variable, enabling a more accurate assessment of the exposure’s true effect on the outcome. This clumping method is a widely accepted standard in MR studies, ensuring the independence of IVs and mitigating potential confounding effects.

In order to evaluate the possible impact of weak instrumental bias, we utilized F-statistics and noted that values >10 signified the lack of such bias, thereby reinforcing the established causal relationship (Burgess and Thompson, 2011). In this article, we used the equation F = [(N − K − 1)/K] × [R²/(1 − R²)], where the exposure factors’ sample size is represented by N, and K is the number of IVs. In addition, R ² denotes the amount of exposure factor variance that can be attributed to the IVs. This quality control criterion was implemented based on two methodological principles: (i) Mitigation of weak instrument bias: Genetic variants with an F-statistic <10 were excluded, as such weak instruments may induce attenuation bias (a downward bias in causal effect estimates toward the null); (ii) Enhancement of causal inference validity: By retaining only strong instruments (F ≥ 10), we reduced type I error inflation and improved the precision of exposure–outcome association estimates. This dual-filtering approach aligns with MR best practices to ensure analytical robustness.

In screening IVs via Phenoscanner v2.0 (http://www.phenoscanner.medschl.cam.ac.uk/), we systematically excluded SNPs with pleiotropic associations across 5 rigorously defined domains to minimize selection bias: (1) disease phenotypes [removing variants associated with vestibular disorders and systemic comorbidities (eg, diabetes, hypertension, cardiovascular diseases)]; (2) demographic confounders (excluding ancestry-related markers, age-associated SNPs, or genetic variants linked to educational attainment); (3) environmental/lifestyle exposures (eg, trauma history); (4) pharmacogenetic interactions (excluding variants affecting drug metabolism pathways); and (5) genetic factors.

Statistical analysis

For circulating cytokines with a single SNP, we utilized the Wald ratio test to examine the association between identified IVs and vestibular disorder (Burgess et al., 2017). We utilized three MR analysis techniques, namely weighted median (WM), IVW, and MR-Egger, for multiple SNPs, with IVW serving as the primary method of analysis. Given that the genetic variant meets the IV hypothesis, the IVW method combines Wald ratio estimates, specifically those of the causal effect of multiple SNPs. This offers a reliable measurement of the causal effect of exposure on the outcome (Burgess et al., 2013). The WM and MR-Egger methods can serve as complementary techniques for verifying significant causal correlations identified through the IVW method. Such methods are also used for direction validation. In order to determine the potential causality between circulating cytokines and the risk of vestibular disorders, we employed the odds ratio (OR). The IVW and MR-Egger methods applied Cochran’s Q statistic to assess heterogeneity (Cohen et al., 2015). If the P value was greater than 0.05, no heterogeneity was taken into account. The presence of pleiotropy was evaluated using MR-Egger regression. A P value <0.05 signifies the existence of pleiotropy. In addition, we performed sensitivity analyses using the “leave-one-out” method to demonstrate whether individual SNPs affect the causal relationship between exposure and outcome. The R software (version 4.2.2) and “TwoSampleMR” package were used for all statistical analyses in the MR study (Lawlor et al., 2008). “Strengthening the Reporting of Observational Studies in Epidemiology Statement” (STROBE) checklist for our studies is provided online Supplementary Table S2.

Results

Genetic IVs

Variants were automatically selected as primary instruments for the inflammatory cytokines. Supplementary Table S3 itemizes the primary information data for these SNPs, including effects and other alleles, beta, standard error of beta, P value, and F value. The F-statistic values for every SNP exceeded 10, denoting the absence of genetic tool bias in this MR study.

MR analyses for vestibular disorders

MR analyses with a relaxed P value threshold of 5 × 10⁻⁶ were executed while taking into account the limited range of genetic variants, as well as the restricted number of SNPs and the relative sizes of their corresponding moderate effect sizes. Using these parameters (P < 5 × 10⁻⁶, r² < 0.001) a grand total of 171 SNPs connected to 41 cytokines were discovered (Supplementary Table S2). The IVs all had F-statistics greater than 10, suggesting the absence of IV bias in the findings, thus supporting their reliability. A two-sample MR analysis was used to determine the impact of every SNP on vestibular disorders.

We examined a total of 41 inflammatory cytokines using more relaxed thresholds (P < 5 × 10⁻⁶).

The findings revealed a nominal correlation between vestibular disorders and 2 circulating cytokines. The application of the IVW approach revealed a correlation between genetically predicted vascular endothelial growth factor (VEGF) and a reduced susceptibility to vestibular disorders (P = 0.046, OR = 0.999, 95% CI = 0.999–1.000, IVW) (Fig. 2). Also, the risk of vestibular disorders was found to be lower with genetically predicted IL-7 (P = 0.033, OR = 0.999, 95% CI = 0.998–1.000, IVW) (Fig. 2).

FIG. 2.

MR results of causal effects between inflammatory cytokines and vestibular disorders. MP1b, macrophage inflammatory protein-1 beta; MCP1, monocyte chemoattractant protein-1; MIG, monokine induced by gamma interferon; IP10, interferon gamma-induced protein 10; CTACK, cutaneous t-cell attracting chemokine; RANTES, regulated on activation, normal T cell expressed and secreted; MP1a, macrophage inflammatory protein-1 alpha; GROa, growth-regulated oncogene-alpha; SDF1a, stromal cell-derived factor 1 alpha; MCP3, monocyte chemoattractant protein-3; SCGFb, stem cell growth factor beta; PDGFbb, platelet-derived growth factor BB; SCF, stem cell factor; GCSF, granulocyte colony-stimulating factor; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; MCSF, macrophage colony-stimulating factor; DNGF, dendritic cell-derived nerve growth factor; FGFBasic, fibroblast growth factor basic; IL-1b, interleukin-1 beta; IL1ra, interleukin-1 receptor antagonist; IL-2, interleukin-2; IL2ra, interleukin-2 receptor alpha; IL-4, interleukin-4; IL-5, interleukin-5; IL-6, interleukin-6; IL-7, interleukin-7; IL-10, interleukin-10; IL-12p70, interleukin-12 p70; IL-13, interleukin-13; IL-16, interleukin-16; IL-17, interleukin-17; IL-18, interleukin-18; TRAIL, TNF-related apoptosis-inducing ligand; IFNg, interferon gamma; MIF, macrophage migration inhibitory factor; TNFa, tumor necrosis factor alpha; TNFb, tumor necrosis factor beta; MR, Mendelian randomization; OR, odds ratio; CI, confidence interval.

Figure 3 presents the scatter plots illustrating the outcomes of the 5 methods.

FIG. 3.

Scatter plots illustrating the outcomes of the five methods between VEGF, IL-7, and vestibular disorders; VEGF (A); IL-7 (B). IL-7, interleukin-7; MR, Mendelian randomization; SNP, single nucleotide polymorphism; VEGF, vascular endothelial growth factor.

In terms of direction and magnitude, consistent causal estimates were yielded by the WM, simple mode, weighted mode, and MR-Egger methods. The results from the MR-PRESSO analysis did not identify any outliers. Between the IVs in VEGF and IL-7 GWAS, no significant heterogeneity was found through the Cochran Q test for MR Egger and IVW (Supplementary Tables S4 and S5).

In order to strengthen the robustness of these findings, we carried out an Egger pleiotropy test on the included SNPs, which did not indicate any presence of level pleiotropy (P > 0.05) (Supplementary Tables S4 and S5). Furthermore, we performed a leave-one-out sensitivity analysis, wherein each SNP was iteratively excluded to assess the influence of the remaining SNPs on the overall findings. This approach demonstrated that no single SNP exerted a disproportionate effect on the results, thereby reinforcing the robustness and reliability of the observed associations (Fig. 4).

FIG. 4.

Leave-one-out analysis illustrating the causal effects of VEGF and IL-7 on vestibular disorders; VEGF (A); IL-7 (B). IL-7, interleukin-7; MR, Mendelian randomization; SNPs, single nucleotide polymorphism; VEGF, vascular endothelial growth factor.

MR analyses for inflammatory cytokines

In order to investigate the potential for reverse causation, the exposure was set as vestibular disorders, and the outcome was set as inflammatory cytokines. Employing a P value threshold P < 5 × 10^–6 (see Supplementary Table S6), we employed four SNPs previously linked to vestibular disorders through GWAS as IVs, demonstrating a significant and independent correlation with vestibular disorders. It is worth noting that the data did not support a reverse causation link between individual inflammatory cytokines and vestibular disorders (Fig. 5). Equally important, using the IVW method, the corresponding values for VEGF (P = 0.458, IVW) (Supplementary Table S6) and IL-7 (P = 0.322, IVW) were obtained.

FIG. 5.

MR results of causal effects between vestibular disorders and inflammatory cytokines. MP1b, macrophage inflammatory protein-1 beta; MCP1, monocyte chemoattractant protein-1; MIG, monokine induced by gamma interferon; IP10, interferon gamma-induced protein 10; CTACK, cutaneous t-cell attracting chemokine; RANTES, regulated on activation, normal T cell expressed and secreted; MP1a, macrophage inflammatory protein-1 alpha; GROa, growth-regulated oncogene-alpha; SDF1a, stromal cell-derived factor 1 alpha; MCP3, monocyte chemoattractant protein-3; SCGFb, stem cell growth factor beta; PDGFbb, platelet-derived growth factor BB; SCF, stem cell factor; GCSF, granulocyte colony-stimulating factor; VEGF, vascular endothelial growth factor; HGF, hepatocyte growth factor; MCSF, macrophage colony-stimulating factor; DNGF, dendritic cell-derived nerve growth factor; FGFBasic, fibroblast growth factor basic; IL-1b, interleukin-1 beta; IL1ra, interleukin-1 receptor antagonist; IL-2, interleukin-2; IL2ra, interleukin-2 receptor alpha; IL-4, interleukin-4; IL-5, interleukin-5; IL-6, interleukin-6; IL-7, interleukin-7; IL-10, interleukin-10; IL-12p70, interleukin-12 p70; IL-13, interleukin-13; IL-16, interleukin-16; IL-17, interleukin-17; IL-18, interleukin-18; TRAIL, TNF-related apoptosis-inducing ligand; IFNg, interferon gamma; MIF, macrophage migration inhibitory factor; TNFa, tumor necrosis factor alpha; TNFb, tumor necrosis factor beta; MR, Mendelian randomization; OR, odds ratio; CI, confidence interval.

Discussion

To the best of our knowledge, this MR study is the first of its kind to examine the potential causal link between 41 circulating cytokines and vestibular disorders. A possible link was found between 2 cytokines and the incidence of vestibular disorders after analyzing cytokines as exposure variables (P < 5.0 × 10⁻⁶). Genetically predicted VEGF and IL-7 were linked to vestibular disorders. Conversely, no causal association was found between vestibular disorders and any cytokines when using the former (vestibular disorders) as the exposure variable. These cytokines could potentially predict the likelihood of developing vestibular disorders and aid in diagnosis. To validate these hypotheses, the complexities of the cytokine network in vivo require additional clinical and basic experiments.

Previous studies have extensively documented the occurrence of immune response in the vestibular system among both humans and animal models. The existing literature indicates that the endolymphatic sac (ES) may play a role in immune function within the inner ear due to its immunological capabilities and involvement in transepithelial ion transport (Møller et al., 2015a, 2015b; Rask-Andersen et al., 1991). Danckwardt-Lilliestr and others’ discovery of microorganisms (Mycoplasma pneumoniae) within the lumen of human internal lymphatic vessels (ED) served as validation for the theory that the immune defense organ of the inner ear is the ES (Danckwardt-Lillieström et al., 1992). The immune function of the inner ear has been the main focus of past studies, particularly regarding the humoral immune responses and adaptive immune system. In a recent study, Jennifer and her team have elucidated the involvement of macrophages in the innate immune response of the normal human inner ear (O’Malley et al., 2016). According to Kampfe Nordstrom and others, MHCII is expressed on the vasculature and helical ganglia macrophages, which are vital in initiating immune responses targeted toward specific antigens (Broderick, 2019). Moreover, Moller and others identified the presence of genes related to the cellular and humoral innate immune system, such as beta-defensin and lactoferrin, as well as Toll-like receptors 4 and 7, in ES (Møller et al., 2015a). Based on these findings, ES has been shown to possess molecular evidence that supports its ability to recognize and process immunoreactive antigens through immunological mechanisms.

VEGF, known as endothelial cell-specific mitogen, serves as a potent and broadly specific regulator of vascular endothelial cells (Ferrara et al., 2003). It is believed to have a crucial function in the processes of angiogenesis and lymphangiogenesis (Ye et al., 2021). Nevertheless, more recently, VEGF has garnered considerable attention for its neurotrophic and neuroprotective effects, being recognized as a neuroregulatory factor in the nervous system (Beazley-Long et al., 2013; Ruiz de Almodovar et al., 2009). In 2009, Fetoni and others observed that the expression of VEGF was upregulated in the cochlea and the vestibule under noisy environments, highlighting that VEGF has a repair role in both areas (Fetoni et al., 2009). In its usual function, VEGF operates via the receptor tyrosine kinases VEGFR-1 (FLT1), -2 (KDR, FLK1), and -3 (FLT4)-transmembrane proteins that contain tyrosine kinase sequences in their intracellular parts (Zachary and Gliki, 2001). Through the downstream protein kinase C pathway, the expression of VEGF receptor 2 (KDR/Flk-1) has been found to activate endothelial nitric oxide synthase, playing a part in the regulation of neurotrophic and neurostructural elements (Shen et al., 1999; Wu et al., 1999). Alexander and others also reported about the constitutive expression of VEGF Flt-1 and KDR/Flk-1 in the vestibule of guinea pigs (Hess et al., 2000). Our research revealed a correlation between VEGF and a reduced likelihood of developing vestibular disorders. The former was identified as having a nominal causal effect on the latter, consistent with previous studies, indicating a potential protective effect against such disorders.

IL-7 and vestibular disorders: Epithelial and stromal cells are the primary sources of IL-7, which is essential in maintaining T cell survival, growth, and homeostasis. Anti-IL-7Rα monoclonal antibodies have been found to effectively target pathogenic memory immune cells, resulting in beneficial therapeutic outcomes for chronic inflammatory illnesses that are T-cell mediated. Jing Zou et al. (2022) reported a significant elevation in serum IL-7 levels among MD patients compared with healthy control volunteers (Zou et al., 2022). Our findings offer a contrasting viewpoint. Concerning IL-7 and vestibular disorders, there is currently a dearth of research that explains their biological connection and mechanism. Our research is the first to propose that IL-7 might hold promise as a protective agent against vestibular disorders, providing valuable insights into the underlying biological mechanisms and potential treatment options. In light of the disparate findings, additional research is necessary to determine the exact mechanism of IL-7 in the development of vestibular disorders.

While our study employs robust MR methodologies to infer causal relationships, certain limitations warrant further consideration. One key area is the potential impact of F-statistics on the strength of IVs and the robustness of our findings. Although all selected IVs demonstrated F-statistics exceeding the threshold of 10, which is commonly considered indicative of strong instruments, ∼50% of the F-statistics were <100. This may suggest some susceptibility to weak instrument bias, particularly for exposures with a limited number of associated SNPs. This limitation has two primary implications: (1) Reduced statistical power: Instruments with lower F-statistics may weaken the statistical power of the MR analysis, potentially obscuring causal effects, particularly for exposures with small effect sizes or high variability. (2) Potential bias in estimates: While F-statistics >10 mitigate the likelihood of substantial weak instrument bias, minor biases may still attenuate observed effects, leading to underestimation of the true causal relationships.

To address these concerns, we conducted extensive sensitivity analyses, including pleiotropy and heterogeneity tests. These methods consistently affirmed the robustness of our findings, reducing the potential influence of weak instrument bias. Future research should focus on identifying additional SNPs associated with circulating cytokines to strengthen instruments and reduce bias. Leveraging larger GWAS datasets and employing advanced techniques could further enhance precision. Simulations or bias quantification analyses may also provide valuable insights into the potential influence of weaker instruments, ensuring more comprehensive evaluations of causal relationships.

Overall, our research provides a foundation for comprehending the cytokine dynamics involved in vestibular disorders. To unlock its full potential for real-world use, it is imperative to tackle the limitations outlined, widen the scope of the dataset, and incorporate sophisticated techniques. Prior to incorporating potential biomarkers into clinical practice guidelines, it is essential to thoroughly validate them in a diverse and extensive cohort and systematically evaluate their clinical significance.

Conclusions

In essence, with regard to circulating cytokines and vestibular disorders, our research thoroughly investigated their causal relationship. The findings of our MR study suggest a potential causal link between two circulating cytokines (VEGF and IL-7) and an altered susceptibility to vestibular disorders. Despite this, further validation in a larger cohort is necessary to substantiate the link between these two variables. This research could offer novel perspectives on the processes underlying the development of vestibular disorders.

Ethics Approval and Consent to Participate

All data used in this study were obtained from publicly available databases; further ethics approval and informed consent were not required.

Consent for Publication

Not applicable.

Footnotes

Acknowledgments

The authors acknowledge the participants and investigators of the FinnGen study. The authors also express their gratitude to the GWAS meta-analysis conducted by Ahola-Olli, as well as the FINRISK 1997 and FINRISK 2002 studies. The authors want to acknowledge the UK Biobank for providing the dataset for GWAS data of vestibular disorders.

Authors’ Contributions

S.K. and Z.H.M. contributed to the conceptualization and design of the study. S.K. and L.H.W. were responsible for developing the research framework and composing the article. L.H.W. and H.M.M. performed the data analysis and generated the visual representations. S.K. and L.H.W. participated in reviewing and editing the article. All authors approved the final version of the article.

Data Availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

Author Disclosure Statement

The authors declare that there are no financial interests associated with this work.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

Supplementary Table S6

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