Causal relationships between inflammatory factors and Periodontitis: A bidirectional Mendelian randomization study

doi:10.21203/rs.3.rs-3227034/v1

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Causal relationships between inflammatory factors and Periodontitis: A bidirectional Mendelian randomization study

https://doi.org/10.21203/rs.3.rs-3227034/v1

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Objective

Periodontitis, a inflammatory disease, has been associated with systemic inflammatory markers, including C-reactive protein (CRP). However, the causal links between these factors and periodontitis are unclear. This study aims to elucidate these causal relationships using a bidirectional Mendelian randomization (MR) approach. (MR-PRESSO) technique.

Materials and Methods

Materials and Methods: We utilized a two-way summary-level MR design, capitalizing on publicly available summary statistics from genome-wide association studies (GWAS) for periodontitis and 42 systemic inflammatory markers, including CRP. We selected robust, independent single nucleotide polymorphisms (SNPs) as instrumental variables and performed the inverse-variance weighted (IVW) method to analyze the Wald ratios for each genetic variant. To account for potential pleiotropic bias, sensitivity analyses were conducted using methods such as MR-Egger regression, weighted median strategies, and the MR-Pleiotropy RESidual Sum and Outlier (MR-PRESSO) technique.

Results

Our analysis reveals that higher levels of IL-1β (IVW estimate odds ratio [ORIVW] per SD genetic cytokines alteration: 2.26; 95% confidence interval [CI]: 1.02 − 5.00; P = 0.05), IL-6 (0.54, 0.29 − 1.00; P = 0.05), and IL-9 (0.56, 0.32 − 0.98; P = 0.04) are associated with an increased susceptibility to periodontitis. In contrast, no significant relationship was found between CRP or any other systemic inflammatory markers and periodontitis.

Conclusion

Our analysis specifically identifies increased levels of IL-1β, IL-6, and IL-9 as significant risk factors for developing periodontitis. However, no substantial link was observed between CRP and other inflammatory markers studied, implying that the inflammatory pathway to periodontitis may be cytokine-specific.

Clinical Relevance:

Our study provides genetic evidence into the interplay between CRP, systemic inflammatory markers, and periodontitis. Treatment strategies aimed at specific inflammatory markers could hold potential for reducing the risk of periodontitis.

Bidirectional

Inflammatory factors

Mendelian randomization

Periodontitis

Periodontitis, a pervasive inflammatory pathology impacting the supporting structures of teeth, is characterized by symptoms such as gum swelling, bleeding, formation of periodontal pockets, loss of attachment, and alveolar bone resorption. Regarded as the primary culprit for adult tooth loss, the prevalence of periodontitis is alarmingly surging, thus classifying it as the sixth global pandemic ^[1]. The World Health Organization has demarcated it as a crucial disease necessitating preventive measures ^[2], while the medical fraternity acknowledges it as the third major health menace subsequent to cancer and cardiovascular diseases ^[3].Efforts to decode the risk factors for periodontitis have spanned across demographic attributes (such as age, oral hygiene practices, and dietary habits) ^[4], genetic elements ^[5], and endogenous inflammatory characteristics (such as the intensity of immune response) ^[6]. Yet, the precise etiology of periodontitis remains enigmatic, thereby underscoring the need for deeper exploration. Contrarily, due to the irreversible nature of periodontitis, the irreversible changes in the homeostasis of cytokines induced by inflammation could eventually lead to disease relapse or residual issues ^[7]. As we delve deeper into the biology of periodontitis, the crucial roles of inflammatory elements like leukocytes, growth regulators, interferon, and tumor necrosis factor have been extensively confirmed in the disease's pathogenesis ^[8–9]. Researchers frequently probe into potential inflammatory conditions using a range of biomarkers, with the acute-phase protein CRP being a commonly tested marker ^[10]. Therefore, our research centers on CRP and other inflammatory factors to examine their possible causal links with periodontitis.

In spite of the critical role that inflammatory factors assume in the initiation of periodontitis, the importance of systemic inflammatory regulators in the pathogenesis of the disease has not been sufficiently recognized. These systemic regulators have the potential to influence the body's immune response, thereby further affecting the development of periodontitis^[11]. While a plethora of epidemiological, genetic, and biological studies have consistently confirmed the association of inflammatory factors with periodontitis^[12–13], previous research may not have fully encapsulated causality and comprehensive understanding. Furthermore, it's essential to understand that the inflammatory reaction is a fluctuating process, and measuring a single time point's high or low value might not accurately reflect the overall trajectory of inflammatory factor alterations. In the same vein, the autonomous role of individual serum cytokine changes, which can reciprocally affect each other, should not be dismissed when evaluating. Recent literature surveys have revealed conflicting outcomes regarding the relationship between inflammatory factors and periodontitis. For example, one study found a correlation between IL-2 gene promoter polymorphisms and periodontitis ^[14], while others proposed that IL-2 promoter gene polymorphisms might not be linked to susceptibility to periodontitis ^[15]. As a result, a comprehensive elucidation of the inflammatory factors influencing the risk of periodontitis and their respective contributions is still necessary. This highlights the need for a persuasive analytical design to draw valid conclusions.

Given the potential biases in observational studies, such as the inability to control for potential confounders and issues of reverse causality, MR presents a more robust analytical approach. MR leverages genetic variations as surrogate markers for exposure, facilitating sound etiological deductions. MR exhibits fewer confounding factors, given that genetic changes in germline cells are randomly distributed during meiosis, effectively symbolizing lifelong exposure free from the adverse effects of reverse causality. As a further refinement of the MR approach, bidirectional MR can be utilized to discern the causal pathway among correlated phenotypes^[16]. In our research, we conducted a bidirectional MR examination using the most recent genome-wide association summary-level data to assess the causal associations of inflammatory mediators and controllers with periodontitis. Employing this bidirectional analytical approach enabled us to differentiate between the upstream and downstream elements of the disease process while effectively mitigating the effect of reverse causality.

2.1 Research Framework

A succinct illustration of the bidirectional Mendelian Randomization approach is provided(Fig. 1). Mendelian Randomization is based on three core assumptions: (1) the chosen genetic variants, used as instrumental variables, demonstrate strong correlation with the exposure under investigation; (2) the genetic variants do not correlate with potential confounding variables; and (3) the genetic variants influence the outcomes solely via the exposure of interest, excluding involvement of other pathways. In our study, we employed summary-level data from previously published GWAS of 41 systemic inflammatory controllers, including CRP, and data related to periodontitis. Initially, we selected genetic variants linked with each inflammatory factor to elucidate the causal relationship between these factors and periodontitis. Following this, we used the genetic variants associated with periodontitis to infer the causal relationship between periodontitis and inflammatory factors.

2.2 Genetic Tools for Inflammation Factors

We sourced the genetic variants of CRP from a meta-analysis of GWAS encompassing 206,158 individuals of European ancestry within the inflammation working group (CIWG) cohort^[17]. The evaluation of genetic association for CRP took into account factors such as sex,age and demographic composition. As for the genetic markers of 41 systemic inflammation modulators, they were derived from the largest cytokine-related GWAS meta-analysis so far, carried out across three distinct cohorts. These cohorts comprised 8,293 individuals of Finnish ancestry from the Young Finns Study (YFS) and "FINRISK" investigations (FINRISK 1997 and FIN-RISK 2002)^[18]. To standardize the concentrations of these 41 cytokines, a bifurcated inverse transformation was conducted. The singular association of 10.7 million genetic variations with cytokine levels was assessed using an additive genetic framework, taking into account factors such as sex,BMI,age, and the top 10 principal genetic components.

2.3 Genetic Tools for Periodontitis Analysis

We utilized GWAS results on 195,395 individuals of European descent from the FinnGen consortium to obtain summary data for periodontitis. The GWAS applied a linear mixed model (LMM) method facilitated by BOLT-LMM, with adjustments made for gender and genotyping array. To transform BOLT-LMM periodontitis association statistics to log odds ratio, the approximation log OR ≈ β/(µ [1-µ]) was used, where β symbolizes the effect size BOLT-LMM reported for periodontitis, and µ is the case fraction of the binary trait. Accordingly, the corresponding standard error (SE) was divided by µ (1 - µ)^[19]. Following these steps, a two-sample MR methodology was employed to infer the causal link between inflammatory markers and periodontitis, based on the GWAS summary statistics. Importantly, there was no overlap in the samples of inflammatory regulators, CRP, and periodontitis, since they were derived from separate polygenic sources.

2.4 Instrumental Variable Selection

To satisfy the assumptions of Mendelian Randomization, all SNPs are predicted from published GWAS and are both robust and independent (within a 10Mb range, R² < 0.001), achieving genome-wide significance (P < 5x10⁻⁸).

F-statistics were employed to assess the robustness of each SNP, this measure being a derivative of the genetic effect size and precision. The impact of the trait can be expressed by the equation F = R²(N − 2) / (1 - R²), where R² signifies the proportion of trait variability attributable to the SNP, and N denotes the number of participants in the GWAS for the associated trait^[20]. R² was calculated using the formula R² = 2xEAF ×(1 - EAF)×β², where EAF is the frequency of the SNPs impact allele and β is the estimated impact of the SNP on the trait. SNPs with an F value below 10 were excluded since an F value exceeding 10 suggests adequate power to confirm the SNP's effectiveness.

2.5 Bidirectional Mendelian Randomization Analysis

A bidirectional two-sample MR methodology was employed, leveraging summarized association data to investigate causality between periodontitis and inflammatory factors. Key data for our analysis included SNP, allele, effect size, SE, and P values^[21].

We conducted thorough data harmonization to guarantee that the influence of each SNP on both exposure and outcome corresponded to the same allele. In our principal analysis, we computed Wald ratio estimates for every genetic variant and integrated these assessments using the IVW approach, which includes multiplicative random effects. This IVW technique enables precise estimates while adjusting for possible heterogeneity among the Wald ratio estimates derived from SNPs^[22]. For the 41 evaluated cytokines, their effects were presented as alterations in inverse-normalized cytokine concentrations, commensurate with each effect allele dosage. Inverse normalization is a statistical treatment method used to restore normalized data to its original scale. The effects of CRP were reported as changes in natural log-transformed CRP concentrations induced by each effect allele dosage. The natural log transformation is a common method for dealing with concentration data, reducing the impact of extreme values and making data more normally distributed. The anticipated impact of CRP on periodontitis was given as the OR and its 95% CI, each corresponding to a 1% genetic predicted alteration in CRP. The demonstrated effect of periodontitis on systemic inflammatory regulators was similarly communicated using OR values and their respective 95% CIs.

2.6 Sensitivity Analysis

We employed several sensitivity analysis techniques, including MR-Egger method, weighted median approach, and MR-PRESSO. The MR-Egger analysis evaluates the pleiotropy of instrumental variables; an intercept deviating from zero indicates a potential bias in the IVW approximation. We also adopted the weighted median approach, which identifies the causal estimate as the MR estimate at the median, proving advantageous when handling numerous potentially invalid or pleiotropic genetic variations. MR-PRESSO identifies horizontal pleiotropy through a global test and, when necessary, rectifies potential pleiotropic outliers by excluding them. We further applied the Cochran Q test and I^2 index to assess the heterogeneity of the IVW estimates. All evaluations were two-sided and executed utilizing the TwoSampleMR (version 0.5.7) and MRPRESSO (version 1.0) packages in R software (version 4.3.1). The reporting adhered to the guidelines set by the STROBE-MR guidelines.

3.1 Bidirectional Causal Effect between CRP and Periodontitis

We selected 10 SNPs with genome-wide significance in relation to CRP. The application of these significant SNPs showed no link between genetically predicted CRP levels and periodontitis risk (P-value = 0.52). For examining the causal impact of periodontitis on CRP, we used 16 SNPs, which provided no supporting evidence (P-value = 0.37). The outcomes from various MR methods aligned with those from the IVW method, and we found no indications of horizontal pleiotropy or heterogeneity (Fig. 2).

3.2 Causal Effect of Systemic Inflammatory Regulators on the Risk of Periodontitis

Strong instrumental variables were supplied by the genome-wide significant SNPs of eight inflammatory regulators. Figure 3 presents the impact of these eight genetically anticipated systemic inflammatory regulators on the risk of periodontitis. Importantly, no correlation with periodontitis was detected in any analysis, irrespective of whether multiple comparison corrections were applied. Neither the MR-PRESSO global test nor the MR-Egger intercept test detected any indications of horizontal pleiotropy, and the Cochran Q test revealed no signs of heterogeneity.We examined all 41 inflammatory regulators. We found a causal association between periodontitis and three factors, namely Interleukin-1B (IL-1B), Interleukin-6 (IL-6), and Interleukin-9 (IL-9). No significant horizontal pleiotropy was detected in the MR-Egger intercept(Fig. 3).

3.3 Causal Impact of Periodontitis on Levels of Systemic Inflammatory Regulators

To assess the effect of reverse causation, we extracted 16 SNPs with strong and independent associations with periodontitis, with a significance P-value < 1x10^-6. We observed no significant association between periodontitis and inflammatory factors(Fig. 4)^[23].

Through our research, we executed a bidirectional MR analysis using the most recent genome-wide association summary-level data to explore the causal connections between CRP, periodontitis, and systemic inflammatory factors. This approach offers superior statistical power and balanced pleiotropy when MR assumptions are met, distinguishing it from other MR methods. By adopting a bidirectional analysis strategy, we effectively differentiated between the upstream and downstream components of the disease chain, eliminating concerns related to reverse causality. To mitigate potential pleiotropic effects, we utilized various MR methods, including MR-PRESSO and MR-Egger, to bolster the dependability and sturdiness of our MR analysis.

Preliminary results from this bidirectional MR analysis indicate a positive causal association between systemic inflammatory factors, namely Interleukin-1β (IL-1β), Interleukin-9 (IL-9), Interleukin-6 (IL-6), and periodontitis, whereas no such relation was found with CRP. Following multiple comparisons with IVW, the estimates from sensitivity analyses were inconsistent. Conversely, reverse variant analysis revealed no positive causal relations between periodontitis and related inflammatory factors, including CRP. Subsequent to the exclusion of outliers, the final model showed no significant pleiotropy, thereby supporting the reliability of our preliminary analysis results.Overall, our research findings provide modest evidence for a bidirectional causal relationship between systemic inflammatory factors and periodontitis, with a positive causal association from the former to the latter, but not vice versa. This finding challenges the conventional understanding that periodontitis leads to increased systemic inflammatory factor indicators. Instead, our research findings affirm the theory that inflammatory factors are instrumental in advancing the progression of periodontitis and act as predictive markers for the disease stage of periodontitis.In past research, IL-1β and IL-6 have been extensively studied, given their central role in inflammation and immune responses, including the pathogenesis of periodontitis^[24–25]. However, these studies primarily relied on observational research, potentially influenced by confounding factors. Our study, using Mendelian randomization analysis, circumvents these confounders, thus providing more robust evidence supporting a causal relationship between IL-1β and IL-6 and periodontitis. Our study also found a positive causal association between IL-9 and periodontitis. IL-9, is a cytokine predominantly produced by TH2 cells. It plays a crucial role in a variety of immune responses and inflammatory reactions, including asthma, allergies, and autoimmune diseases^[26]. Within the immune system, IL-9 promotes the growth and differentiation of certain cells, such as mast cells and T cells, a process that is integral to the regulation of immune responses^[27].While the role of IL-9 in periodontitis is not fully understood, some studies have unveiled its potential role in modulating immune responses and inflammation. This new finding of our research might initiate novel research directions to further explore the role of IL-9 in periodontitis. However, our research did not find a positive causal relationship between CRP and periodontitis.This contrasts with some earlier observational research findings, which associate CRP levels with the severity of periodontitis^[28]. Our results might suggest that, although CRP is a critical inflammation marker, there may not exist a direct causal link between it and the risk of periodontitis. This could be because the level of CRP is influenced by numerous factors, including other inflammatory responses and lifestyle factors, which may obscure the potential relationship between CRP and periodontitis.

It's noteworthy that our research did not find a causal association between some widely discussed inflammatory factors, such as TNF-α, IL-23, and IL-17, and periodontitis^[29]. These factors have been the subject of numerous randomized controlled trials and observational studies, but the results have been inconsistent. For example, one study found that patients with periodontitis treated with a gel containing hyaluronic acid demonstrated significant decreases in TNF-αlevels in the blood^[30]; another showed that Th17 cells, IL-17, and IL-23 play important roles in periodontal disease and immune-mediated inflammatory disease^[31]. Thus, the positive correlations observed in previous studies need further clarification.To address this, we employed genetic variations as instrumental variables to minimize the impact of alterations in inflammatory cytokine levels due to medication treatments or disease complications.

Our study boasts several strengths. First, the solidity of genetic instrumental variables allowed us to carry out an all-encompassing MR analysis linking inflammatory factors and periodontitis risk for the first time. This novel approach is key in determining whether genetic predisposition to periodontitis can cause alterations in circulating inflammatory factors, and whether changes in these factors can affect the risk of periodontitis^[32]. Additionally, the genetic instruments used in our study are free of confounders in the exposure-outcome relationship, and we've accounted for genetic principal components to reduce the potential collider bias that might infringe upon MR assumptions.

Our research also has several limitations. Firstly, the focus of the present study was solely on the relationship between systemic inflammatory factors and periodontitis. It is essential to explore the associations between inflammatory factors and other types of periodontitis, such as aggressive periodontitis, necrotizing ulcerative periodontitis, and others, in future investigations. Secondly, we did not examine the complications of periodontitis in our study, as the etiology and prognosis of each clinical symptom display heterogeneity, making such analysis challenging. Additionally, the constraints of lower statistical power and small sample size would need to be considered. Moreover, the changes in inflammatory factors in any real clinical scenario could be influenced by unpredictable factors, posing a challenge to definitive conclusions. Thirdly, the case-control structure of the original datasets and the potential infringement of one assumption in two-sample Mendelian randomization (indicating that the two samples do not represent the same base population) represent additional constraints that should be recognized. Fourthly, some sensitivity analysis methods did not support the significance obtained in the preliminary analysis. Therefore, additional investigations are needed to confirm our study findings. Fifthly, MR analysis aims to assess the causal impact of lifelong exposure on the outcome and may not always align perfectly with clinical outcomes.

In conclusion,our research underscores the pivotal roles of Interleukin-1β (IL-1B), Interleukin-6 (IL-6), and Interleukin-9 (IL-9) in the pathogenesis of periodontitis, potentially paving the way for novel preventive and therapeutic strategies for this disease. Notably, despite CRP being a significant inflammation marker, our results suggest there may not be a direct causal link between CRP levels and the likelihood of periodontitis. These insights could have significant implications for future research and clinical practice.

In summary, this Mendelian randomization study posits a causal linkage between inflammation and periodontitis. Through rigorous analysis and evaluation, we've identified that there is a causal association between periodontitis and the interleukins IL-1B, IL-6, and IL-9. These findings underscore the crucial role these interleukins play in the pathogenesis of periodontal disease, providing critical biological foundations for further prevention and treatment of periodontitis.

Acknowledgements

We deeply thank our study participants and our research staff.

A. Author contributions

Conceptualization: Mianxing Wei, Qian Yang, Qingquan Guo. Data curation: Mianxing Wei, Xiaoying Dai, Yuxuan Li. Formal analysis: Mianxing Wei, Qian Yang, Xiaoying Dai, Yuxuan Li. Investigation: Qingquan Guo, Mianxing Wei, Xiaoying Dai, Qian Yang. Methodology: Mianxing Wei, Qian Yang, Qingquan Guo, Yuxuan Li, Xiaoying Dai. Project administration: Qingquan Guo, Mianxing Wei. Supervision: Qingquan Guo, Mianxing Wei, Qian Yang. Validation: Mianxing Wei, Qian Yang, Qingquan Guo, Xiaoying Dai, Yuxuan Li. Visualization: Mianxing Wei, Qingquan Guo, Qian Yang, Xiaoying Dai, Yuxuan Li. Writing—original draft: Mianxing Wei, Qian Yang, Qingquan Guo, Xiaoying Dai, Yuxuan Li. Writing—review and editing: Qingquan Guo, Mianxing Wei, Qian Yang, Xiaoying Dai, Yuxuan Li. The work reported in the paper has been performed by the authors, unless clearly specified in the text.

B. Ethics Approval and Consent to Participate

Not Applicable

C. Funding

This study was supported by the Science and Technology Project of Deyang City.（NO.2022SZ057）

D. Conflict of Interests

The authors declare that they have no conflicts of interest.

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No competing interests reported.

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Causal relationships between inflammatory factors and Periodontitis: A bidirectional Mendelian randomization study

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Abstract

Objective

Materials and Methods

Results

Conclusion

Clinical Relevance:

Figures

1. Introduction

2. Materials and Methods

2.1 Research Framework

2.2 Genetic Tools for Inflammation Factors

2.3 Genetic Tools for Periodontitis Analysis

2.4 Instrumental Variable Selection

2.5 Bidirectional Mendelian Randomization Analysis

2.6 Sensitivity Analysis

3. Results

3.1 Bidirectional Causal Effect between CRP and Periodontitis

3.2 Causal Effect of Systemic Inflammatory Regulators on the Risk of Periodontitis

3.3 Causal Impact of Periodontitis on Levels of Systemic Inflammatory Regulators

4. Discussion

5. Conclusion

Declarations

References

Additional Declarations

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