Mendelian Randomization Reveal Causal Relationship Between Periodontitis and Coronary Atherosclerosis

Mendelian Randomization Reveal Causal Relationship Between Periodontitis and Coronary Atherosclerosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Mendelian Randomization Reveal Causal Relationship Between Periodontitis and Coronary Atherosclerosis Zhengrui Li, Qi Wang, Xufeng Huang, Yinteng Wu, Rao Fu, Xutao Wen, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3360691/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objectives Growing evidence appears to intimate a profound connection between periodontitis and coronary atherosclerosis (CA), yet the existence of a causal relationship remains unclear. Through the implementation of Mendelian randomization analysis, We further evaluated the potential causal link between chronic/acute periodontitis (CP/AP) and CA. Objectives Utilizing genome-wide association study (GWAS) summary statistics, we incorporated periodontitis data derived from European samples (n1 = 198,441; n2 = 195,762) and CA data from 61,194 cases. We conducted a two sample, bidirectional Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method as the main analytical approach. Supplementary analyses were executed through MR Egger, Weighted median (WM), IVW, Simple mode, and Weighted mode approaches. Results The IVW analysis revealed no significant causal relationship between CA and periodontitis (CA-CP: OR = 2.110, 95% CI = 1.483–3.003, P = 0.527; CA-AP: OR = 0.414, 95% CI = 0.051–3.384, P = 0.644). Similarly, the bidirectional analysis did not identify impact of periodontitis on CA (OR = 1.000, 95% CI = 0.999–1.001, P = 0.953). The supplementary analyses corroborated these findings. Conclusions While studies highlighting a correlation between periodontitis and CA, our comprehensive analysis does not corroborate a causal connection between periodontitis and CA. Further research is needed to elucidate other potential shared mechanisms and causal evidence between periodontitis and CA. Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction As we all know, periodontitis is a widespread oral health disorder affecting approximately 50% of the neral population and 11% of the global population[ 1 , 2 ], making it one of the most common human diseases. It can be classified into acute and chronic forms (AP / CP), both of which impose a significant burden on patients, severely impacting their quality of life and overall well-being[ 3 ]. Coronary atherosclerosis (CA), a principal contributor to global mortality[ 4 ], continues to claim approximately 17.8 million lives annually[ 5 ] despite advancements in therapeutic interventions and preventative strategies. Acknowledged conventional risk factors encompass aging, cholesterol, hypertension, or dyslipidemia[ 6 – 9 ]. However, the implications of inflammatory disease as a pivotal driver in the onset and progression of CA has become gradually recognized[ 10 ]. A substantial accumulation of evidence substantiates an critical correlation between severe periodontitis and several systemic diseases[ 11 – 14 ]. In fact, severe periodontitis has been independently and indubitably linked with all-cause and cardiovascular mortality across diverse cohorts[ 15 – 17 ], especially coronary atherosclerosis. Proposed mechanisms involve bacteremia and its resultant systemic inflammatory consequences[ 13 ], such as elevated C-reactive protein (CRP) levels, as well as oxidative stress (OS). Among populations beset with multiple comorbidities[ 18 – 21 ], such as chronic kidney disease (CKD) concurrent withdiabetes and periodontitis, periodontitis has been significantlycorrelated with diminished all-cause and cardiovascular mortality rates. As such, periodontal disease (PD), especially periodontitis emerges as a potentially modifiable non-conventional risk factor for CA Numerous studies have demonstrated the positive association between periodontitis and the risk of developing atherosclerotic disease[ 22 ]. Epidemiological evidence suggests that patients with periodontitis exhibit notable endothelial dysfunction[ 6 ], as evidenced by impaired flow-mediated dilation (FMD), increased arterial stiffness (such as PWV - pulse wave velocity), augmented carotid intima-media thickness (cIMT), and elevated arterial calcification scores. Cohort studies have also shown a correlation between periodontitis and higher coronary atherosclerosis mortality rates[ 23 ]. Some hypotheses propose that dysregulated oral microbiota from periodontitis may indirectly or directly trigger systemic diseases by disseminating into the cardiovascular system[ 13 ]. At the same time, current biological experiments cannot validate these hypotheses nor establish periodontitis as the key cause of atherosclerosis. Although periodontitis is associated with coronary atherosclerosis, the relationship remains unclear. Two-sample Mendelian randomization (MR) analysis is a statistical method aimed at inferring potential causal relationships from observed associations[ 24 ]. MR utilizes exposure-associated genetic variants as proxy indicators to evaluate the relationship between the potential indicators and outcomes[ 24 ]. Given the urgency to investigate the potential causal link between periodontitis and coronary atherosclerosis. Scholars have employed MR analysis to study the relationship between periodontitis and multiple non-oral diseases[ 25 – 35 ], including arthritis, hypertension, psoriasis, Parkinson's disease, inflammatory bowel disease (IBD), etc. However, most studies have not provided strong supporting a significant causal relationship between the periodontitis and these diseases, suggesting that periodontitis may be a comorbid condition or that other shared disease mechanisms are yet to be explored. We conducted a two-sample, bidirectional Mendelian randomization analysis using genome-wide association study (GWAS) summary data to investigate the potential relationship between periodontitis and coronary atherosclerosis. By employing this rigorous approach, we aim to enhance our understanding of the intricate interplay between periodontal disease and cardiovascular disease. This research endeavor is expected to contribute valuable insights to the field, inform future investigations, and shed light on the underlying mechanisms linking these two conditions. Materials and methods Data assumption and preparation The workflow of our study is depicted in Fig. 1 . We utilized statistical genetic data on periodontitis from the European sample FinnGen database ( https://www.finngen.fi/en ), including chronic periodontitis (finn-b-K11_PERIODON_CHRON, case: 3046, control: 195395) and acute periodontitis (finn-b-K11_PERIODON_ACUTE, case: 367, control: 195395). Data on coronary atherosclerosis from the OpenGWAS ( https://gwas.mrcieu.ac.uk ), a publicly accessible database with stringent quality control (ukb-d-I9_CORATHER, case: 14334 control: 346860), were also from a European sample. Local institutional review boards and ethical committees approved all studies contained in the three datasets. Coronary atherosclerosis cases were selected per the International Classification of Diseases. The American Academy of Periodontology (AAP) defines periodontitis, apart from being broadly classified into acute and chronic forms, as cases assessed by comparable standards through probing depth or self-reported. Periodontitis cases can be categorized based on the following criteria: (1) Mild periodontitis: ≥2 interproximal sites with attachment loss (AL) ≥ 3 mm and ≥ 2 interproximal sites with probing depth (PD) ≥ 4 mm (not on the same tooth) or one site with PD ≥ 5 mm. (2) Moderate periodontitis: ≥2 interproximal sites with AL ≥ 4 mm (not on the same tooth) or ≥ 2 interproximal sites with PD ≥ 5 mm (not on the same tooth). (3) Severe periodontitis: ≥2 interproximal sites with AL ≥ 6 mm (not on the same tooth) and ≥ 1 interproximal site with PD ≥ 5 mm. In this study, we conducted a bidirectional, two-sample Mendelian randomization (MR) investigation to elucidate the potential causal association between periodontitis and coronary atherosclerosis. Mendelian randomization and statistical analysis Data analysis was conducted using R (version 4.2.1) with the 'TwoSampleMR (0.5.6)' and 'MR-PRESSO (1.0)' packages. Mendelian randomization (MR) utilizes genetic variants as instrumental variables (IVs) to estimate causal effects of risk factors on complex diseases. Various methods were employed to assess the potential causal relationship between periodontitis and coronary atherosclerosis (CA), with the primary analysis employing the inverse variance-weighted (IVW) method. Additional MR testing methods, including MR Egger, Weighted median (WM), IVW, Simple mode, and Weighted mode, were used for supplementary analyses to accurately evaluate causal effects and correct for horizontal pleiotropy. IVs were selected based on a threshold of P < 5×10 − 6 . The association between periodontitis and CA risk was expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Bonferroni correction was applied for multiple comparisons across different classification levels, and statistical significance was set at different p-values. To examine heterogeneity among the selected single nucleotide polymorphisms (SNPs), Cochran's Q test was performed. If heterogeneity was detected (p < 0.05), the random-effects IVW method was employed; otherwise, the fixed-effects IVW method was used. Given that IVW results may be influenced by valid instruments and potential pleiotropy, sensitivity analyses were conducted to assess the robustness of the associations. Firstly, the weighted median method was utilized to estimate associations, as it provides reliable causal effect estimates even when effective instruments are limited, and it remains valid when less than 50% of the information is derived from invalid instruments. Secondly, MR-Egger regression was employed to test for potential horizontal pleiotropy, with a p-value of the intercept less than 0.05 indicating the presence of pleiotropy among the SNPs. The IVW analysis assumes that all genetic variants are valid instrumental variables with strong causal inference capabilities. We harmonized the SNPs by removing incompatible alleles and palindromic SNPs with intermediate allele frequencies. Due to variations in experimental conditions, selected populations, and SNPs, heterogeneity may exist in two-sample MR analysis, which can introduce bias to causal effect estimates. Therefore, heterogeneity tests were conducted for the primary IVW analysis and MR-Egger regression in this study, with p-values > 0.05 indicating no heterogeneity among the IVs. One assumption of MR analysis is that the instrumental variable affects the outcome solely through the exposure, hence testing for horizontal pleiotropy is essential to understand the causal relationship between the exposure and outcome. The intercept value in MR-Egger regression is used to assess pleiotropy, with an intercept close to 0 indicating close similarity to IVW regression. The smaller the likelihood and significance of pleiotropy, the more the SNP is associated solely with the exposure and unrelated to other confounding variables. In this study, the p-value of the pleiotropy test was employed to evaluate the presence of pleiotropy. If the p-value is greater than 0.05, the influence of pleiotropy in the causal analysis is considered minimal or non-existent, and its impact can be disregarded. Consistency of the results was assessed through a leave-one-out analysis. Result Causal effects of Coronary Atherosclerosis on Chronic and Acute Periodontitis For the Mendelian randomization (MR) analysis, a total of 60 single nucleotide polymorphisms (SNPs) were identified, with Coronary Atherosclerosis (CA) considered as the exposure and periodontitis (chronic/acute) as the outcome. Among these SNPs, 31 were excluded as their alleles did not meet the specified criteria. Consequently, 29 SNPs were retained for further MR analysis. The results for CA and acute periodontitis demonstrated that MR-egger (OR = 0.032, 95% CI = 0.000-7.423, P = 0.226), WM (OR = 0.679, 95% CI = 0.180–2.571, P = 0.818), IVW (OR = 2.110, 95% CI = 1.483–3.003, P = 0.527), Simple mode (OR = 0.567, 95% CI = 0.071–4.537, P = 0.854), and weighted model (OR = 0.285, 95% CI = 0.020–3.984, P = 0.597) demonstrated no impact of CA on chronic periodontitis (Table 1 , Fig. 2 A). Sensitivity analysis demonstrated the robustness of the current two-sample MR analysis (Figure S1 ), indicating the absence of instrumental variable bias in the causal inference. The Cochrane Q test did not reveal heterogeneity among these IVs (P = 0.8547, I 2 = 0.382034). The heterogeneity test displayed the impact of coronary atherosclerosis on the risk of periodontitis (Table 2 ): Egger regression intercept = 0.032, Standard error = 0.015, Directionality p-value = 0.0433. The absence of heterogeneity among these instrumental variables (IVs) was indicated, as there was no significant heterogeneity detected. Scatter plots depicting the effect sizes of single nucleotide polymorphisms (SNPs) for chronic periodontitis and coronary atherosclerosis are presented (Fig. 3 A). Funnel plot analysis also corroborated these results (Figure S1 ), revealing that direction and horizontal pleiotropy were insignificant, and the evidence for directional pleiotropy was markedly insufficient. Table 1 The relationship between genetically instrumented coronary atherosclerosis (CA) and chronic/acute periodontitis (CP / AP) was estimated using Mendelian randomization. Outcome Exposure MR Method nSNP Beta SE OR 95% CI p.val Chronic periodontitis Coronary atherosclerosis MR Egger 29 -3.456 2.786 0.032 0.000-7.423 0.226 WM 29 -0.3867 1.679 0.679 0.180–2.571 0.818 IVW 29 0.7467 1.18 2.110 1.483–3.003 0.527 Simple mode 29 -0.5674 3.061 0.567 0.071–4.537 0.854 Weighted mode 29 -1.254 2.345 0.285 0.020–3.984 0.597 Acute periodontitis Coronary atherosclerosis MR Egger 29 0.479 0.691 1.614 0.417–6.255 0.510 WM 29 -0.4145 1.317 0.661 0.050–8.730 0.948 IVW 29 -0.882 1.072 0.414 0.051–3.384 0.644 Simple mode 29 -0.51 1.241 0.600 0.053–6.837 0.404 Weighted mode 29 -3.579 1.692 0.028 0.001–0.769 0.645 Periodontitis Coronary atherosclerosis MR Egger 5 -0.001467 0.003447 0.999 0.992–1.005 0.699 WM 5 0.000282 0.0004831 1.000 0.999–1.001 0.559 IVW 5 0.00002859 0.0004805 1.000 0.999–1.001 0.953 Simple mode 5 0.000684 0.000707 1.001 0.999–1.002 0.388 Weighted mode 5 0.0006446 0.0007783 1.001 0.999–1.002 0.454 Table 2 Heterogeneityassessment of MR-Egger and IVW test for directional pleiotropy. Outcome Exposure Heterogeneity Q Q_df I 2 Q_p.val Chronic periodontitis Coronary atherosclerosis MR Egger 17.49 27 0.543739 0.9183 IVW 20.26 28 0.382034 0.8547 Acute periodontitis Coronary atherosclerosis MR Egger 29.25 27 0.076923 0.3488 IVW 30.23 28 0.073768 0.3522 Periodontitis Coronary atherosclerosis MR Egger 8.284 3 0.637856 0.04049 IVW 8.817 4 0.546331 0.06584 The results of CA and acute periodontitis demonstrated MR-egger (OR = 1.614, 95% CI = 0.417–6.255, P = 0.510), WM (OR = 0.661, 95% CI = 0.050–8.730, P = 0.948), IVW (OR = 0.414, 95% CI = 0.051–3.384, P = 0.644), Simple mode (OR = 0.600, 95% CI = 0.053–6.837, P = 0.404), and weighted median (OR = 0.028, 95% CI = 0.001–0.769, P = 0.645); CA had no impact on acute periodontitis (Table 1 , Fig. 2 B). The Cochrane Q report did not show heterogeneity among these IVs (P = 0.3522, I 2 = 0.073768). The heterogeneity test demonstrated the impact of coronary atherosclerosis on the risk of acute periodontitis (Table 2 ): Egger regression intercept = -0.043, Standard error = 0.045, Directionality p-value = 0.35. The analysis yielded results that indicate the absence of heterogeneity among these instrumental variables (IVs), suggesting a consistent pattern. Scatter plots illustrating the effect sizes of single nucleotide polymorphisms (SNPs) for periodontitis and coronary atherosclerosis are presented for visual representation (Fig. 3 B). The funnel plot analysis confirmed these results (Figure S2), indicating that horizontal pleiotropy was insignificant. Moreover, no high-impact points were detected in the leave-one-out analysis (Figure S2). The study included a substantial sample size of 198,441 individuals with chronic periodontitis, 195,762 individuals with acute periodontitis, and 361,194 individuals with coronary atherosclerosis. The strength of the instrumental variables was assessed by calculating R² and F-statistics using the Effector Allele Frequency (EAF) and effect estimate (BETA). The F-statistic values exceeded 10 in all cases (Table S1 ), with an average value of 66.1 (range: 29.94 ~ 312.83), indicating strong instrumental variables and no significant observable instrumental variable bias. However, the relatively lower R² values suggested challenges in fully explaining the extent of exposure through the instrumental variables. Causal effects of Periodontitis on Coronary Atherosclerosis Due to insufficient exposure data for periodontitis, we merged the CA of the two cohorts, keeping the control group unchanged. Taking periodontitis as the exposure and coronary atherosclerosis as the outcome, we extracted 6 SNPs, with 1 SNP being discarded due to the need for corresponding outcome data. Ultimately, 5 SNPs were chosen for the following MR analysis. The results showed MR-egger (OR = 0.999, 95% CI = 0.992–1.005, P = 0.699), WM (OR = 1.000, 95% CI = 0.999–1.001, P = 0.559), IVW (OR = 1.000, 95% CI = 0.999–1.001, P = 0.953 ), Simple mode (OR = 1.001, 95% CI = 0.999–1.002, P = 0.388), and Weighted mode (OR = 1.001, 95% CI = 0.999–1.002, P = 0.454). No significant association between periodontitis and coronary atherosclerosis was observed, as evidenced by the results presented(Table 1 and Fig. 4 ). All F-statistic values exceeded 10, with an average F-statistic value of 949.2, indicating strong instrumental variables and a lack of observable horizontal pleiotropy (Table S1 ). The MR-Egger analysis also provided no evidence of horizontal pleiotropy when examining the impact of periodontitis on the risk of coronary atherosclerosis (Table 2 ): Egger regression intercept = 0.0018, Standard error = 0.0041, Directionality p-value = 0.69). The leave-one-out analysis yielded no remarkable deviations or anomalies (Figure S3). Consequently, our findings do not support the existence of a bidirectional genetic relationship between periodontitis and coronary atherosclerosis (Fig. 4 ). Furthermore, the Cochrane Q test revealed no significant heterogeneity among the estimates of the included SNPs(P = 0.06584, I 2 = 0.546331). A funnel plot observation revealed no significance in directionality and horizontal pleiotropy (Figure S3). Finally, the F statistics (F > 10, range 29.83 to 39.59) did not exhibit any significant instrumental variable bias (Table S2). Discussion This study employed a bidirectional, two-sample MR analysis to investigate the potential causal association between periodontitis and coronary atherosclerosis. Although numerous clinical data suggest that periodontitis is a high-risk factor for cardiovascular disease, the results from the MR study did not support the evidence of a significant influence of periodontitis on coronary atherosclerosis, and vice versa. We posit that both periodontitis and cardiovascular disease are multifactorial disorders, manifesting in individuals exposed to risk factors over many years[ 15 , 22 ]. The connection between the two diseases is likely far more complex than a simple causal relationship, with other significant associations still present. For instance, oral microbiota represents a crucial link between periodontitis and coronary atherosclerosis. Moreover, other risk factors, (including detrimental habits, smoking, and so on), are prominent shared[ 1 , 6 ]. In general, the outcomes of our Mendelian randomization (MR) analysis diverge from the findings of prior observational studies. Our findings fail to substantiate a causal association between periodontitis and cardiovascular disease, therefore cautioning against prioritizing periodontitis treatment as a means to mitigate the risk of stroke and coronary artery disease. There may be coincidences or confounding by some unknown factors. Furthermore, most current observational studies cannot determine the causal relationship between periodontitis and coronary atherosclerosis[ 13 , 16 , 23 ], only establishing a co-occurrence or association. However, the nature of this association has yet to be deeply researched, merely elucidating a comorbidity phenomenon. Many periodontitis patients often present with a range of systemic issues, as do patients with coronary atherosclerosis. Hence, the presence of shared pathophysiological mechanisms between these conditions may potentially establish a connection between periodontitis and coronary atherosclerosis, thereby warranting further investigation in future studies. Multiple sensitivity analyses were employed to reinforce the robustness of our findings. The instrumental variable-weighted (IVW), weighted median, and MR-Egger methods were utilized to explore the causal relationship between periodontitis and coronary atherosclerosis. However, none of these approaches provided evidence supporting a causal association. The consistent outcomes obtained through these diverse methods lend credibility to our study's findings. Moreover, our study possesses several notable strengths. Firstly, only single nucleotide polymorphisms (SNPs) that exhibited significant associations with clinically-defined periodontitis at the genome-wide level and were replicated in independent cohorts were included as instrumental variables (IVs). This stringent criterion ensures the validity and reliability of our genetic instruments. Additionally, we integrated exposure data from multiple periodontitis cohorts, augmenting the likelihood that all selected periodontitis-associated SNPs genuinely capture the relationship with coronary atherosclerosis. This MR study has limitations. Firstly, the population selected for the study represents only European groups, not entirely capturing the absolute causal relationship between the two diseases in the global population. Moreover, larger data sets are needed to seek associations further. Lastly, the disease characteristics of periodontitis and coronary atherosclerosis at different stages may not fully reflect the association between the two, particularly for acute periodontitis, which has a rapid onset and recovery, its impact on coronary atherosclerosis might be minimal, whereas chronic periodontitis, a long-term chronic disease, may present higher clinical risks due to constant systemic inflammatory impact. In conclusion, the findings of this study do not provide substantial evidence supporting a causal relationship between periodontitis and coronary atherosclerosis, as well as the reverse association. This result contrasts with observational studies and requires further research for validation to achieve a more reasonable and robust conclusion. Future studies should elucidate other potential shared mechanistic interactions and causal evidence between periodontitis and coronary atherosclerosis. The primary objective of this research was to comprehensively investigate the causal association between periodontitis and coronary atherosclerosis, offering valuable insights to clinicians. By enhancing the understanding of the connection between periodontitis and coronary atherosclerosis, this study contributes to the exploration of potential links between periodontitis and systemic diseases, thereby providing valuable references for future investigations in this field. Abbreviations CA: Coronary atherosclerosis MR: Mendelian randomization GWAS: Genome-wide association studies IVW: Inverse-variance weighted CI: Confidence interval OR: Odds ratio WM: weighted median CP/AP: Chronic / Acute periodontitis CRP: C-reactive protein OS: Oxidative stress CKD: Chronic kidney disease PD: Periodontal disease SNP: Single nucleotide polymorphism SE: Standard errors EA: Effect allele OA: Other allele EAF: Effect allele frequency PWV: Pulse wave velocity FMD: Flow-mediated dilation cIMT: carotid intima-media thickness IBD: Inflammatory bowel disease Declarations Conflict of Interests The authors disclose no identified competing financial interests or personal relationships that may have influenced the research presented in this manuscript. Funding The work was supported by the National Natural Science Foundation of China (81771127), the Natural Science Foundation of Xinjiang Uygur Autonomous Region (2022D01C15), the Medical Engineering Cross Foundation of Shanghai Jiao Tong University (YG2015MS06), and the Seed Foundation of the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine (JYZZ196).Stomatology Clinical Research Project of Nation Clinical Research Center for Oral Diseases(NCRCO202330). Ethics Approval and Consent to Participate Not applicable. Informed Consent Not applicable. Author contributions Zhengrui Li: Conceptualization; Data Curation; Formal Analysis; Original Draft Preparation.Qi Wang: Investigation; Methodology; Visualization; Original Draft Preparation. Xufeng Huang: Conceptualization; Data Curation; Visualization.Yinteng Wu: Data Curation; Formal Analysis. Rao Fu: Statistical Analysis. Xutao Wen: Statistical Analysis. Ji’An Liu: Visualization. Yuanguo Chen: Resources; Writing Review & Editing. Ying Liu: Conceptualization; Resources; Supervision. Ling Zhang: Resources; Supervision; Writing Review & Editing. Clinical Relevance Scientific Rationale for Study: The connection between periodontitis and coronary atherosclerosis (CA) has been observed in multiple studies, raising questions about potential causal relationships. This study aimed to provide clarity on this topic through Mendelian randomization analysis. Principal Findings: The bidirectional Mendelian randomization analysis and supplementary analyses, despite utilizing extensive data, did not substantiate a causal relationship between periodontitis (both chronic and acute) and CA. These results challenge the existing notion of a direct causative link. Practical Implications: Although a correlation between periodontitis and CA exists, our rigorous genetic analysis does not support causality. 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Baurecht, H., et al., Relationship between periodontitis and psoriasis: A two-sample Mendelian randomization study . J Clin Periodontol, 2022. 49(6): p. 573–579. Baumeister, S.E., et al., Cortisol and periodontitis: Prospective observational and Mendelian randomization studies . Front Endocrinol (Lausanne), 2023. 14: p. 1100985. Alayash, Z., et al., Association between total body bone mineral density and periodontitis: A Mendelian randomization study . J Periodontol, 2022. Zhao, Z.N., et al., Genetic Predisposition to Periodontitis and Risk of Migraine: A Two-Sample Mendelian Randomization Study . Neurol Ther, 2023. Additional Declarations No competing interests reported. Supplementary Files supplyment.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3360691","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":234827383,"identity":"2ff431da-846c-4336-adef-b4d3034aec4b","order_by":0,"name":"Zhengrui Li","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhengrui","middleName":"","lastName":"Li","suffix":""},{"id":234827384,"identity":"d2857f6e-0fac-4e58-8fee-6c14694e0700","order_by":1,"name":"Qi Wang","email":"","orcid":"","institution":"Jiangsu University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Qi","middleName":"","lastName":"Wang","suffix":""},{"id":234827385,"identity":"c3ca691a-4710-4cba-85b5-20f0b1c2cbb3","order_by":2,"name":"Xufeng Huang","email":"","orcid":"","institution":"University of Debrecen","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xufeng","middleName":"","lastName":"Huang","suffix":""},{"id":234827386,"identity":"a2662c50-9ebe-4b36-b7e7-57ffb32906a7","order_by":3,"name":"Yinteng Wu","email":"","orcid":"","institution":"Guangxi Medical University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yinteng","middleName":"","lastName":"Wu","suffix":""},{"id":234827387,"identity":"2ac9bad8-290b-472f-b01e-bac0e523424a","order_by":4,"name":"Rao Fu","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Rao","middleName":"","lastName":"Fu","suffix":""},{"id":234827388,"identity":"752c3056-5f96-4678-b608-c824aa0c5240","order_by":5,"name":"Xutao Wen","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xutao","middleName":"","lastName":"Wen","suffix":""},{"id":234827389,"identity":"ba8c0d7f-a7d8-4917-b1e4-aad4e87f1d4e","order_by":6,"name":"JiAn Liu","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"JiAn","middleName":"","lastName":"Liu","suffix":""},{"id":234827390,"identity":"658a73a8-e1e0-4720-b479-c0de0c46047e","order_by":7,"name":"Yuanguo Chen","email":"","orcid":"","institution":"Ya'an People's Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Yuanguo","middleName":"","lastName":"Chen","suffix":""},{"id":234827391,"identity":"2f9191d2-66c6-47dd-847f-cce25df69897","order_by":8,"name":"Ying Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA30lEQVRIiWNgGAWjYBACPmYgkcDAIAekDIDIgrAWNqgWY6gWCSK0QOnEBrAWBmK0sPOYSTzcUZu+tr1564YfBRIM/O3dCQw/d+BzGFBL4pnjudvOHCu72QN0mMSZsxsYe88Q0tJ2LHfbjRyzGzxALQYSuRuYGdsIa0k3u//G7OYfErTUJACtMLtNpC1sxRaJbQcMt51JK7stYyDBA/LLwV48Wvj5D2+8+bOtTt7s+OFtN9/8sZHjb+/d+OAnHi1AwAKMi8NwHg+IOIBXAwMD8wcGhjoCakbBKBgFo2BEAwC90Ev0R43OZgAAAABJRU5ErkJggg==","orcid":"","institution":"Sixth Medical Center, PLA General Hospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Liu","suffix":""},{"id":234827392,"identity":"8598d64c-95e2-4a96-844f-838bf54fdf9a","order_by":9,"name":"Ling Zhang","email":"","orcid":"","institution":"Shanghai Jiao Tong University","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ling","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2023-09-16 07:59:17","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3360691/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3360691/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":43769935,"identity":"f37065e8-7b4a-42e2-bd59-da46017e7146","added_by":"auto","created_at":"2023-09-27 14:24:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":446614,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic Illustration of the Two-Sample Mendelian Randomization Study Investigating the Relationship between Periodontitis (Chronic/Acute) and Coronary Atherosclerosis. The depicted design proposes a bidirectional association between periodontitis and coronary atherosclerosis, accounting for potential confounding factors.\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3360691/v1/8d43cb73719bd15416fe7b78.jpg"},{"id":43769938,"identity":"20b7d28f-0e92-4056-a674-54b4d034f769","added_by":"auto","created_at":"2023-09-27 14:24:10","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3309769,"visible":true,"origin":"","legend":"\u003cp\u003eForest plots depicting the causal influence of single nucleotide polymorphisms (SNPs) associated with coronary atherosclerosis on chronic periodontitis (A) and acute periodontitis (B).\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3360691/v1/f8447334db27bcc0e81ab21f.jpg"},{"id":43771683,"identity":"385334d5-84af-4063-b9d4-e23cf3c15b13","added_by":"auto","created_at":"2023-09-27 14:32:09","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3122512,"visible":true,"origin":"","legend":"\u003cp\u003eScatter plots illustrate the genetic associations between coronary atherosclerosis, chronic periodontitis (A), and acute periodontitis (B).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3360691/v1/19792397cdd44a36a0c11956.jpg"},{"id":43769936,"identity":"5ce04fb5-e2ed-4f67-ba42-9a81ebfb4ff1","added_by":"auto","created_at":"2023-09-27 14:24:09","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":2700114,"visible":true,"origin":"","legend":"\u003cp\u003eA. The forest plot illustrates the causal impact of single nucleotide polymorphisms (SNPs) associated with periodontitis on coronary atherosclerosis. B. Genetic association between periodontitis and coronary atherosclerosis.\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3360691/v1/5fca9035415c411e114f8f51.jpg"},{"id":43887916,"identity":"ba22a7a9-a91d-4b5c-8c88-5c27f1a365c4","added_by":"auto","created_at":"2023-09-29 16:52:27","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":570257,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3360691/v1/d70aa765-3915-4b0e-b57a-0656e38bdb96.pdf"},{"id":43769939,"identity":"a33bdad8-597c-4036-8117-dd48650e58e8","added_by":"auto","created_at":"2023-09-27 14:24:10","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":1098074,"visible":true,"origin":"","legend":"","description":"","filename":"supplyment.docx","url":"https://assets-eu.researchsquare.com/files/rs-3360691/v1/647fd948af4da78ee9454c50.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Mendelian Randomization Reveal Causal Relationship Between Periodontitis and Coronary Atherosclerosis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAs we all know, periodontitis is a widespread oral health disorder affecting approximately 50% of the neral population and 11% of the global population[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], making it one of the most common human diseases. It can be classified into acute and chronic forms (AP / CP), both of which impose a significant burden on patients, severely impacting their quality of life and overall well-being[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eCoronary atherosclerosis (CA), a principal contributor to global mortality[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], continues to claim approximately 17.8\u0026nbsp;million lives annually[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] despite advancements in therapeutic interventions and preventative strategies. Acknowledged conventional risk factors encompass aging, cholesterol, hypertension, or dyslipidemia[\u003cspan additionalcitationids=\"CR7 CR8\" citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, the implications of inflammatory disease as a pivotal driver in the onset and progression of CA has become gradually recognized[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA substantial accumulation of evidence substantiates an critical correlation between severe periodontitis and several systemic diseases[\u003cspan additionalcitationids=\"CR12 CR13\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In fact, severe periodontitis has been independently and indubitably linked with all-cause and cardiovascular mortality across diverse cohorts[\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], especially coronary atherosclerosis. Proposed mechanisms involve bacteremia and its resultant systemic inflammatory consequences[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], such as elevated C-reactive protein (CRP) levels, as well as oxidative stress (OS). Among populations beset with multiple comorbidities[\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], such as chronic kidney disease (CKD) concurrent withdiabetes and periodontitis, periodontitis has been significantlycorrelated with diminished all-cause and cardiovascular mortality rates. As such, periodontal disease (PD), especially periodontitis emerges as a potentially modifiable non-conventional risk factor for CA\u003c/p\u003e \u003cp\u003eNumerous studies have demonstrated the positive association between periodontitis and the risk of developing atherosclerotic disease[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Epidemiological evidence suggests that patients with periodontitis exhibit notable endothelial dysfunction[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], as evidenced by impaired flow-mediated dilation (FMD), increased arterial stiffness (such as PWV - pulse wave velocity), augmented carotid intima-media thickness (cIMT), and elevated arterial calcification scores. Cohort studies have also shown a correlation between periodontitis and higher coronary atherosclerosis mortality rates[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Some hypotheses propose that dysregulated oral microbiota from periodontitis may indirectly or directly trigger systemic diseases by disseminating into the cardiovascular system[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. At the same time, current biological experiments cannot validate these hypotheses nor establish periodontitis as the key cause of atherosclerosis.\u003c/p\u003e \u003cp\u003eAlthough periodontitis is associated with coronary atherosclerosis, the relationship remains unclear. Two-sample Mendelian randomization (MR) analysis is a statistical method aimed at inferring potential causal relationships from observed associations[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. MR utilizes exposure-associated genetic variants as proxy indicators to evaluate the relationship between the potential indicators and outcomes[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Given the urgency to investigate the potential causal link between periodontitis and coronary atherosclerosis. Scholars have employed MR analysis to study the relationship between periodontitis and multiple non-oral diseases[\u003cspan additionalcitationids=\"CR26 CR27 CR28 CR29 CR30 CR31 CR32 CR33 CR34\" citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], including arthritis, hypertension, psoriasis, Parkinson's disease, inflammatory bowel disease (IBD), etc. However, most studies have not provided strong supporting a significant causal relationship between the periodontitis and these diseases, suggesting that periodontitis may be a comorbid condition or that other shared disease mechanisms are yet to be explored.\u003c/p\u003e \u003cp\u003eWe conducted a two-sample, bidirectional Mendelian randomization analysis using genome-wide association study (GWAS) summary data to investigate the potential relationship between periodontitis and coronary atherosclerosis. By employing this rigorous approach, we aim to enhance our understanding of the intricate interplay between periodontal disease and cardiovascular disease. This research endeavor is expected to contribute valuable insights to the field, inform future investigations, and shed light on the underlying mechanisms linking these two conditions.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData assumption and preparation\u003c/h2\u003e \u003cp\u003eThe workflow of our study is depicted in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. We utilized statistical genetic data on periodontitis from the European sample FinnGen database (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.finngen.fi/en\u003c/span\u003e\u003cspan address=\"https://www.finngen.fi/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), including chronic periodontitis (finn-b-K11_PERIODON_CHRON, case: 3046, control: 195395) and acute periodontitis (finn-b-K11_PERIODON_ACUTE, case: 367, control: 195395). Data on coronary atherosclerosis from the OpenGWAS (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gwas.mrcieu.ac.uk\u003c/span\u003e\u003cspan address=\"https://gwas.mrcieu.ac.uk\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), a publicly accessible database with stringent quality control (ukb-d-I9_CORATHER, case: 14334 control: 346860), were also from a European sample. Local institutional review boards and ethical committees approved all studies contained in the three datasets.\u003c/p\u003e \u003cp\u003eCoronary atherosclerosis cases were selected per the International Classification of Diseases. The American Academy of Periodontology (AAP) defines periodontitis, apart from being broadly classified into acute and chronic forms, as cases assessed by comparable standards through probing depth or self-reported. Periodontitis cases can be categorized based on the following criteria: (1) Mild periodontitis: \u0026ge;2 interproximal sites with attachment loss (AL)\u0026thinsp;\u0026ge;\u0026thinsp;3 mm and \u0026ge;\u0026thinsp;2 interproximal sites with probing depth (PD)\u0026thinsp;\u0026ge;\u0026thinsp;4 mm (not on the same tooth) or one site with PD\u0026thinsp;\u0026ge;\u0026thinsp;5 mm. (2) Moderate periodontitis: \u0026ge;2 interproximal sites with AL\u0026thinsp;\u0026ge;\u0026thinsp;4 mm (not on the same tooth) or \u0026ge;\u0026thinsp;2 interproximal sites with PD\u0026thinsp;\u0026ge;\u0026thinsp;5 mm (not on the same tooth). (3) Severe periodontitis: \u0026ge;2 interproximal sites with AL\u0026thinsp;\u0026ge;\u0026thinsp;6 mm (not on the same tooth) and \u0026ge;\u0026thinsp;1 interproximal site with PD\u0026thinsp;\u0026ge;\u0026thinsp;5 mm. In this study, we conducted a bidirectional, two-sample Mendelian randomization (MR) investigation to elucidate the potential causal association between periodontitis and coronary atherosclerosis.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eMendelian randomization and statistical analysis\u003c/h2\u003e \u003cp\u003eData analysis was conducted using R (version 4.2.1) with the 'TwoSampleMR (0.5.6)' and 'MR-PRESSO (1.0)' packages. Mendelian randomization (MR) utilizes genetic variants as instrumental variables (IVs) to estimate causal effects of risk factors on complex diseases. Various methods were employed to assess the potential causal relationship between periodontitis and coronary atherosclerosis (CA), with the primary analysis employing the inverse variance-weighted (IVW) method. Additional MR testing methods, including MR Egger, Weighted median (WM), IVW, Simple mode, and Weighted mode, were used for supplementary analyses to accurately evaluate causal effects and correct for horizontal pleiotropy. IVs were selected based on a threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;6\u003c/sup\u003e. The association between periodontitis and CA risk was expressed as odds ratios (ORs) with 95% confidence intervals (CIs). Bonferroni correction was applied for multiple comparisons across different classification levels, and statistical significance was set at different p-values.\u003c/p\u003e \u003cp\u003eTo examine heterogeneity among the selected single nucleotide polymorphisms (SNPs), Cochran's Q test was performed. If heterogeneity was detected (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), the random-effects IVW method was employed; otherwise, the fixed-effects IVW method was used. Given that IVW results may be influenced by valid instruments and potential pleiotropy, sensitivity analyses were conducted to assess the robustness of the associations. Firstly, the weighted median method was utilized to estimate associations, as it provides reliable causal effect estimates even when effective instruments are limited, and it remains valid when less than 50% of the information is derived from invalid instruments. Secondly, MR-Egger regression was employed to test for potential horizontal pleiotropy, with a p-value of the intercept less than 0.05 indicating the presence of pleiotropy among the SNPs.\u003c/p\u003e \u003cp\u003eThe IVW analysis assumes that all genetic variants are valid instrumental variables with strong causal inference capabilities. We harmonized the SNPs by removing incompatible alleles and palindromic SNPs with intermediate allele frequencies. Due to variations in experimental conditions, selected populations, and SNPs, heterogeneity may exist in two-sample MR analysis, which can introduce bias to causal effect estimates. Therefore, heterogeneity tests were conducted for the primary IVW analysis and MR-Egger regression in this study, with p-values\u0026thinsp;\u0026gt;\u0026thinsp;0.05 indicating no heterogeneity among the IVs. One assumption of MR analysis is that the instrumental variable affects the outcome solely through the exposure, hence testing for horizontal pleiotropy is essential to understand the causal relationship between the exposure and outcome. The intercept value in MR-Egger regression is used to assess pleiotropy, with an intercept close to 0 indicating close similarity to IVW regression. The smaller the likelihood and significance of pleiotropy, the more the SNP is associated solely with the exposure and unrelated to other confounding variables. In this study, the p-value of the pleiotropy test was employed to evaluate the presence of pleiotropy. If the p-value is greater than 0.05, the influence of pleiotropy in the causal analysis is considered minimal or non-existent, and its impact can be disregarded. Consistency of the results was assessed through a leave-one-out analysis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Result","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCausal effects of Coronary Atherosclerosis on Chronic and Acute Periodontitis\u003c/h2\u003e \u003cp\u003eFor the Mendelian randomization (MR) analysis, a total of 60 single nucleotide polymorphisms (SNPs) were identified, with Coronary Atherosclerosis (CA) considered as the exposure and periodontitis (chronic/acute) as the outcome. Among these SNPs, 31 were excluded as their alleles did not meet the specified criteria. Consequently, 29 SNPs were retained for further MR analysis.\u003c/p\u003e \u003cp\u003eThe results for CA and acute periodontitis demonstrated that MR-egger (OR\u0026thinsp;=\u0026thinsp;0.032, 95% CI\u0026thinsp;=\u0026thinsp;0.000-7.423, P\u0026thinsp;=\u0026thinsp;0.226), WM (OR\u0026thinsp;=\u0026thinsp;0.679, 95% CI\u0026thinsp;=\u0026thinsp;0.180\u0026ndash;2.571, P\u0026thinsp;=\u0026thinsp;0.818), IVW (OR\u0026thinsp;=\u0026thinsp;2.110, 95% CI\u0026thinsp;=\u0026thinsp;1.483\u0026ndash;3.003, P\u0026thinsp;=\u0026thinsp;0.527), Simple mode (OR\u0026thinsp;=\u0026thinsp;0.567, 95% CI\u0026thinsp;=\u0026thinsp;0.071\u0026ndash;4.537, P\u0026thinsp;=\u0026thinsp;0.854), and weighted model (OR\u0026thinsp;=\u0026thinsp;0.285, 95% CI\u0026thinsp;=\u0026thinsp;0.020\u0026ndash;3.984, P\u0026thinsp;=\u0026thinsp;0.597) demonstrated no impact of CA on chronic periodontitis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). Sensitivity analysis demonstrated the robustness of the current two-sample MR analysis (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e), indicating the absence of instrumental variable bias in the causal inference. The Cochrane Q test did not reveal heterogeneity among these IVs (P\u0026thinsp;=\u0026thinsp;0.8547, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.382034). The heterogeneity test displayed the impact of coronary atherosclerosis on the risk of periodontitis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e): Egger regression intercept\u0026thinsp;=\u0026thinsp;0.032, Standard error\u0026thinsp;=\u0026thinsp;0.015, Directionality p-value\u0026thinsp;=\u0026thinsp;0.0433. The absence of heterogeneity among these instrumental variables (IVs) was indicated, as there was no significant heterogeneity detected. Scatter plots depicting the effect sizes of single nucleotide polymorphisms (SNPs) for chronic periodontitis and coronary atherosclerosis are presented (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA). Funnel plot analysis also corroborated these results (Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e), revealing that direction and horizontal pleiotropy were insignificant, and the evidence for directional pleiotropy was markedly insufficient.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe relationship between genetically instrumented coronary atherosclerosis (CA) and chronic/acute periodontitis (CP / AP) was estimated using Mendelian randomization.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Method\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003enSNP\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eBeta\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSE\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e95% CI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003ep.val\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eChronic\u003c/p\u003e \u003cp\u003eperiodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCoronary atherosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-3.456\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.786\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.000-7.423\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.226\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.3867\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.679\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.679\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.180\u0026ndash;2.571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.818\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e2.110\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e1.483\u0026ndash;3.003\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.527\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.5674\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e3.061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.567\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.071\u0026ndash;4.537\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.854\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-1.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e2.345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.285\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.020\u0026ndash;3.984\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.597\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eAcute periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCoronary atherosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.479\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.691\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.614\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.417\u0026ndash;6.255\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.510\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.4145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.317\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.661\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.050\u0026ndash;8.730\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.948\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.882\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.414\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.051\u0026ndash;3.384\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.644\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.51\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.241\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.600\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.053\u0026ndash;6.837\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.404\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-3.579\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.692\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.001\u0026ndash;0.769\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.645\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003ePeriodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003eCoronary atherosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e-0.001467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.003447\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.999\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.992\u0026ndash;1.005\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.699\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000282\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0004831\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.999\u0026ndash;1.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.559\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.00002859\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0004805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.999\u0026ndash;1.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.953\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.000684\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.000707\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.999\u0026ndash;1.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.388\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0006446\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.0007783\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.999\u0026ndash;1.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e0.454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHeterogeneityassessment of MR-Egger and IVW test for directional pleiotropy.\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHeterogeneity\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eQ\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eQ_df\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eI\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eQ_p.val\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eChronic\u003c/p\u003e \u003cp\u003eperiodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoronary atherosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e17.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.543739\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.9183\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e20.26\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.382034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.8547\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAcute periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoronary atherosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e29.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.076923\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.3488\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e30.23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.073768\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.3522\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePeriodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCoronary atherosclerosis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.284\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.637856\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.04049\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.817\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.546331\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.06584\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe results of CA and acute periodontitis demonstrated MR-egger (OR\u0026thinsp;=\u0026thinsp;1.614, 95% CI\u0026thinsp;=\u0026thinsp;0.417\u0026ndash;6.255, P\u0026thinsp;=\u0026thinsp;0.510), WM (OR\u0026thinsp;=\u0026thinsp;0.661, 95% CI\u0026thinsp;=\u0026thinsp;0.050\u0026ndash;8.730, P\u0026thinsp;=\u0026thinsp;0.948), IVW (OR\u0026thinsp;=\u0026thinsp;0.414, 95% CI\u0026thinsp;=\u0026thinsp;0.051\u0026ndash;3.384, P\u0026thinsp;=\u0026thinsp;0.644), Simple mode (OR\u0026thinsp;=\u0026thinsp;0.600, 95% CI\u0026thinsp;=\u0026thinsp;0.053\u0026ndash;6.837, P\u0026thinsp;=\u0026thinsp;0.404), and weighted median (OR\u0026thinsp;=\u0026thinsp;0.028, 95% CI\u0026thinsp;=\u0026thinsp;0.001\u0026ndash;0.769, P\u0026thinsp;=\u0026thinsp;0.645); CA had no impact on acute periodontitis (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). The Cochrane Q report did not show heterogeneity among these IVs (P\u0026thinsp;=\u0026thinsp;0.3522, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.073768). The heterogeneity test demonstrated the impact of coronary atherosclerosis on the risk of acute periodontitis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e): Egger regression intercept = -0.043, Standard error\u0026thinsp;=\u0026thinsp;0.045, Directionality p-value\u0026thinsp;=\u0026thinsp;0.35. The analysis yielded results that indicate the absence of heterogeneity among these instrumental variables (IVs), suggesting a consistent pattern. Scatter plots illustrating the effect sizes of single nucleotide polymorphisms (SNPs) for periodontitis and coronary atherosclerosis are presented for visual representation (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). The funnel plot analysis confirmed these results (Figure S2), indicating that horizontal pleiotropy was insignificant. Moreover, no high-impact points were detected in the leave-one-out analysis (Figure S2).\u003c/p\u003e \u003cp\u003eThe study included a substantial sample size of 198,441 individuals with chronic periodontitis, 195,762 individuals with acute periodontitis, and 361,194 individuals with coronary atherosclerosis. The strength of the instrumental variables was assessed by calculating R\u0026sup2; and F-statistics using the Effector Allele Frequency (EAF) and effect estimate (BETA). The F-statistic values exceeded 10 in all cases (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e), with an average value of 66.1 (range: 29.94\u0026thinsp;~\u0026thinsp;312.83), indicating strong instrumental variables and no significant observable instrumental variable bias. However, the relatively lower R\u0026sup2; values suggested challenges in fully explaining the extent of exposure through the instrumental variables.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eCausal effects of Periodontitis on Coronary Atherosclerosis\u003c/h2\u003e \u003cp\u003eDue to insufficient exposure data for periodontitis, we merged the CA of the two cohorts, keeping the control group unchanged. Taking periodontitis as the exposure and coronary atherosclerosis as the outcome, we extracted 6 SNPs, with 1 SNP being discarded due to the need for corresponding outcome data. Ultimately, 5 SNPs were chosen for the following MR analysis. The results showed MR-egger (OR\u0026thinsp;=\u0026thinsp;0.999, 95% CI\u0026thinsp;=\u0026thinsp;0.992\u0026ndash;1.005, P\u0026thinsp;=\u0026thinsp;0.699), WM (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI\u0026thinsp;=\u0026thinsp;0.999\u0026ndash;1.001, P\u0026thinsp;=\u0026thinsp;0.559), IVW (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI\u0026thinsp;=\u0026thinsp;0.999\u0026ndash;1.001, P\u0026thinsp;=\u0026thinsp;0.953 ), Simple mode (OR\u0026thinsp;=\u0026thinsp;1.001, 95% CI\u0026thinsp;=\u0026thinsp;0.999\u0026ndash;1.002, P\u0026thinsp;=\u0026thinsp;0.388), and Weighted mode (OR\u0026thinsp;=\u0026thinsp;1.001, 95% CI\u0026thinsp;=\u0026thinsp;0.999\u0026ndash;1.002, P\u0026thinsp;=\u0026thinsp;0.454). No significant association between periodontitis and coronary atherosclerosis was observed, as evidenced by the results presented(Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAll F-statistic values exceeded 10, with an average F-statistic value of 949.2, indicating strong instrumental variables and a lack of observable horizontal pleiotropy (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). The MR-Egger analysis also provided no evidence of horizontal pleiotropy when examining the impact of periodontitis on the risk of coronary atherosclerosis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e): Egger regression intercept\u0026thinsp;=\u0026thinsp;0.0018, Standard error\u0026thinsp;=\u0026thinsp;0.0041, Directionality p-value\u0026thinsp;=\u0026thinsp;0.69). The leave-one-out analysis yielded no remarkable deviations or anomalies (Figure S3). Consequently, our findings do not support the existence of a bidirectional genetic relationship between periodontitis and coronary atherosclerosis (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eFurthermore, the Cochrane Q test revealed no significant heterogeneity among the estimates of the included SNPs(P\u0026thinsp;=\u0026thinsp;0.06584, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0.546331). A funnel plot observation revealed no significance in directionality and horizontal pleiotropy (Figure S3). Finally, the F statistics (F\u0026thinsp;\u0026gt;\u0026thinsp;10, range 29.83 to 39.59) did not exhibit any significant instrumental variable bias (Table S2).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study employed a bidirectional, two-sample MR analysis to investigate the potential causal association between periodontitis and coronary atherosclerosis. Although numerous clinical data suggest that periodontitis is a high-risk factor for cardiovascular disease, the results from the MR study did not support the evidence of a significant influence of periodontitis on coronary atherosclerosis, and vice versa.\u003c/p\u003e \u003cp\u003eWe posit that both periodontitis and cardiovascular disease are multifactorial disorders, manifesting in individuals exposed to risk factors over many years[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. The connection between the two diseases is likely far more complex than a simple causal relationship, with other significant associations still present. For instance, oral microbiota represents a crucial link between periodontitis and coronary atherosclerosis. Moreover, other risk factors, (including detrimental habits, smoking, and so on), are prominent shared[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn general, the outcomes of our Mendelian randomization (MR) analysis diverge from the findings of prior observational studies. Our findings fail to substantiate a causal association between periodontitis and cardiovascular disease, therefore cautioning against prioritizing periodontitis treatment as a means to mitigate the risk of stroke and coronary artery disease. There may be coincidences or confounding by some unknown factors. Furthermore, most current observational studies cannot determine the causal relationship between periodontitis and coronary atherosclerosis[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], only establishing a co-occurrence or association. However, the nature of this association has yet to be deeply researched, merely elucidating a comorbidity phenomenon. Many periodontitis patients often present with a range of systemic issues, as do patients with coronary atherosclerosis. Hence, the presence of shared pathophysiological mechanisms between these conditions may potentially establish a connection between periodontitis and coronary atherosclerosis, thereby warranting further investigation in future studies.\u003c/p\u003e \u003cp\u003eMultiple sensitivity analyses were employed to reinforce the robustness of our findings. The instrumental variable-weighted (IVW), weighted median, and MR-Egger methods were utilized to explore the causal relationship between periodontitis and coronary atherosclerosis. However, none of these approaches provided evidence supporting a causal association. The consistent outcomes obtained through these diverse methods lend credibility to our study's findings.\u003c/p\u003e \u003cp\u003eMoreover, our study possesses several notable strengths. Firstly, only single nucleotide polymorphisms (SNPs) that exhibited significant associations with clinically-defined periodontitis at the genome-wide level and were replicated in independent cohorts were included as instrumental variables (IVs). This stringent criterion ensures the validity and reliability of our genetic instruments. Additionally, we integrated exposure data from multiple periodontitis cohorts, augmenting the likelihood that all selected periodontitis-associated SNPs genuinely capture the relationship with coronary atherosclerosis.\u003c/p\u003e \u003cp\u003eThis MR study has limitations. Firstly, the population selected for the study represents only European groups, not entirely capturing the absolute causal relationship between the two diseases in the global population. Moreover, larger data sets are needed to seek associations further. Lastly, the disease characteristics of periodontitis and coronary atherosclerosis at different stages may not fully reflect the association between the two, particularly for acute periodontitis, which has a rapid onset and recovery, its impact on coronary atherosclerosis might be minimal, whereas chronic periodontitis, a long-term chronic disease, may present higher clinical risks due to constant systemic inflammatory impact.\u003c/p\u003e \u003cp\u003eIn conclusion, the findings of this study do not provide substantial evidence supporting a causal relationship between periodontitis and coronary atherosclerosis, as well as the reverse association. This result contrasts with observational studies and requires further research for validation to achieve a more reasonable and robust conclusion. Future studies should elucidate other potential shared mechanistic interactions and causal evidence between periodontitis and coronary atherosclerosis. The primary objective of this research was to comprehensively investigate the causal association between periodontitis and coronary atherosclerosis, offering valuable insights to clinicians. By enhancing the understanding of the connection between periodontitis and coronary atherosclerosis, this study contributes to the exploration of potential links between periodontitis and systemic diseases, thereby providing valuable references for future investigations in this field.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCA: Coronary atherosclerosis\u003c/p\u003e\n\u003cp\u003eMR: Mendelian randomization\u003c/p\u003e\n\u003cp\u003eGWAS: Genome-wide association studies\u003c/p\u003e\n\u003cp\u003eIVW: Inverse-variance weighted\u003c/p\u003e\n\u003cp\u003eCI: Confidence interval\u003c/p\u003e\n\u003cp\u003eOR: Odds ratio\u003c/p\u003e\n\u003cp\u003eWM: weighted median\u003c/p\u003e\n\u003cp\u003eCP/AP: Chronic / Acute periodontitis\u003c/p\u003e\n\u003cp\u003eCRP: C-reactive protein\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOS: Oxidative stress\u003c/p\u003e\n\u003cp\u003eCKD: Chronic kidney disease\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePD: Periodontal disease\u003c/p\u003e\n\u003cp\u003eSNP: Single nucleotide polymorphism\u003cbr\u003e\u0026nbsp;SE: Standard errors\u003cbr\u003e\u0026nbsp;EA: Effect allele\u003c/p\u003e\n\u003cp\u003eOA: Other allele\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEAF: Effect allele frequency\u003c/p\u003e\n\u003cp\u003ePWV: Pulse wave velocity\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFMD: Flow-mediated dilation\u003c/p\u003e\n\u003cp\u003ecIMT: carotid intima-media thickness\u003c/p\u003e\n\u003cp\u003eIBD: Inflammatory bowel disease\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors disclose no identified competing financial interests or personal relationships that may have influenced the research presented in this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe work was supported by the National Natural Science Foundation of China (81771127), the Natural Science Foundation of Xinjiang Uygur Autonomous Region (2022D01C15), the Medical Engineering Cross Foundation of Shanghai Jiao Tong University (YG2015MS06),\u0026nbsp;and the Seed Foundation of the Ninth People\u0026apos;s Hospital, Shanghai Jiao Tong University School of Medicine (JYZZ196).Stomatology Clinical Research Project of Nation Clinical Research Center for Oral Diseases(NCRCO202330).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed Consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eZhengrui Li: Conceptualization; Data Curation; Formal Analysis; Original Draft Preparation.Qi Wang: Investigation; Methodology; Visualization; Original Draft Preparation. Xufeng Huang: Conceptualization; Data Curation; Visualization.Yinteng Wu: Data Curation; Formal Analysis.\u003c/p\u003e\n\u003cp\u003eRao Fu: Statistical Analysis. Xutao Wen: Statistical Analysis. Ji\u0026rsquo;An Liu: Visualization. Yuanguo Chen: Resources; Writing Review \u0026amp; Editing. Ying Liu: Conceptualization; Resources; Supervision. \u0026nbsp;Ling Zhang: Resources; Supervision; Writing Review \u0026amp; Editing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical Relevance\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eScientific Rationale for Study:\u0026nbsp;\u003c/em\u003eThe connection between periodontitis and coronary atherosclerosis (CA) has been observed in multiple studies, raising questions about potential causal relationships. This study aimed to provide clarity on this topic through Mendelian randomization analysis.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrincipal Findings:\u0026nbsp;\u003c/em\u003eThe bidirectional Mendelian randomization analysis and supplementary analyses, despite utilizing extensive data, did not substantiate a causal relationship between periodontitis (both chronic and acute) and CA. These results challenge the existing notion of a direct causative link.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePractical Implications:\u0026nbsp;\u003c/em\u003eAlthough a correlation between periodontitis and CA exists, our rigorous genetic analysis does not support causality. Clinicians and researchers should be cautious about directly attributing CA to periodontitis, and further studies are needed to explore shared mechanisms or other potential causal pathways linking these two conditions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSlots, J., \u003cem\u003ePeriodontitis: facts, fallacies and the future.\u003c/em\u003e Periodontol 2000, 2017. 75(1): p.\u0026nbsp;7\u0026ndash;23.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKwon, T., I.B. Lamster, and L. Levin, \u003cem\u003eCurrent Concepts in the Management of Periodontitis\u003c/em\u003e. Int Dent J, 2021. 71(6): p.\u0026nbsp;462\u0026ndash;476.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBartold, P.M., \u003cem\u003eLifestyle and periodontitis: The emergence of personalized periodontics.\u003c/em\u003e Periodontol 2000, 2018. 78(1): p.\u0026nbsp;7\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBoudoulas, K.D., et al., \u003cem\u003eCoronary Atherosclerosis: Pathophysiologic Basis for Diagnosis and Management\u003c/em\u003e. Prog Cardiovasc Dis, 2016. 58(6): p.\u0026nbsp;676\u0026ndash;92.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eStone, P.H., P. Libby, and W.E. Boden, \u003cem\u003eFundamental Pathobiology of Coronary Atherosclerosis and Clinical Implications for Chronic Ischemic Heart Disease Management-The Plaque Hypothesis: A Narrative Review\u003c/em\u003e. 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Clin Oral Investig, 2021. 25(6): p.\u0026nbsp;4085\u0026ndash;4095.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrlandi, M., F. Graziani, and F. D'Aiuto, \u003cem\u003ePeriodontal therapy and cardiovascular risk.\u003c/em\u003e Periodontol 2000, 2020. 83(1): p.\u0026nbsp;107\u0026ndash;124.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathur, A., et al., \u003cem\u003eAortic aneurysm\u003c/em\u003e. J Transl Int Med, 2016. 4(1): p.\u0026nbsp;35\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNibali, L., et al., \u003cem\u003ePeriodontitis and implant complications in diabetes.\u003c/em\u003e Periodontol 2000, 2022. 90(1): p.\u0026nbsp;88\u0026ndash;105.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSerni, L., et al., \u003cem\u003eAssociation between chronic kidney disease and periodontitis. A systematic review and metanalysis\u003c/em\u003e. Oral Dis, 2023. 29(1): p.\u0026nbsp;40\u0026ndash;50.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eParsegian, K., et al., \u003cem\u003eAssociation between periodontitis and chronic kidney disease.\u003c/em\u003e Periodontol 2000, 2022. 89(1): p.\u0026nbsp;114\u0026ndash;124.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahishale, V., et al., \u003cem\u003ePrevalence and impact of diabetes, hypertension, and cardiovascular diseases in chronic obstructive pulmonary diseases: A hospital-based cross-section study\u003c/em\u003e. J Transl Int Med, 2015. 3(4): p.\u0026nbsp;155\u0026ndash;160.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchenkein, H.A., et al., \u003cem\u003eMechanisms underlying the association between periodontitis and atherosclerotic disease.\u003c/em\u003e Periodontol 2000, 2020. 83(1): p.\u0026nbsp;90\u0026ndash;106.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHerrera, D., et al., \u003cem\u003ePeriodontal diseases and association with atherosclerotic disease.\u003c/em\u003e Periodontol 2000, 2020. 83(1): p.\u0026nbsp;66\u0026ndash;89.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBowden, J. and M.V. Holmes, \u003cem\u003eMeta-analysis and Mendelian randomization: A review\u003c/em\u003e. Res Synth Methods, 2019. 10(4): p.\u0026nbsp;486\u0026ndash;496.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYin, K.J., et al., \u003cem\u003eNo Genetic Causal Association Between Periodontitis and Arthritis: A Bidirectional Two-Sample Mendelian Randomization Analysis\u003c/em\u003e. Front Immunol, 2022. 13: p.\u0026nbsp;808832.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, Z., et al., \u003cem\u003eAssociation between inflammatory bowel disease and periodontitis: A bidirectional two-sample Mendelian randomization study\u003c/em\u003e. J Clin Periodontol, 2023. 50(6): p.\u0026nbsp;736\u0026ndash;743.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang, Y.B., et al., \u003cem\u003eCausal Association Between Periodontitis and Type 2 Diabetes: A Bidirectional Two-Sample Mendelian Randomization Analysis\u003c/em\u003e. Front Genet, 2021. 12: p.\u0026nbsp;792396.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeng, Z., et al., \u003cem\u003eAssociation between periodontitis and COVID-19 infection: a two-sample Mendelian randomization study\u003c/em\u003e. PeerJ, 2023. 11: p.\u0026nbsp;e14595.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMa, C., et al., \u003cem\u003ePeriodontitis and stroke: A Mendelian randomization study\u003c/em\u003e. Brain Behav, 2023. 13(2): p.\u0026nbsp;e2888.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiao, R., et al., \u003cem\u003eCausal association between asthma and periodontitis: A two-sample Mendelian randomization analysis\u003c/em\u003e. Oral Dis, 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDing, M., et al., \u003cem\u003eAssociation between periodontitis and breast cancer: two-sample Mendelian randomization study\u003c/em\u003e. Clin Oral Investig, 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaurecht, H., et al., \u003cem\u003eRelationship between periodontitis and psoriasis: A two-sample Mendelian randomization study\u003c/em\u003e. J Clin Periodontol, 2022. 49(6): p.\u0026nbsp;573\u0026ndash;579.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaumeister, S.E., et al., \u003cem\u003eCortisol and periodontitis: Prospective observational and Mendelian randomization studies\u003c/em\u003e. Front Endocrinol (Lausanne), 2023. 14: p.\u0026nbsp;1100985.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlayash, Z., et al., \u003cem\u003eAssociation between total body bone mineral density and periodontitis: A Mendelian randomization study\u003c/em\u003e. J Periodontol, 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhao, Z.N., et al., \u003cem\u003eGenetic Predisposition to Periodontitis and Risk of Migraine: A Two-Sample Mendelian Randomization Study\u003c/em\u003e. Neurol Ther, 2023.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3360691/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3360691/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eGrowing evidence appears to intimate a profound connection between periodontitis and coronary atherosclerosis (CA), yet the existence of a causal relationship remains unclear. Through the implementation of Mendelian randomization analysis, We further evaluated the potential causal link between chronic/acute periodontitis (CP/AP) and CA.\u003c/p\u003e\u003ch2\u003eObjectives\u003c/h2\u003e \u003cp\u003eUtilizing genome-wide association study (GWAS) summary statistics, we incorporated periodontitis data derived from European samples (n1\u0026thinsp;=\u0026thinsp;198,441; n2\u0026thinsp;=\u0026thinsp;195,762) and CA data from 61,194 cases. We conducted a two sample, bidirectional Mendelian randomization (MR) analysis using the inverse-variance weighted (IVW) method as the main analytical approach. Supplementary analyses were executed through MR Egger, Weighted median (WM), IVW, Simple mode, and Weighted mode approaches.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe IVW analysis revealed no significant causal relationship between CA and periodontitis (CA-CP: OR\u0026thinsp;=\u0026thinsp;2.110, 95% CI\u0026thinsp;=\u0026thinsp;1.483\u0026ndash;3.003, P\u0026thinsp;=\u0026thinsp;0.527; CA-AP: OR\u0026thinsp;=\u0026thinsp;0.414, 95% CI\u0026thinsp;=\u0026thinsp;0.051\u0026ndash;3.384, P\u0026thinsp;=\u0026thinsp;0.644). Similarly, the bidirectional analysis did not identify impact of periodontitis on CA (OR\u0026thinsp;=\u0026thinsp;1.000, 95% CI\u0026thinsp;=\u0026thinsp;0.999\u0026ndash;1.001, P\u0026thinsp;=\u0026thinsp;0.953). The supplementary analyses corroborated these findings.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eWhile studies highlighting a correlation between periodontitis and CA, our comprehensive analysis does not corroborate a causal connection between periodontitis and CA. Further research is needed to elucidate other potential shared mechanisms and causal evidence between periodontitis and CA.\u003c/p\u003e","manuscriptTitle":"Mendelian Randomization Reveal Causal Relationship Between Periodontitis and Coronary Atherosclerosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2023-09-27 14:24:04","doi":"10.21203/rs.3.rs-3360691/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"bedf115b-d298-45a2-8b23-934f9cf29b5d","owner":[],"postedDate":"September 27th, 2023","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2023-10-09T06:44:31+00:00","versionOfRecord":[],"versionCreatedAt":"2023-09-27 14:24:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3360691","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3360691","identity":"rs-3360691","version":["v1"]},"buildId":"-HB7Z8yhvgn0wM9Nzuekk","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}