A causal association study between chronic kidney disease and oral health

A causal association study between chronic kidney disease and oral health | 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 A causal association study between chronic kidney disease and oral health Guilian Zhang, Duojiao Xu, Guoxia Yu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4318284/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 Background Observational studies have shown that chronic kidney disease can lead to changes in oral health, but the conclusions remain controversial. Thus, we conducted a Mendelian randomization study from the perspective of genetic analysis to assess the causal association between chronic kidney disease and oral health conditions, including dental caries, pulp diseases, periapical tissues, and diseases of the gum and periodontal tissues. Methods We performed inverse variance weighted random effects Mendelian randomization analyses and several sensitivity Mendelian randomization analyses using summary statistics from genome-wide association studies of European people. Results We found a positive causal relationship between chronic kidney disease and dental caries, and the effect odds ratio of chronic kidney disease on dental caries was 1.368 (95% CI, 1.124-1.664; P = 0.002). There was no direct causal relationship between chronic kidney disease and diseases of the pulp and periapical tissues and diseases of the gum and periodontal tissues, with the effect odds ratio of 1.176 (95% CI, 0.973-1.420; P = 0.094) and 1.201 (95% CI, 0.977-1.477; P = 0.08). Conclusion Our findings suggest that chronic kidney disease could affect oral health, but only with a direct causal link to dental caries. chronic kidney disease oral health caries Mendelian randomization analyses Figures Figure 1 Figure 2 Figure 3 Background Chronic kidney disease (CKD) has become a global public health problem. Kidney Diseases: A Guide to Improving Global Outcomes defines chronic kidney disease as "an abnormality in the structure or function of the kidney that persists for more than three months and has health implications.” [ 1 ] According to the latest estimates, more than 850 million people worldwide suffer from kidney disease [ 2 ]. The prevalence of CKD is 9% of the world's population and as high as 12% in some high-income countries [ 3 ]. CKD is also one of the fastest-growing causes of death [ 4 ]. Additionally, observational studies have shown that CKD can cause systemic changes, including oral changes such as dental caries [ 5 ], gingivitis [ 6 ], periodontitis [ 7 ], enamel hypoplasia, and changes in saliva flow and composition [ 8 , 9 ]. Notably, the oral effects correspond to the age of the CKD patient and their duration, and the effects include both deciduous teeth and permanent teeth [ 10 ]. Thus, proper oral care and preventive measures should be taken to avoid potentially severe oral concerns in patients with CKD. In contrast, oral health problems, such as pain, swelling, infection, and bacteremia, can cause lesions in other body parts and negatively affect quality of life and systemic health [ 11 ]. Therefore, increasing awareness of related oral diseases in patients with CKD, especially those with terminal disease [ 12 ], will improve the quality of life of these patients and the effectiveness of multidisciplinary diagnostic and treatment approaches. Few studies have comprehensively evaluated the association between CKD and oral conditions. As a result, this study used Mendelian randomization (MR) analysis, using genetic variation as an instrumental variable, to retrieve the most recent statistical data from genome-wide association studies to investigate causality between CKD risk factors and oral outcomes, including dental caries, diseases of the pulp and periapical tissues and diseases of the gum and periodontal tissues, as comprehensively as possible. Methods Study Design and Data Data was derived from the IEU database for the European population, including men and women, in 2021 (Table 1 ). CKD exposure data included 216,743 subjects (3,902 cases and 212,841 controls) and 16,380,459 SNPs. Outcome data of oral diseases were from the same population, including 199,565 subjects (dental caries 4,170 cases with 16,380,411 SNPs, Diseases of pulp and periapical tissues 5,354 cases with 16,380,387 SNPs, Gingivitis and periodontal diseases 4,120 cases with 16,380,400 SNPs). Following quality control, the causal relationship between CKD and oral diseases was analyzed using Mendelian randomization analyses. Table 1 IEU database details Chronic kidney disease dental caries diseases of pulp and periapical tissues diseases of gum and periodontal tissues Dataset finn-b-N14_CHRONKIDNEYDIS finn-b-K11_CARIES finn-b-K11_PULP_PERIAPICAL finn-b-K11_GINGIVITIS_PERIODONTAL Year 2021 2021 2021 2021 Population European European European European Sex Males and Females Males and Females Males and Females Males and Females case 3902 4170 5354 4120 control 212841 195395 195395 195395 Number of SNPs 16380459 16380411 16380387 16380400 Instrumental variable Selection We first screened out the single nucleic acid polymorphisms (SNPs) associated with CKD, and their significance threshold was P 10. We conducted a linkage disequilibrium threshold of r 2 < 0.01 to remove the linkage imbalance in a 500kb window. These selected SNPs must satisfy three core assumptions. Assumption 1: SNPs significantly correlate with exposure, meaning SNPs could effectively predict exposure. Assumption 2: SNPs must be independent of the outcome. That is, SNPs could only affect the outcome through exposure. Assumption 3: SNPs must be independent of confounding factors associated with exposure or outcomes (Fig. 1 ). To eliminate SNPs that do not conform to Hypothesis 2 and Hypothesis 3, we screened them individually through the Phenoscanner website. Mendelian Randomization All analyses were performed in R 4.3.0 using the Two Sample MR package. Five analysis methods were included in the package: inverse variance weighted (IVW), MR Egger, Weighted median, Simple mode, and Weighted mode. Among them, we chose inverse variance-weighted (IVW) analysis as the primary method to evaluate the causal effect. Because IVW estimation is the most effective analysis method when all inverse variance-weighted variables are valid instrumental variables [ 13 ]. When pleiotropy was absent, IVW was more suitable than the MR-Egger method. The Weighted median method (WME) was supplemental to MR-egger. Sensitivity analyses We used the MR-Egger regression to assess whether directional pleiotropy was present. MR-PRESSO was used to verify the presence of heterogeneity among the instruments. The influential points were investigated using a leave-one-out analysis. Results Instrumental variable Selection Through screening three hypotheses, three SNPs were selected: rs17220157, rs9271365, and rs77924615. The minimum F-value statistic is 20.3 and filtered one by one through the Phenoscanner website, indicating that all instrumental variables are sufficient for MR Analysis. Mendelian Randomization From the IVW analysis, the odds ratio (OR) of CKD on dental caries was 1.3676 (95% CI, 1.1241–1.6640; P = 0.0018) (Table 2 ) (Fig. 2 A). A positive correlation was also between CKD and dental caries(b = 0.3130). However, the OR of CKD on diseases of the pulp and periapical tissues and the OR of CKD on diseases of the gum and periodontal tissues were not found to be statistically significant (P = 0.0935; P = 0.0824) (Table 2 ) (Fig. 2 B and C). Table 2 MR Analysis of CKD and oral diseases b Pval OR OR_lci95 OR_uci95 dental caries Inverse variance weighted 0.313084 0.001754 ** 1.367637 1.124089 1.663952 MR Egger -0.14061 0.796112 0.868826 0.378507 1.994304 Weighted median 0.255845 0.025193 1.291553 1.032336 1.615859 Simple mode 0.242434 0.249048 1.274348 0.948354 1.712401 Weighted mode 0.224091 0.202012 1.251185 0.989587 1.581936 diseases of pulp and periapical tissues Inverse variance weighted 0.161838 0.093523 1.17567 0.97307 1.420454 MR Egger 0.004064 0.995603 1.004072 0.316935 3.180976 Weighted median 0.191826 0.039476 1.21146 1.009283 1.454136 Simple mode 0.284563 0.209941 1.329181 0.978777 1.805029 Weighted mode 0.014153 0.91124 1.014254 0.813862 1.263986 diseases of gum and periodontal tissues Inverse variance weighted 0.183115 0.082446 1.200952 0.976727 1.476653 MR Egger -0.3021 0.616784 0.739264 0.312242 1.75028 Weighted median 0.122941 0.23923 1.130818 0.921455 1.387749 Simple mode 0.105982 0.557485 1.111802 0.825573 1.497267 Weighted mode 0.087386 0.556805 1.091317 0.854211 1.394239 SD Standard deviation *p < .05, **p < .01, ***p < .001 Sensitivity analyses Neither horizontal pleiotropy was detected by MR-Egger (Table 3 ), nor heterogeneity was found by MR-PRESSO detection (Table 3 ). No significant outlier in the leave-one-out analysis indicated that our causal estimation was not driven by specific SNPs (Fig. 3 ). Table 3 P value of pleiotropy and heterogeneity analysis of CKD and oral diseases dental caries diseases of pulp and periapical tissues diseases of gum and periodontal tissues heterogeneity MR-PRESSO 0.2662 0.0844 0.2520 Inverse variance weighted 0.2557 0.2015 0.2237 pleiotropy MR Egger 0.4702 0.8291 0.4605 Discussion In this study, we conducted a direct genetic analysis of CKD and oral health status. We found that CKD may increase the incidence of dental caries but did not directly affect diseases of the pulp and periapical tissues or the gum and periodontal tissues. This study was the first to find that CKD could directly cause dental caries through genetic analysis. However, the relevant clinical studies were still inconclusive. Cláudia RSD Menezes found no difference in the mean dental caries index (decayed, missing, filled surface of permanent teeth, and DMFT) between 107 enrolled CKD patients and 107 participants without systemic disease [ 5 ]. But it has also been found that the incidence of dental caries in patients with end-stage renal disease has increased [ 14 ]. Mizutani K found that mortality in patients with end-stage renal disease was associated with oral hygiene and dental caries [ 15 ]. In the reviewed studies, Marcia Rejane Thomas Canabarro Andrade found that the average caries index of deciduous teeth (decayed, missing, filled surface of deciduous teeth, and dmft) and permanent teeth (DMFT) of CKD patients was lower than that of the matched control group [ 9 ]. However, methodological deficiencies still made the evaluated studies prone to bias. Moreover, the disease's stage or onset could profoundly impact the outcome or detection of the cause. Especially in patients with CKD, subjects receiving different treatment regimens may exhibit various oral manifestations [ 16 ]. There is also still a lack of well-designed studies, such as longitudinal and multicenter studies, to fully support this scientific evidence. In patients with renal dysfunction, vitamin D absorption is reduced, calcium level is reduced, and mineral metabolism is affected [ 17 ]. Unfortunately, if the metabolism changes occur at the stage of tooth development, it will subsequently affect the formation of tooth hard tissue. Studies have also reported that the incidence of enamel hypoplasia in patients with CKD is higher than that of normal people [ 18 ]. Enamel hypocalcification will reduce the resistance to caries, which may cause the incidence of caries to increase. The permeability of the glomerular filtration membrane increases, resulting in the loss of a large amount of protein in the plasma, causing changes in the composition and secretion of saliva in patients with kidney disease [ 19 ]. The decrease in saliva flow reduces the cleaning and scouring effect on the tooth surface, causing plaque accumulation and increasing the possibility of caries. However, it has also been reported that the increase of urea in saliva indirectly causes an increase in saliva PH [ 20 ]. If the PH value is maintained above the critical level of enamel demineralization, it may not increase the occurrence of caries. There is a four-factor theory of caries. That is, time, host, diet, and bacteria jointly determine the occurrence of caries [ 21 ]. This article did not discuss the host factors determined by time and parental genetics. Patients with CKD must eat a carbohydrate-rich diet to reduce the load on the kidneys, which may increase the risk of tooth decay. Studies have shown that the use of glucocorticoids and cytotoxic drugs in CKD further affects the stability of the oral microenvironment. Still, it has also been reported that the number of Streptococcus mutans, one of the pathogens causing dental caries, has decreased [ 22 ]. However, the microbial population is large and complex, and more comprehensive and overall research is still needed. As a comprehensive whole, the final result is the result of multiple interactions between positive and negative feedback loops. Furthermore, our study investigated the direct causal relationship between CKD and dental caries, helping to identify the fundamental problems that lead to the disease and find clear targets to achieve good treatment results. In this study, no direct relationship was found between diseases of the pulp and periapical tissues and CKD. There are few clinical studies on this issue. Root canal therapy is a routine treatment for pulpitis and apicitis. A Taiwan report identified that root canal therapy can reduce mortality in patients with end-stage renal disease [ 23 , 24 ]. Moreover, pulpitis and apical periodontitis occur when caries progress to a later stage, mainly because they do not skip caries in most cases, except for atretic pulpitis and retrograde periapical periodontitis. However, there is a current lack of research and exploration in this area. In this study, no direct causal relationship between kidney disease and gingivitis was found by genetic analysis. There are few clinical studies on the effects of CKD on gingivitis. Studies have shown that some medications taken for kidney disease, such as calcium channel blockers, can cause drug-induced gum hyperplasia [ 25 ]. Some patients with end-stage renal disease require peritoneal dialysis, and the gums are prone to bleeding and inflammation due to decreased coagulation function [ 12 , 26 ]. A genetic analysis of CKD and periodontitis was done in 2019, and they did not find a causal relationship [ 27 ]. Notably, our study reached the same conclusion using updated GWAS data in 2021. Additionally, relevant clinical studies are abundant. According to the latest systematic review analysis in 2023, 60% of these reports showed a link between CKD and periodontitis [ 28 ]. The prevalence of periodontitis in patients with CKD varies widely, ranging from 34.35–93.65%, and the strength of evidence is low. This can be explained by the different diagnostic criteria and methods used to assess periodontitis. Although the genetic analysis of CKD could not directly affect the occurrence of periodontitis, the indirect effect of CKD may impact periodontitis. Periodontal disease is a multi-factor disease [ 29 ]. On the one hand, microorganisms are the starting factor of periodontal disease. It has been reported that increased glomerular filtration rate in CKD patients leads to protein loss, indirectly causing changes in saliva flow rate and composition, which may exert strong selection pressure on oral microbiota and lead to changes in community structure [ 30 ]. Changes in the blood composition of patients with CKD indirectly cause changes in saliva pH, which provides more favorable growth conditions for several periodontal pathogens such as Porphyromonas gingivalis, Prevotella intermedia, and Clostridium nucleatum, inducing changes in community structure and triggering the development of periodontal disease [ 31 ]. Shiyuan Guo also found that patients with CKD had increased oral microbial diversity compared to the control group [ 24 ]. On the other hand, periodontitis is mainly due to the loss of alveolar bone. Calcium loss in CKD patients is often accompanied by mineral metabolism disorders, affecting all aspects of bone physiology, including bone volume, turnover, and mineralization [ 32 ]. It has also been reported that failing kidneys are unable to hydroxyl inactive vitamin D (25-hydroxyvitamin D) into its active form calcitriol (1, 25-dihydroxycholecalciferol) [ 33 ]. In addition, systemic hypocalcemia and hyperphosphatemia caused by CKD are associated with impaired renal phosphate excretion, leading to the development of periodontal disease [ 34 ]. Finding the real cause of the disease, whether direct or indirect, will help us to treat the disease. Limitations Unlike traditional observational epidemiology, MR analysis is less susceptible to environmental factors, and genetic variation as an instrumental variable allows unbiased detection of causal effects. We conducted a two-sample Mendelian randomization study using a wide range of recent GWAS data to explore the oral health status of patients with CKD. However, due to the lack of relevant data on Asian people with CKD, the data on European populations was used in this paper and may be biased. Another disadvantage was that endodontic and periapical diseases were grouped without further detailed grouping when collecting GWAS data, which was somewhat lacking in accuracy. However, these two diseases belong to a large group of diseases, and the treatment methods are also the same. Furthermore, the practice of data consolidation was acceptable. As such, the data for gingivitis and periodontitis showed a similar pattern. Conclusion In conclusion, our MR study found that CKD has a direct causal relationship with dental caries, but no direct causal relationship with pulp and periapical tissues and diseases of gum and periodontal tissues. The occurrence of diseases results from the combination of direct and indirect factors. Combining MR with observational studies allows an in-depth analysis of the direct and indirect factors contributing to the disease. Therefore, finding targeted approaches will improve the oral health of patients with CKD and the effectiveness of diagnostic and treatment approaches in both disciplines. Declarations Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Guilian Zhang. The first draft of the manuscript was written by Duojiao Xu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Ethics Approval and Consent to Participate Ethical approval is not required because this study was based on a public GWAS database. Funding This work was supported by grants from the National Key R&D Program of China (2016YFC1000804). Conflict of Interests The authors have no relevant financial or non-financial interests to disclose. Data deposition information item IEU database URL: https://gwas.mrcieu.ac.uk/ Acknowledgments We thank the GWAS Consortium: IEU databases for providing the aggregated statistics used in this study. The authors thank AiMi Academic Services (www.aimieditor.com) for English language editing and review services . References STEVENS PE, LEVIN A, Kidney DIGO. Evaluation and Management of Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline. ANN INTERN MED. 2013; 158:825-830. doi:10.7326/0003-4819-158-11-201306040-00007. Global, Regional, and National Burden of Chronic Kidney Disease, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017. LANCET. 2020; 395:709-733. doi:10.1016/S0140-6736(20)30045-3. Foreman KJ, Marquez N, Dolgert A, et al. 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An Update On Possible Pathogenic Mechanisms of Periodontal Pathogens On Renal Dysfunction. CRIT REV MICROBIOL. 2019; 45:514-538. doi:10.1080/1040841X.2018.1553847. Zhang X, Chen H, Lu W, Zhu L, Zhou W, Song Z. Characterization of the Subgingival Microbiota in the Peritoneal Dialysis Patients with Periodontitis. ARCH ORAL BIOL. 2020; 115:104742. doi:10.1016/j.archoralbio.2020.104742. Kanjevac T, Bijelic B, Brajkovic D, Vasovic M, Stolic R. Impact of Chronic Kidney Disease Mineral and Bone Disorder On Jaw and Alveolar Bone Metabolism: A Narrative Review. ORAL HLTH PREV DENT. 2018; 16:79-85. doi:10.3290/j.ohpd.a39858. Sun K, Shen H, Liu Y, Deng H, Chen H, Song Z. Assessment of Alveolar Bone and Periodontal Status in Peritoneal Dialysis Patients. FRONT PHYSIOL. 2021; 12:759056. doi:10.3389/fphys.2021.759056. Baioni CS, De Souza CM, Ribeiro Braosi AP, et al. Analysis of the Association of Polymorphism in the Osteoprotegerin Gene with Susceptibility to Chronic Kidney Disease and Periodontitis. J PERIODONTAL RES. 2008; 43:578-584. doi:10.1111/j.1600-0765.2008.01098.x. Additional Declarations No competing interests reported. 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4318284","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":296917676,"identity":"536739c3-e204-41c6-81d5-cf6c810f7b2d","order_by":0,"name":"Guilian Zhang","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Guilian","middleName":"","lastName":"Zhang","suffix":""},{"id":296917681,"identity":"791c45cb-51a6-46b2-a809-e1afad3056f2","order_by":1,"name":"Duojiao Xu","email":"","orcid":"","institution":"Capital Medical University","correspondingAuthor":false,"prefix":"","firstName":"Duojiao","middleName":"","lastName":"Xu","suffix":""},{"id":296917684,"identity":"486a7db4-daa8-4de5-afa7-55c5a4d57869","order_by":2,"name":"Guoxia Yu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwUlEQVRIiWNgGAWjYPACCQZ+CQY2ErVIziBRCwODwQ1itRjcSL8m8bHNQt74dvOzBww1NtEM7GcPENCSUyY544yE4bY7x8wNGI6l5Tbw5CUQ0pImzVMhwbjtRg6bBGPD4dwGCR4DIrQYSNhvnkG8lvRjIFsSN0gQq0XyzBtmS6BfkmfcOWYmkQD0SxtPDn4tfMfTH9742FZn2z+7+ZnEhxqb3H72M/i1KBxAdkYCEBOMHfkG9geE1IyCUTAKRsFIBwA6oEL/v5Ji3gAAAABJRU5ErkJggg==","orcid":"","institution":"Capital Medical University","correspondingAuthor":true,"prefix":"","firstName":"Guoxia","middleName":"","lastName":"Yu","suffix":""}],"badges":[],"createdAt":"2024-04-24 12:38:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4318284/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4318284/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":55759366,"identity":"d1d26396-eaf8-4801-9bf1-1a0d0a6b2f6c","added_by":"auto","created_at":"2024-05-02 18:25:18","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":83247,"visible":true,"origin":"","legend":"\u003cp\u003eSchematic Overview of the SNP Selection Hypothesis.\u003c/p\u003e","description":"","filename":"fig.1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4318284/v1/0727d011d0588cc62f6be5ea.jpg"},{"id":55759367,"identity":"609ad4c0-fbae-4167-8079-f560d2371154","added_by":"auto","created_at":"2024-05-02 18:25:18","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":899108,"visible":true,"origin":"","legend":"\u003cp\u003eMR Analysis of CKD and Oral Diseases.\u003c/p\u003e\n\u003cp\u003eA: MR Analysis of CKD and Dental Caries.\u003c/p\u003e\n\u003cp\u003eB: MR Analysis of CKD and Diseases of the Pulp and Periapical Tissues.\u003c/p\u003e\n\u003cp\u003eC: MR Analysis of CKD and Diseases of the Gum and Periodontal Tissues.\u003c/p\u003e\n\u003cp\u003eThe light blue lines were IVW analysis and MR Fitting results. Figure A showed that with the increase of CKD, the risk of caries was also increased, and it was statistically significant.\u003c/p\u003e","description":"","filename":"fig.2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4318284/v1/49738871cbcbc3fb291a7770.jpg"},{"id":55759368,"identity":"61fca388-b05b-4aa1-b043-4103ac75ce86","added_by":"auto","created_at":"2024-05-02 18:25:18","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":558800,"visible":true,"origin":"","legend":"\u003cp\u003eMR Analysis of CKD and Oral Diseases.\u003c/p\u003e\n\u003cp\u003eA: MR Analysis of CKD and Dental Caries.\u003c/p\u003e\n\u003cp\u003eB: MR Analysis of CKD and Diseases of the Pulp and Periapical Tissues.\u003c/p\u003e\n\u003cp\u003eC: MR Analysis of CKD and Diseases of the Gum and Periodontal Tissues.\u003c/p\u003e\n\u003cp\u003eThe light blue lines were IVW analysis and MR Fitting results. Figure A showed that with the increase of CKD, the risk of caries was also increased, and it was statistically significant.\u003c/p\u003e","description":"","filename":"fig.3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4318284/v1/53b0eaacda7523772bad0705.jpg"},{"id":62084418,"identity":"af70d7a2-7054-4ec9-a60f-2e757297ad40","added_by":"auto","created_at":"2024-08-09 06:30:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1977020,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4318284/v1/9e599d2d-8932-4e06-8c63-e7169f3aa5de.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A causal association study between chronic kidney disease and oral health","fulltext":[{"header":"Background","content":"\u003cp\u003eChronic kidney disease (CKD) has become a global public health problem. Kidney Diseases: A Guide to Improving Global Outcomes defines chronic kidney disease as \"an abnormality in the structure or function of the kidney that persists for more than three months and has health implications.\u0026rdquo; [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] According to the latest estimates, more than 850\u0026nbsp;million people worldwide suffer from kidney disease [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. The prevalence of CKD is 9% of the world's population and as high as 12% in some high-income countries [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. CKD is also one of the fastest-growing causes of death [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Additionally, observational studies have shown that CKD can cause systemic changes, including oral changes such as dental caries [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], gingivitis [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], periodontitis [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e], enamel hypoplasia, and changes in saliva flow and composition [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Notably, the oral effects correspond to the age of the CKD patient and their duration, and the effects include both deciduous teeth and permanent teeth [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Thus, proper oral care and preventive measures should be taken to avoid potentially severe oral concerns in patients with CKD. In contrast, oral health problems, such as pain, swelling, infection, and bacteremia, can cause lesions in other body parts and negatively affect quality of life and systemic health [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Therefore, increasing awareness of related oral diseases in patients with CKD, especially those with terminal disease [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], will improve the quality of life of these patients and the effectiveness of multidisciplinary diagnostic and treatment approaches. Few studies have comprehensively evaluated the association between CKD and oral conditions. As a result, this study used Mendelian randomization (MR) analysis, using genetic variation as an instrumental variable, to retrieve the most recent statistical data from genome-wide association studies to investigate causality between CKD risk factors and oral outcomes, including dental caries, diseases of the pulp and periapical tissues and diseases of the gum and periodontal tissues, as comprehensively as possible.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eStudy Design and Data\u003c/p\u003e \u003cp\u003eData was derived from the IEU database for the European population, including men and women, in 2021 (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). CKD exposure data included 216,743 subjects (3,902 cases and 212,841 controls) and 16,380,459 SNPs. Outcome data of oral diseases were from the same population, including 199,565 subjects (dental caries 4,170 cases with 16,380,411 SNPs, Diseases of pulp and periapical tissues 5,354 cases with 16,380,387 SNPs, Gingivitis and periodontal diseases 4,120 cases with 16,380,400 SNPs). Following quality control, the causal relationship between CKD and oral diseases was analyzed using Mendelian randomization analyses.\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\u003eIEU database details\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic kidney disease\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003edental caries\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ediseases of pulp and periapical tissues\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ediseases of gum and periodontal tissues\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDataset\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003efinn-b-N14_CHRONKIDNEYDIS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efinn-b-K11_CARIES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003efinn-b-K11_PULP_PERIAPICAL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003efinn-b-K11_GINGIVITIS_PERIODONTAL\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eEuropean\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSex\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMales and Females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eMales and Females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eMales and Females\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eMales and Females\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecase\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3902\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4170\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5354\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003econtrol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e212841\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e195395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e195395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e195395\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNumber of SNPs\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16380459\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e16380411\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16380387\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e16380400\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\u003eInstrumental variable Selection\u003c/p\u003e \u003cp\u003eWe first screened out the single nucleic acid polymorphisms (SNPs) associated with CKD, and their significance threshold was P\u0026thinsp;\u0026lt;\u0026thinsp;5\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;8\u003c/sup\u003e. The F statistic was used to assess the strength of genetic variables, and a strong correlation was indicated when F\u0026thinsp;\u0026gt;\u0026thinsp;10. We conducted a linkage disequilibrium threshold of r\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01 to remove the linkage imbalance in a 500kb window. These selected SNPs must satisfy three core assumptions. Assumption 1: SNPs significantly correlate with exposure, meaning SNPs could effectively predict exposure. Assumption 2: SNPs must be independent of the outcome. That is, SNPs could only affect the outcome through exposure. Assumption 3: SNPs must be independent of confounding factors associated with exposure or outcomes (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). To eliminate SNPs that do not conform to Hypothesis 2 and Hypothesis 3, we screened them individually through the Phenoscanner website.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eMendelian Randomization\u003c/p\u003e \u003cp\u003eAll analyses were performed in R 4.3.0 using the Two Sample MR package. Five analysis methods were included in the package: inverse variance weighted (IVW), MR Egger, Weighted median, Simple mode, and Weighted mode. Among them, we chose inverse variance-weighted (IVW) analysis as the primary method to evaluate the causal effect. Because IVW estimation is the most effective analysis method when all inverse variance-weighted variables are valid instrumental variables [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. When pleiotropy was absent, IVW was more suitable than the MR-Egger method. The Weighted median method (WME) was supplemental to MR-egger.\u003c/p\u003e \u003cp\u003eSensitivity analyses\u003c/p\u003e \u003cp\u003eWe used the MR-Egger regression to assess whether directional pleiotropy was present. MR-PRESSO was used to verify the presence of heterogeneity among the instruments. The influential points were investigated using a leave-one-out analysis.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eInstrumental variable Selection\u003c/p\u003e \u003cp\u003eThrough screening three hypotheses, three SNPs were selected: rs17220157, rs9271365, and rs77924615. The minimum F-value statistic is 20.3 and filtered one by one through the Phenoscanner website, indicating that all instrumental variables are sufficient for MR Analysis.\u003c/p\u003e \u003cp\u003eMendelian Randomization\u003c/p\u003e \u003cp\u003eFrom the IVW analysis, the odds ratio (OR) of CKD on dental caries was 1.3676 (95% CI, 1.1241\u0026ndash;1.6640; P\u0026thinsp;=\u0026thinsp;0.0018) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). A positive correlation was also between CKD and dental caries(b\u0026thinsp;=\u0026thinsp;0.3130). However, the OR of CKD on diseases of the pulp and periapical tissues and the OR of CKD on diseases of the gum and periodontal tissues were not found to be statistically significant (P\u0026thinsp;=\u0026thinsp;0.0935; P\u0026thinsp;=\u0026thinsp;0.0824) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB and C).\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\u003eMR Analysis of CKD and oral diseases\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eb\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePval\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOR_lci95\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eOR_uci95\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\u003edental caries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInverse variance weighted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.313084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.001754\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.367637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.124089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.663952\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.14061\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.796112\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.868826\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.378507\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.994304\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.255845\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.025193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.291553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.032336\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.615859\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.242434\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.249048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.274348\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.948354\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.712401\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.224091\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.202012\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.251185\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.989587\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.581936\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003ediseases of pulp and periapical tissues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInverse variance weighted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.161838\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.093523\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.17567\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.97307\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.420454\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.004064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.995603\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.004072\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.316935\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.180976\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.191826\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.039476\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.21146\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1.009283\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.454136\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.284563\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.209941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.329181\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.978777\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.805029\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.014153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.91124\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.014254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.813862\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.263986\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"4\" rowspan=\"5\"\u003e \u003cp\u003ediseases of gum and periodontal tissues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInverse variance weighted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.183115\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.082446\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.200952\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.976727\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.476653\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.3021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.616784\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.739264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.312242\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.75028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWeighted median\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.122941\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.23923\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.130818\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.921455\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.387749\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSimple mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.105982\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.557485\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.111802\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.825573\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.497267\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eWeighted mode\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.087386\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.556805\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.091317\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.854211\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1.394239\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eSD Standard deviation *p\u0026thinsp;\u0026lt;\u0026thinsp;.05, **p\u0026thinsp;\u0026lt;\u0026thinsp;.01, ***p\u0026thinsp;\u0026lt;\u0026thinsp;.001\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eSensitivity analyses\u003c/p\u003e \u003cp\u003eNeither horizontal pleiotropy was detected by MR-Egger (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), nor heterogeneity was found by MR-PRESSO detection (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). No significant outlier in the leave-one-out analysis indicated that our causal estimation was not driven by specific SNPs (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eP value of pleiotropy and heterogeneity analysis of CKD and oral diseases\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\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=\"char\" char=\".\" 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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003edental caries\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ediseases of pulp and periapical tissues\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ediseases of gum and periodontal tissues\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\u003eheterogeneity\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMR-PRESSO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.2662\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0844\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.2520\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eInverse variance weighted\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.2557\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.2237\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003epleiotropy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMR Egger\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.4702\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.8291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.4605\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 \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we conducted a direct genetic analysis of CKD and oral health status. We found that CKD may increase the incidence of dental caries but did not directly affect diseases of the pulp and periapical tissues or the gum and periodontal tissues.\u003c/p\u003e \u003cp\u003eThis study was the first to find that CKD could directly cause dental caries through genetic analysis. However, the relevant clinical studies were still inconclusive. Cl\u0026aacute;udia RSD Menezes found no difference in the mean dental caries index (decayed, missing, filled surface of permanent teeth, and DMFT) between 107 enrolled CKD patients and 107 participants without systemic disease [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. But it has also been found that the incidence of dental caries in patients with end-stage renal disease has increased [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Mizutani K found that mortality in patients with end-stage renal disease was associated with oral hygiene and dental caries [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In the reviewed studies, Marcia Rejane Thomas Canabarro Andrade found that the average caries index of deciduous teeth (decayed, missing, filled surface of deciduous teeth, and dmft) and permanent teeth (DMFT) of CKD patients was lower than that of the matched control group [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. However, methodological deficiencies still made the evaluated studies prone to bias. Moreover, the disease's stage or onset could profoundly impact the outcome or detection of the cause. Especially in patients with CKD, subjects receiving different treatment regimens may exhibit various oral manifestations [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. There is also still a lack of well-designed studies, such as longitudinal and multicenter studies, to fully support this scientific evidence.\u003c/p\u003e \u003cp\u003eIn patients with renal dysfunction, vitamin D absorption is reduced, calcium level is reduced, and mineral metabolism is affected [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Unfortunately, if the metabolism changes occur at the stage of tooth development, it will subsequently affect the formation of tooth hard tissue. Studies have also reported that the incidence of enamel hypoplasia in patients with CKD is higher than that of normal people [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Enamel hypocalcification will reduce the resistance to caries, which may cause the incidence of caries to increase. The permeability of the glomerular filtration membrane increases, resulting in the loss of a large amount of protein in the plasma, causing changes in the composition and secretion of saliva in patients with kidney disease [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The decrease in saliva flow reduces the cleaning and scouring effect on the tooth surface, causing plaque accumulation and increasing the possibility of caries. However, it has also been reported that the increase of urea in saliva indirectly causes an increase in saliva PH [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. If the PH value is maintained above the critical level of enamel demineralization, it may not increase the occurrence of caries.\u003c/p\u003e \u003cp\u003eThere is a four-factor theory of caries. That is, time, host, diet, and bacteria jointly determine the occurrence of caries [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. This article did not discuss the host factors determined by time and parental genetics. Patients with CKD must eat a carbohydrate-rich diet to reduce the load on the kidneys, which may increase the risk of tooth decay. Studies have shown that the use of glucocorticoids and cytotoxic drugs in CKD further affects the stability of the oral microenvironment. Still, it has also been reported that the number of Streptococcus mutans, one of the pathogens causing dental caries, has decreased [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. However, the microbial population is large and complex, and more comprehensive and overall research is still needed. As a comprehensive whole, the final result is the result of multiple interactions between positive and negative feedback loops. Furthermore, our study investigated the direct causal relationship between CKD and dental caries, helping to identify the fundamental problems that lead to the disease and find clear targets to achieve good treatment results.\u003c/p\u003e \u003cp\u003eIn this study, no direct relationship was found between diseases of the pulp and periapical tissues and CKD. There are few clinical studies on this issue. Root canal therapy is a routine treatment for pulpitis and apicitis. A Taiwan report identified that root canal therapy can reduce mortality in patients with end-stage renal disease [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Moreover, pulpitis and apical periodontitis occur when caries progress to a later stage, mainly because they do not skip caries in most cases, except for atretic pulpitis and retrograde periapical periodontitis. However, there is a current lack of research and exploration in this area.\u003c/p\u003e \u003cp\u003eIn this study, no direct causal relationship between kidney disease and gingivitis was found by genetic analysis. There are few clinical studies on the effects of CKD on gingivitis. Studies have shown that some medications taken for kidney disease, such as calcium channel blockers, can cause drug-induced gum hyperplasia [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Some patients with end-stage renal disease require peritoneal dialysis, and the gums are prone to bleeding and inflammation due to decreased coagulation function [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eA genetic analysis of CKD and periodontitis was done in 2019, and they did not find a causal relationship [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Notably, our study reached the same conclusion using updated GWAS data in 2021. Additionally, relevant clinical studies are abundant. According to the latest systematic review analysis in 2023, 60% of these reports showed a link between CKD and periodontitis [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. The prevalence of periodontitis in patients with CKD varies widely, ranging from 34.35\u0026ndash;93.65%, and the strength of evidence is low. This can be explained by the different diagnostic criteria and methods used to assess periodontitis.\u003c/p\u003e \u003cp\u003eAlthough the genetic analysis of CKD could not directly affect the occurrence of periodontitis, the indirect effect of CKD may impact periodontitis. Periodontal disease is a multi-factor disease [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. On the one hand, microorganisms are the starting factor of periodontal disease. It has been reported that increased glomerular filtration rate in CKD patients leads to protein loss, indirectly causing changes in saliva flow rate and composition, which may exert strong selection pressure on oral microbiota and lead to changes in community structure [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Changes in the blood composition of patients with CKD indirectly cause changes in saliva pH, which provides more favorable growth conditions for several periodontal pathogens such as Porphyromonas gingivalis, Prevotella intermedia, and Clostridium nucleatum, inducing changes in community structure and triggering the development of periodontal disease [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. Shiyuan Guo also found that patients with CKD had increased oral microbial diversity compared to the control group [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. On the other hand, periodontitis is mainly due to the loss of alveolar bone. Calcium loss in CKD patients is often accompanied by mineral metabolism disorders, affecting all aspects of bone physiology, including bone volume, turnover, and mineralization [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. It has also been reported that failing kidneys are unable to hydroxyl inactive vitamin D (25-hydroxyvitamin D) into its active form calcitriol (1, 25-dihydroxycholecalciferol) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In addition, systemic hypocalcemia and hyperphosphatemia caused by CKD are associated with impaired renal phosphate excretion, leading to the development of periodontal disease [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Finding the real cause of the disease, whether direct or indirect, will help us to treat the disease.\u003c/p\u003e\n\u003ch3\u003eLimitations\u003c/h3\u003e\n\u003cp\u003eUnlike traditional observational epidemiology, MR analysis is less susceptible to environmental factors, and genetic variation as an instrumental variable allows unbiased detection of causal effects. We conducted a two-sample Mendelian randomization study using a wide range of recent GWAS data to explore the oral health status of patients with CKD. However, due to the lack of relevant data on Asian people with CKD, the data on European populations was used in this paper and may be biased. Another disadvantage was that endodontic and periapical diseases were grouped without further detailed grouping when collecting GWAS data, which was somewhat lacking in accuracy. However, these two diseases belong to a large group of diseases, and the treatment methods are also the same. Furthermore, the practice of data consolidation was acceptable. As such, the data for gingivitis and periodontitis showed a similar pattern.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our MR study found that CKD has a direct causal relationship with dental caries, but no direct causal relationship with pulp and periapical tissues and diseases of gum and periodontal tissues. The occurrence of diseases results from the combination of direct and indirect factors. Combining MR with observational studies allows an in-depth analysis of the direct and indirect factors contributing to the disease. Therefore, finding targeted approaches will improve the oral health of patients with CKD and the effectiveness of diagnostic and treatment approaches in both disciplines.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Guilian Zhang. The first draft of the manuscript was written by Duojiao Xu and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics Approval and Consent to Participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEthical approval is not required because this study was based on a public GWAS database.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by grants from the National Key R\u0026amp;D Program of China (2016YFC1000804).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData deposition information item\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIEU database URL: https://gwas.mrcieu.ac.uk/\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the GWAS Consortium: IEU databases for providing the aggregated statistics used in this study. The authors thank AiMi Academic Services (www.aimieditor.com) for English language editing and review services\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eSTEVENS PE, LEVIN A, Kidney DIGO. Evaluation and Management of Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2012 Clinical Practice Guideline. ANN INTERN MED. 2013; 158:825-830. doi:10.7326/0003-4819-158-11-201306040-00007.\u003c/li\u003e\n\u003cli\u003eGlobal, Regional, and National Burden of Chronic Kidney Disease, 1990-2017: A Systematic Analysis for the Global Burden of Disease Study 2017. LANCET. 2020; 395:709-733. doi:10.1016/S0140-6736(20)30045-3.\u003c/li\u003e\n\u003cli\u003eForeman KJ, Marquez N, Dolgert A, et al. Forecasting Life Expectancy, Years of Life Lost, and All-Cause and Cause-Specific Mortality for 250 Causes of Death: Reference and Alternative Scenarios for 2016-40 for 195 Countries and Territories. 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Investigation of the Impact of Endodontic Therapy On Survival Among Dialysis Patients in Taiwan: A Nationwide Population-Based Cohort Study. International Journal of Environmental Research and Public Health. 2021; 18:326. doi:10.3390/ijerph18010326.\u003c/li\u003e\n\u003cli\u003eGuo S, Wu G, Liu W, et al. Characteristics of Human Oral Microbiome and its Non-Invasive Diagnostic Value in Chronic Kidney Disease. BIOSCIENCE REP. 2022; 42. doi:10.1042/BSR20210694.\u003c/li\u003e\n\u003cli\u003eAkar H, Akar GC, Carrero JJ, Stenvinkel P, Lindholm B. Systemic Consequences of Poor Oral Health in Chronic Kidney Disease Patients. CLIN J AM SOC NEPHRO. 2011; 6:218-226. doi:10.2215/CJN.05470610.\u003c/li\u003e\n\u003cli\u003eChabria D, Weintraub RG, Kilpatrick NM. Mechanisms and Management of Gingival Overgrowth in Paediatric Transplant Recipients: A Review. INT J PAEDIATR DENT. 2003; 13:220-229. doi:10.1046/j.1365-263x.2003.00465.x.\u003c/li\u003e\n\u003cli\u003eYang J, Chen T, Zhu Y, Bai M, Li X. Causal Inference Between Chronic Periodontitis and Chronic Kidney Disease: A Bidirectional Mendelian Randomization Analysis in a European Population. FRONT GENET. 2021; 12. doi:10.3389/fgene.2021.676136.\u003c/li\u003e\n\u003cli\u003eSerni L, Caroti L, Barbato L, Nieri M, Serni S, Cirami CL, Cairo F. Association Between Chronic Kidney Disease and Periodontitis. A Systematic Review and Metanalysis. ORAL DIS. 2023; 29:40-50. doi:10.1111/odi.14062.\u003c/li\u003e\n\u003cli\u003eKinane DF, Stathopoulou PG, Papapanou PN. Periodontal Diseases. NAT REV DIS PRIMERS. 2017; 3. doi:10.1038/nrdp.2017.38.\u003c/li\u003e\n\u003cli\u003eChopra A, Sivaraman K. An Update On Possible Pathogenic Mechanisms of Periodontal Pathogens On Renal Dysfunction. CRIT REV MICROBIOL. 2019; 45:514-538. doi:10.1080/1040841X.2018.1553847.\u003c/li\u003e\n\u003cli\u003eZhang X, Chen H, Lu W, Zhu L, Zhou W, Song Z. Characterization of the Subgingival Microbiota in the Peritoneal Dialysis Patients with Periodontitis. ARCH ORAL BIOL. 2020; 115:104742. doi:10.1016/j.archoralbio.2020.104742.\u003c/li\u003e\n\u003cli\u003eKanjevac T, Bijelic B, Brajkovic D, Vasovic M, Stolic R. Impact of Chronic Kidney Disease Mineral and Bone Disorder On Jaw and Alveolar Bone Metabolism: A Narrative Review. ORAL HLTH PREV DENT. 2018; 16:79-85. doi:10.3290/j.ohpd.a39858.\u003c/li\u003e\n\u003cli\u003eSun K, Shen H, Liu Y, Deng H, Chen H, Song Z. Assessment of Alveolar Bone and Periodontal Status in Peritoneal Dialysis Patients. FRONT PHYSIOL. 2021; 12:759056. doi:10.3389/fphys.2021.759056.\u003c/li\u003e\n\u003cli\u003eBaioni CS, De Souza CM, Ribeiro Braosi AP, et al. Analysis of the Association of Polymorphism in the Osteoprotegerin Gene with Susceptibility to Chronic Kidney Disease and Periodontitis. J PERIODONTAL RES. 2008; 43:578-584. doi:10.1111/j.1600-0765.2008.01098.x.\u003c/li\u003e\n\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":"chronic kidney disease, oral health, caries, Mendelian randomization analyses","lastPublishedDoi":"10.21203/rs.3.rs-4318284/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4318284/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eObservational studies have shown that chronic kidney disease can lead to changes in oral health, but the conclusions remain controversial. Thus, we conducted a Mendelian randomization study from the perspective of genetic analysis to assess the causal association between chronic kidney disease and oral health conditions, including dental caries, pulp diseases, periapical tissues, and diseases of the gum and periodontal tissues.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe performed inverse variance weighted random effects Mendelian randomization analyses and several sensitivity Mendelian randomization analyses using summary statistics from genome-wide association studies of European people.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe found a positive causal relationship between chronic kidney disease and dental caries, and the effect odds ratio of chronic kidney disease on dental caries was 1.368 (95% CI, 1.124-1.664; P = 0.002). There was no direct causal relationship between chronic kidney disease and diseases of the pulp and periapical tissues and diseases of the gum and periodontal tissues, with the effect odds ratio of 1.176 (95% CI, 0.973-1.420; P = 0.094) and 1.201 (95% CI, 0.977-1.477; P = 0.08).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur findings suggest that chronic kidney disease could affect oral health, but only with a direct causal link to dental caries.\u003c/p\u003e","manuscriptTitle":"A causal association study between chronic kidney disease and oral health","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-02 18:25:13","doi":"10.21203/rs.3.rs-4318284/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":"524ea1bb-40f6-4b9f-accd-bcb892daf235","owner":[],"postedDate":"May 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-16T10:57:36+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-02 18:25:13","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4318284","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4318284","identity":"rs-4318284","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}