Causal association between micronutrients and oral diseases: a bidirectional two-sample Mendelian randomization study

Causal association between micronutrients and oral diseases: a bidirectional two-sample Mendelian randomization study | 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 Causal association between micronutrients and oral diseases: a bidirectional two-sample Mendelian randomization study Lei Wu, Yanling Chang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6332891/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 Previous studies had shown that multivitamin and mineral deficiencies increase the risk of oral diseases. To this end, we conducted a Mendelian randomization (MR) analysis to assess the causal relationship between micronutrients and oral diseases. Methods We performed bidirectional MR analyses utilizing publicly available summary statistics from independent European-ancestry cohorts. The study investigated potential causal associations between 15 micronutrients levels and the risk of 13 oral diseases. Five distinct MR methods were employed for analysis, with the inverse variance weighted (IVW) method serving as the primary approach for causal inference. Furthermore, sensitivity analyses were conducted to assess potential horizontal pleiotropy and heterogeneity in the results, demonstrating the robustness of the findings. Results MR analyses revealed significant associations between the levels of 7 micronutrients and the risk of 8 oral diseases. Notably, vitamin B9 demonstrated a protective effect against cleft lip and palate (IVW, OR = 0.2584; 95% CI, 0.0919–0.7267; P = 0.0103), vitamin D showed a protective effect against chronic periodontitis (IVW, OR = 0.4595; 95% CI, 0.2455–0.8598; P = 0.0150), and vitamin E exhibited a protective effect against pulp and periapical diseases (IVW, OR = 0.6927; 95% CI, 0.4801–0.9993; P = 0.0496). Reverse MR analyses indicated causal associations between 8 oral diseases and 5 micronutrient levels. These findings were robust across extensive sensitivity analyses. Conclusion Our results strongly supported the important role of micronutrients in oral diseases. These findings provided a valuable reference for better management of oral diseases. Mendelian randomization Micronutrients Oral diseases Figures Figure 1 Figure 2 Figure 3 1. Introduction Oral health is an indispensable indicator for evaluating the quality of life. However, oral diseases, as common health issues, significantly impair patients' quality of life [ 1 , 2 ]. Oral diseases encompass a range of pathological conditions affecting the oral and facial structures, primarily resulting from microbial imbalance leading to tissue destruction [ 3 – 6 ]. These diseases include dental caries, periodontal diseases, oral cancer, and other mucosal-related disorders, imposing a substantial global health burden that affects approximately 3.9 billion people worldwide [ 7 – 9 ]. This study encompassed 13 common oral diseases, including dental caries, chronic periodontitis, acute periodontitis, diseases of pulp and periapical tissues, impacted teeth, cleft lip and cleft palate, oral cavity cancer, oropharyngeal cancer, mouth ulcers, toothache, loose teeth, bleeding gums, and painful gums. These oral diseases are typically caused by the interplay of multiple factors, involving biological susceptibility and social determinants, necessitating targeted public health interventions. Micronutrients are essential minerals that constitute only 0.01% of the body weight but play crucial physiological roles [ 10 ]. Their metabolic homeostasis is directly related to core biological processes such as immune regulation, redox balance, and enzyme catalytic activity [ 11 , 12 ]. Previous research has shown a strong association between micronutrient deficiencies and the occurrence of oral diseases [ 13 ]. For instance, vitamin D plays a crucial role in facilitating the absorption of calcium and phosphorus, essential nutrients for healthy dental development [ 14 , 15 ]. Deficiencies in vitamin D during pregnancy and early childhood can impact dental development [ 16 , 17 ]. A lack of vitamin C can lead to gingival bleeding and necrosis, triggering a series of periodontal diseases [ 18 , 19 ]. Additionally, micronutrients like iron and magnesium are also relevant to oral health, with deficiencies potentially causing unstable teeth or other oral issues [ 20 – 23 ]. In summary, the intake of these micronutrients is crucial for maintaining good oral health, as both deficiencies and excesses can lead to oral diseases. Therefore, this study included 15 micronutrients, including vitamins A, B9, B6, B12, C, D, E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc, to investigate the causal associations between micronutrient levels and oral diseases. Existing research has revealed potential links between micronutrient and the risk of oral diseases [ 13 , 24 ]. However, these associations are influenced by numerous confounding factors, such as smoking and alcohol consumption. Therefore, comprehensively understanding the relationship between micronutrients and oral disease risk is crucial for developing effective prevention and management strategies. Mendelian randomisation (MR) uses genetic variation as instrumental variables (IVs) for causal inferences, which can overcome the confounding biases and reverse causality issues present in traditional epidemiological studies [ 25 , 26 ]. This new approach provides more robust genetic associations [ 27 , 28 ]. In line with this objective, we used a two-sample MR (TSMR) approach to evaluate the causal relationships between 15 micronutrients and the risk of 13 oral diseases, considering the potential impact of reverse causality. These findings aim to provide valuable insights that can inform clinical decision-making for preventive interventions. 2. Materials and methods 2.1 Study design Figure 1 illustrated the general flowchart of this study. In brief, we conducted a TSMR method using publicly available summary statistics and data collected from previous literature. Fifteen micronutrients were used as exposures and thirteen oral diseases as outcomes. To reduce demographic bias, both the exposure and outcome cohorts were restricted to individuals of European ancestry. The data used in this study were obtained from publicly available sources with participant consent and ethical approval, thus no additional institutional review board (IRB) ethical approval was required. Notably, all MR analyses were based on three core assumptions: (1) IVs must be strongly associated with the exposure; (2) IVs should be unrelated to confounding factors; and (3) IVs must not have a direct relationship with the outcome, influencing it only through the exposure. 2.2 Exposure data The genome-wide association studies (GWAS) data for the micronutrients included in our study comprised the following 15 elements: vitamins A, B9, B6, B12, C, D, E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc. Specifically, GWAS data for vitamins A and B9 were obtained from the GWAS Catalog ( https://www.ebi.ac.uk/gwas/ ) database, with accession numbers GCST90200405 and GCST90012742, respectively. GWAS data for vitamins B12, D, and E were accessed from the OpenGWAS project ( https://gwas.mrcieu.ac.uk/ ), with corresponding GWAS IDs as detailed in Table 1 . Comprehensive data information was provided in Supplementary Table S1 . The GWAS data for vitamin C consisted of 11 SNPs reported in a GWAS study [ 29 ], from which we selected 10 SNPs after excluding one (rs174547). This excluded SNP was reported to have pleiotropic effects on the FADS1 gene and was associated with numerous glycerophospholipids or sphingolipids, hence its exclusion. Furthermore, available genetic instrumental variables for vitamins B6, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc were obtained from published literature [ 30 ]. Detailed information regarding the instrumental variables for the nutrients obtained from the literature was provided in Supplementary Table S2 . 2.3 Outcome data GWAS data on oral diseases were publicly available through the IEU OpenGWAS project online database ( https://gwas.mrcieu.ac.uk/ ). The study encompassed 13 oral diseases: dental caries, chronic periodontitis, acute periodontitis, diseases of pulp and periapical tissues, impacted teeth, cleft lip and cleft palate, oral cavity cancer, oropharyngeal cancer, mouth ulcers, toothache, loose teeth, bleeding gums, and painful gums. The corresponding GWAS IDs for each disease were detailed in Table 1 . Additional relevant data information was provided in Supplementary Table S1 . Table 1 Detailed information of the GWAS data in our analysis Exposure/Outcome Year ID Population Sample size Control Case Dental caries 2018 ukb-d-K02 European 361,194 359,084 2,110 Chronic periodontitis 2021 finn-b-K11_PERIODON_CHRON European 198,441 195,395 3,046 Acute periodontitis 2021 finn-b-K11_PERIODON_ACUTE European 195,764 195,395 367 Diseases of pulp and periapical tissues 2021 finn-b-K11_PULP_PERIAPICAL European 200,749 195,395 5,354 Impacted teeth 2018 ukb-b-7534 European 463,010 461,414 1,596 Cleft lip and cleft palate 2021 finn-b-Q17_CLEFT_LIP_CLEFT_PALATE European 218,792 218,611 181 Oral cavity cancer 2021 ieu-b-4961 European 372,373 372,016 357 Oropharyngeal cancer 2021 ieu-b-4968 European 372,510 372,016 494 Mouth ulcers 2018 ukb-b-6458 European 461,113 414,011 47,102 Toothache 2018 ukb-b-19191 European 461,113 442,149 18,964 Loose teeth 2018 ukb-b-12849 European 461,113 442,132 18,981 Bleeding gums 2018 ukb-b-7872 European 461,113 400,895 60,218 Painful gums 2018 ukb-b-11161 European 461,113 447,799 13,314 Vitamin A 2023 GCST90200405 European / / / Vitamin B9 2021 GCST90012742 European / / / Vitamin B12 2018 ukb-b-19524 European 64,979 / / Vitamin D 2018 ukb-b-18593 European 64,979 / / Vitamin E 2018 ukb-b-6888 European 64,979 / / 2.4 Selection of instrumental variables IVs for vitamin D, vitamin B6, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc were obtained from literature and had undergone rigorous screening in previous studies. For other exposures, we also employed stringent criteria to select IVs. The criteria for choosing IVs were as follows: (1) SNPs with a genome-wide significance threshold of P < 5e-08 were selected as IVs, while a more relaxed threshold of P < 5e-06 was used for exposures with few associated genetic loci [ 31 ]; (2) SNPs were clumped to exclude the effects of linkage disequilibrium (r² = 0.001, allele distance = 10,000 kb); (3) An F-statistic was used to test for weak instruments, with SNPs having an F-statistic below 10 being excluded [ 32 , 33 ]; (4) SNPs with palindromic structures and incompatible were removed. Finally, SNPs identified as outliers by MR-PRESSO testing and those closely associated with confounding factors (such as smoking and alcohol consumption) were also excluded. 2.5 Analysis of MR We conducted MR analyses using five regression models: MR-Egger regression, inverse variance weighted (IVW), weighted median, weighted mode, and simple mode, with the IVW serving as the primary analysis [ 34 ]. Initially, we performed forward MR analyses to comprehensively investigate the causal relationships between the levels of 15 micronutrients and the risk of 13 oral diseases. Additionally, considering that oral disease patients might experience impaired chewing and swallowing functions, which could affect food selection and intake, potentially leading to deficiencies in essential micronutrients [ 35 ], we performed reverse MR analyses using the same workflow to assess whether oral diseases as exposure factors causally influence micronutrient levels. 2.6 Sensitivity analysis We performed sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, and leave-one-out methods, to validate the reliability and robustness of our findings. We assessed heterogeneity using Cochran's Q tests for both IVW and MR-Egger, where P < 0.05 indicated the presence of heterogeneity, prompting the use of a random-effects IVW model; otherwise, a fixed-effects model was applied. The MR-Egger intercept was used to evaluate pleiotropy, with a significant intercept (P < 0.05) indicating overall directional pleiotropy [ 33 ]. Additionally, we employed MR-PRESSO to identify outlier SNPs and performed a global test to confirm pleiotropy [ 36 ]. Finally, to assess whether individual SNPs influenced the causal estimates, we performed leave-one-out analyses to evaluate the impact of each SNP on the observed causal relationships. 2.7 Statistical analyses We conducted TSMR analyses using R software (version 4.3.1) and the R packages "TwoSampleMR" (version 0.6.8) and "MR-PRESSO" (version 1.0). In the MR analyses, a P-value < 0.05 indicated a significant causal relationship between exposure and outcome. 3. Results 3.1 Causal association between micronutrients and oral diseases We conducted MR analyses to investigate the causal relationships between 15 micronutrients and 13 oral diseases. The results from the IVW method were presented in Fig. 2 , revealing a total of 10 significant causal associations. Our study found that higher levels of micronutrients generally acted as protective factors of the risk of oral diseases. Specifically, high levels of vitamin B6 were negatively associated with the risk of mouth ulcers and loose teeth. High levels of vitamin B9 were negatively associated with the risk of cleft lip and cleft palate. High levels of vitamin D were negatively associated with chronic periodontitis. High levels of vitamin E were negatively associated with diseases of pulp and periapical tissues. High levels of vitamin C were negatively associated with dental caries. Calcium levels were negatively associated with diseases of pulp and periapical tissues and loose teeth. Iron levels were negatively associated with bleeding gums. Zinc levels were negatively associated with oropharyngeal cancer. No causal relationships were observed between other micronutrients and oral diseases. Additional MR analysis results were provided in Supplementary Table S3. 3.2 Reverse Mendelian randomisation analysis results To evaluate whether oral diseases as exposure factors causally influence micronutrient levels, we conducted reverse MR analyses. The IVW results were presented in Fig. 3 . The findings indicated that the genetic susceptibility to bleeding gums was negatively associated with vitamin B12 levels. The genetic susceptibility to dental caries and acute periodontitis was negatively associated with vitamin D levels. The genetic susceptibility to disease of pulp and periapical tissues and painful gums was positively associated with serum ferritin levels. The genetic susceptibility to dental caries was positively associated with serum iron levels. The genetic susceptibility to toothache was negatively associated with transferrin saturation levels. The genetic susceptibility to mouth ulcers was positively associated with calcium levels. The genetic susceptibility to chronic periodontitis was positively associated with vitamin B6 levels. No other reverse causal associations were observed. Additional MR analysis results were provided in Supplementary Table S4. 3.3 Sensitivity analysis results We conducted multiple sensitivity analyses, comprising Cochran's Q tests, MR-Egger intercept tests, and MR-PRESSO global tests, to strengthen the robustness and reliability of our results. In most cases, Cochran's Q test for heterogeneity yielded P-values greater than 0.05, suggesting that significant heterogeneity was not observed. Although heterogeneity was detected in some results, it did not render the MR estimates invalid using the random-effects IVW model in this study, which can balance the aggregated heterogeneity. Furthermore, we used MR-Egger intercept tests and MR-PRESSO global tests to detect pleiotropy, with P > 0.05 indicating no significant pleiotropy observed. The results of the sensitivity analyses are presented in Tables 2 and 3 , and Supplementary Tables S5 and S6. Leave-one-out analyses, scatter plots, and funnel plots further validated the stability of our findings (Supplementary Figures S1 and S2). In summary, the sensitivity analyses ensured that our results were reliable. Table 2 Sensitivity analysis of causal relationship between Micronutrients and Oral Disease Exposure Outcome method Q Q_pvalue MR_egger_intercept Pvalue MR.PRESSO Forward MR Vitamin B9 Cleft lip and cleft palate MR Egger 2.6022 0.6264 -0.3106 0.3064 0.545 Vitamin B9 Cleft lip and cleft palate IVW 3.975 0.553 Vitamin D Chronic periodontitis MR Egger 12.4291 0.0873 -0.0058 0.933 0.178 Vitamin D Chronic periodontitis IVW 12.4426 0.1325 Vitamin E Diseases of pulp and periapical tissues MR Egger 2.4545 0.9821 -0.0016 0.9267 0.998 Vitamin E Diseases of pulp and periapical tissues IVW 2.4635 0.9914 Vitamin C Dental caries MR Egger 12.0743 0.0981 -1.00E-04 0.5704 0.192 Vitamin C Dental caries IVW 12.6856 0.1231 calcium Diseases of pulp and periapical tissues MR Egger 177.0089 0.9142 0.0048 0.1792 0.767 calcium Diseases of pulp and periapical tissues IVW 178.8257 0.9064 calcium Loose teeth MR Egger 307.5934 1.29e-5 1e-04 0.2311 0.201 calcium Loose teeth IVW 309.7064 1.106e-5 / / / iron Bleeding gums IVW 3.3825 0.0659 / / / selenium Chronic periodontitis MR Egger 0.3871 0.9429 -0.0615 0.5906 0.920 selenium Chronic periodontitis IVW 0.7475 0.9453 selenium Mouth ulcers MR Egger 2.0118 0.7336 -0.002 0.193 0.589 selenium Mouth ulcers IVW 4.4566 0.4857 VitaminB6 Mouth ulcers IVW 0.7595 0.3835 / / / VitaminB6 Loose teeth IVW 0.0218 0.8827 / / / zinc Oropharyngeal cancer MR Egger 0.0268 0.8699 1e-04 0.7638 / zinc Oropharyngeal cancer IVW 0.1782 0.9147 Table 3 Sensitivity analysis of reverse MR Exposure Outcome method Q Q_pvalue MR_egger_intercept Pvalue MR.PRESSO Reverse MR Bleeding gums VitaminB12 MR Egger 53.2444 0.0513 -0.0015 0.6846 0.05 Bleeding gums VitaminB12 IVW 53.4792 0.0612 Dental caries VitaminD MR Egger 8.0668 0.8392 0.0016 0.7436 0.886 Dental caries VitaminD IVW 8.1784 0.8798 Acute periodontitis VitaminE MR Egger 3.8204 0.701 -0.0014 0.7469 0.801 Acute periodontitis VitaminE IVW 3.9345 0.7873 Diseases of pulp and periapical tissues ironferritin MR Egger 12.8798 0.1681 -0.0044 0.3467 0.176 Diseases of pulp and periapical tissues ironferritin IVW 14.2906 0.1601 Painful gums ironferritin MR Egger 9.5526 0.1448 -0.0067 0.4368 0.208 Painful gums ironferritin IVW 10.6571 0.1543 Dental caries ironserum MR Egger 15.1521 0.3678 -0.0025 0.4899 0.426 Dental caries ironserum IVW 15.6963 0.4025 Toothache irontsat MR Egger 12.1898 0.3495 -2.00E-04 0.9759 0.445 Toothache irontsat IVW 12.1909 0.4305 Mouth ulcers Ca MR Egger 18.6666 0.0969 0.0013 0.3974 0.167 Mouth ulcers Ca IVW 19.8648 0.0986 Chronic periodontitis VitaminB6 MR Egger 12.7006 0.1766 0.0034 0.6099 0.249 Chronic periodontitis VitaminB6 IVW 13.0949 0.2184 4. Discussion Oral diseases are a global health issue affecting millions of people. Our study aimed to investigate the causal associations between micronutrients and oral diseases. Our findings revealed that elevated levels of eight micronutrients were inversely associated with the risk of eight oral diseases. Notably, vitamin B9 was significantly negatively associated with the risk of cleft lip and cleft palate. Vitamin D was significantly negatively associated with the risk of chronic periodontitis. Vitamin E was significantly negatively associated with the risk of diseases of pulp and periapical tissues. The OR value between the remaining micronutrients and other oral diseases was relatively weak. Considering that oral health issues might limit patients' intake of certain foods, such as hard or high-fiber foods, which were often rich in essential micronutrients [ 37 , 38 ], we performed reverse MR analyses to investigate the causal associations between the genetic susceptibility to oral diseases and micronutrient levels. The results showed that eight oral diseases had causal associations with five micronutrient levels. In summary, this study systematically analyzed the causal associations between multiple oral diseases and micronutrients, revealing the importance of these nutrients in oral disease. Vitamin B9 has a strong biological association with the development of cleft lip and palate. It is essential for embryonic development, especially in the formation and closure of the neural tube [ 39 ]. A deficiency in vitamin B9 may lead to developmental abnormalities, including cleft lip and palate [ 40 , 41 ]. Additionally, research indicates that prenatal supplementation with vitamin B9 can reduce the incidence of cleft lip and palate [ 42 , 43 ]. In summary, vitamin B9 has a significant biological role in preventing cleft lip and palate by ensuring normal embryonic development and reducing the risk of these conditions. Regarding the association between vitamin D and the risk of chronic periodontitis, numerous studies have been conducted, but no definitive consensus has been reached. Vitamin D is vital for the absorption of calcium and phosphorus, which are essential for maintaining healthy periodontal bone structure [ 44 – 46 ]. A deficiency in vitamin D may lead to reduced bone density, increasing the risk of periodontal diseases [ 47 , 48 ]. Furthermore, vitamin D possesses immunomodulatory and anti-inflammatory effects, which can mitigate inflammatory responses in the oral cavity, thereby decreasing the severity of periodontitis [ 49 – 51 ]. Some studies suggest that vitamin D levels are associated with the severity of periodontitis, and a deficiency may increase the risk of developing the disease [ 52 , 53 ]. However, the results are inconsistent, with some studies failing to find a direct link between vitamin D levels and the risk of periodontitis [ 54 ]. Our study supports a protective role of vitamin D in reducing the risk of chronic periodontitis, although additional studies are required to clarify its specific role in periodontitis. As for the relationship between vitamin E and diseases of pulp and periapical tissues, fewer studies have been conducted. Vitamin E can protect cells from oxidative stress, which may help maintain the health of oral tissues, including the gums and surrounding tissues [ 55 , 56 ]. Vitamin E also promotes cellular regeneration and healing, which may aid in the repair and maintenance of oral tissues [ 57 ]. Additionally, the anti-inflammatory properties of vitamin E help to reduce inflammatory responses in the oral cavity, potentially influencing the health of pulp and periapical tissues indirectly [ 58 – 60 ]. In summary, these findings provide important information regarding the role of micronutrients in oral diseases. Reverse MR analyses revealed that micronutrients play multifaceted roles in oral diseases. The genetic susceptibility to diseases of pulp and periapical tissues, painful gums, and dental caries was positively associated with increased iron levels. This may be attributed to iron metabolic imbalance, as iron overload can lead to increased oxidative stress by promoting the production of reactive oxygen species (ROS), disrupting the intracellular redox balance [ 61 ]. This could exacerbate inflammatory responses and damage in oral tissues, affecting the health of pulp and periapical tissues [ 62 , 63 ]. Additionally, abnormal iron metabolism can enhance inflammatory reactions within the oral cavity, such as the oxidative stress caused by ferritin autophagy in periodontitis, which may be related to the occurrence of gingival pain and other oral diseases [ 64 , 65 ]. Furthermore, the genetic susceptibility to mouth ulcers was positively associated with calcium levels. This may be because calcium is involved in maintaining the health of oral mucosa, and changes in calcium levels could affect the integrity and repair capacity of oral mucosa [ 66 , 67 ]. However, this association requires further research for confirmation. The association between vitamin B6 and chronic periodontitis may be related to vitamin B6's role in regulating the immune system and influencing the intensity of inflammatory responses [ 68 , 69 ]. Vitamin B6 serves as a coenzyme for various enzymes involved in the metabolism of carbohydrates, proteins, and fats [ 70 ]. Chronic periodontitis is an inflammatory disease triggered by bacterial infection, and studies have shown that vitamin B6 metabolic pathways are significantly elevated in periodontitis patients [ 71 – 73 ]. All in all, these findings provide new insights for nutritional interventions in oral diseases. In summary, our study systematically analyzed the causal relationships between various micronutrients and oral diseases, revealing the roles of micronutrients in oral diseases and highlighting their importance in oral health. However, this study also has certain limitations. Firstly, our study population comprised individuals of European ancestry, which restricts the generalizability of our results to other populations. Future studies should include GWAS data from diverse populations and ethnicities to validate these discoveries. Secondly, the sample size of the available GWAS data for the selected oral diseases is limited, necessitating future research with larger GWAS datasets to further confirm these associations. Lastly, although we pioneered a comprehensive analysis of the causal relationships between multiple micronutrients and oral disease risks, additional studies are required to uncover the precise mechanisms through which micronutrients impact the development of oral diseases. Nevertheless, our study provide new perspectives and useful insights into potential strategies for alleviating pathological symptoms in oral disease patients. 5. Conclusion Our study systematically analyzed the causal associations between micronutrients and oral diseases. By highlighting the importance of micronutrients in oral health, our research provided valuable references and guidance for the prevention and management of oral diseases. Future research needs to explore the specific mechanisms by which micronutrients influence oral diseases and to validate these findings across different populations, thereby advancing oral health. Declarations Ethics approval and consent to participate Not applicable. Competing interests The authors declare that they have no potential conflicts of interest. Consent for publication Not applicable. Clinical trial number Not applicable Funding None. Author Contribution C.Y.L. contributed to the study design. C.Y.L. conducted the literature search. C.Y.L. and W.L. acquired the data. W.L. and C.Y.L. wrote the article. C.Y.L. performed data analysis. W.L. drafted. C.Y.L. and W.L. revised the article and gave the final approval of the version to be submitted. All authors read and approved the final manuscript. Acknowledgments Not applicable. Availability of data and materials The data and materials in the current study are available from the corresponding author on reasonable request. 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Wang, Osteoporosis and periodontal diseases - An update on their association and mechanistic links, Periodontology 2000 89(1) (2022) 99-113. G.K. Schwalfenberg, A review of the critical role of vitamin D in the functioning of the immune system and the clinical implications of vitamin D deficiency, Molecular nutrition & food research 55(1) (2011) 96-108. U. Van der Velden, D. Kuzmanova, I.L. Chapple, Micronutritional approaches to periodontal therapy, Journal of clinical periodontology 38 Suppl 11 (2011) 142-58. K. Liu, H. Meng, J. Hou, Activity of 25-hydroxylase in human gingival fibroblasts and periodontal ligament cells, PloS one 7(12) (2012) e52053. K.A. Boggess, J.A. Espinola, K. Moss, J. Beck, S. Offenbacher, C.A. Camargo, Jr., Vitamin D status and periodontal disease among pregnant women, Journal of periodontology 82(2) (2011) 195-200. A.E. Millen, K.M. Hovey, M.J. LaMonte, M. Swanson, C.A. Andrews, M.A. Kluczynski, R.J. Genco, J. Wactawski-Wende, Plasma 25-hydroxyvitamin D concentrations and periodontal disease in postmenopausal women, Journal of periodontology 84(9) (2013) 1243-56. G. Antonoglou, M. Knuuttila, O. Niemelä, L. Hiltunen, T. Raunio, R. Karttunen, O. Vainio, P. Ylöstalo, T. Tervonen, Serum 1,25(OH)D level increases after elimination of periodontal inflammation in T1DM subjects, The Journal of clinical endocrinology and metabolism 98(10) (2013) 3999-4005. J. Pincemail, S. Meziane, On the Potential Role of the Antioxidant Couple Vitamin E/Selenium Taken by the Oral Route in Skin and Hair Health, Antioxidants (Basel, Switzerland) 11(11) (2022). S. Reppuccia, F. Crocetto, E. Gragnano, P. D'Alessandro, M. Vetrella, G. Saccone, B. Arduino, Oil-based vitamin E oral spray for oral health in pregnancy, Future science OA 8(4) (2022) Fso790. S. Najeeb, M.S. Zafar, Z. Khurshid, S. Zohaib, K. Almas, The Role of Nutrition in Periodontal Health: An Update, Nutrients 8(9) (2016). I. Elmadfa, A.L. Meyer, The Role of the Status of Selected Micronutrients in Shaping the Immune Function, Endocrine, metabolic & immune disorders drug targets 19(8) (2019) 1100-1115. G. Çankaya, M.S. Ocak, S. Dündar, H. Özercan İ, Investigation of the relationship between apical periodontitis and host modulation provided by nutritional supplement: a study in rats, BMC oral health 25(1) (2025) 336. C. Niamonitos, G. Shklar, A.A. Krakow, Effects of vitamin E dietary supplements on the exposed dental pulp in rats, Oral surgery, oral medicine, and oral pathology 59(6) (1985) 627-36. N.W. Solomons, K. Schümann, 3.2 Iron: Nutritional Deficiency and Excess, World review of nutrition and dietetics 124 (2022) 221-228. M. Kilian, I.L. Chapple, M. Hannig, P.D. Marsh, V. Meuric, A.M. Pedersen, M.S. Tonetti, W.G. Wade, E. Zaura, The oral microbiome - an update for oral healthcare professionals, British dental journal 221(10) (2016) 657-666. H. Hatipoglu, M.G. Hatipoglu, L.B. Cagirankaya, F. Caglayan, Severe periodontal destruction in a patient with advanced anemia: A case report, European journal of dentistry 6(1) (2012) 95-100. E. Boyer, S. Le Gall-David, B. Martin, S.B. Fong, O. Loréal, Y. Deugnier, M. Bonnaure-Mallet, V. Meuric, Increased transferrin saturation is associated with subgingival microbiota dysbiosis and severe periodontitis in genetic haemochromatosis, Scientific reports 8(1) (2018) 15532. H.T. Fadel, M.A. Zolaly, M.O. Alharbi, L.A. Qarah, M.S. Alrehili, A.D. Alamri, A.M. Tarawah, Oral Health Profiles and Related Quality of Life in Thalassemia Children in Relation to Iron Overload: A Cross-Sectional Study, International journal of environmental research and public health 17(24) (2020). B. Wang, A. Danjo, H. Kajiya, K. Okabe, M.A. Kido, Oral epithelial cells are activated via TRP channels, Journal of dental research 90(2) (2011) 163-7. R.F. Li, Q.W. Man, J.Y. Liu, Y.Y. Zheng, X. Gao, H.M. Liu, Overexpression of T-type calcium channel Cav3.1 in oral squamous cell carcinoma: association with proliferation and anti-apoptotic activity, Journal of molecular histology 52(3) (2021) 511-520. D. Salata, M. Budkowska, B. Dołegowska, [Sphingosine-1-phosphate--molecular maestro], Postepy biochemii 58(3) (2012) 281-91. P. Zhang, K. Tsuchiya, T. Kinoshita, H. Kushiyama, S. Suidasari, M. Hatakeyama, H. Imura, N. Kato, T. Suda, Vitamin B6 Prevents IL-1β Protein Production by Inhibiting NLRP3 Inflammasome Activation, The Journal of biological chemistry 291(47) (2016) 24517-24527. K. Stach, W. Stach, K. Augoff, Vitamin B6 in Health and Disease, Nutrients 13(9) (2021). E. Ikeda, T. Shiba, Y. Ikeda, W. Suda, A. Nakasato, Y. Takeuchi, M. Azuma, M. Hattori, Y. Izumi, Japanese subgingival microbiota in health vs disease and their roles in predicted functions associated with periodontitis, Odontology 108(2) (2020) 280-291. M.X. Chen, Y.J. Zhong, Q.Q. Dong, H.M. Wong, Y.F. Wen, Global, regional, and national burden of severe periodontitis, 1990-2019: An analysis of the Global Burden of Disease Study 2019, Journal of clinical periodontology 48(9) (2021) 1165-1188. J. Zhu, W. Xu, S. Wu, D. Song, Vitamin B6 status, type 2 diabetes mellitus, and periodontitis: evidence from the NHANES database 2009-2010, BMC oral health 25(1) (2025) 299. Additional Declarations No competing interests reported. Supplementary Files SupplementaryTableS16.xlsx STROBEMRchecklistfillable.pdf 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. 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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-6332891","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":453997148,"identity":"6bdd4520-e2d9-4f61-bd1f-8ce319c46052","order_by":0,"name":"Lei Wu","email":"","orcid":"","institution":"Jinhua Fifth Hospital","correspondingAuthor":false,"prefix":"","firstName":"Lei","middleName":"","lastName":"Wu","suffix":""},{"id":453997149,"identity":"eefb7928-1279-44ee-a7c4-2980df0e6560","order_by":1,"name":"Yanling Chang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIiWNgGAWjYDACCSjNxwwkPlSwyfEzMx9+QJQWNqAWxhln+Iwl29nSDIjTAsTMvC1yiRvO8yhI4NPBP7v52cOvbXZ5bOy8h1/wNpgZGx/mYTBgqLGJxmnJnWPmxrJtycVszHxpFpI70uTMDvMeeMBwLC23AYcWA4kEM2nJNubENmYeMwPDM8eMzQ7zJRgwNhzGoyX9G1BLPURLYtv/xM3NPAYS+LXkmEl+bDsM0mL84GAbW+IGZgJaJG7klEkznDsOtoWx4QybscRhYCAn4PEL/4z0bZI/yqoT+/nPGH/+A4rK/sOHH3yoscGpBQSYednANBsiOhLwKAcBxh9/IFo/EFA4CkbBKBgFIxQAANqSVovnv471AAAAAElFTkSuQmCC","orcid":"","institution":"Jinhua Fifth Hospital","correspondingAuthor":true,"prefix":"","firstName":"Yanling","middleName":"","lastName":"Chang","suffix":""}],"badges":[],"createdAt":"2025-03-29 08:38:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6332891/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6332891/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":82354294,"identity":"e1d0fc7c-f71a-4b0d-b6dd-795ab13e040d","added_by":"auto","created_at":"2025-05-09 11:09:50","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":2146497,"visible":true,"origin":"","legend":"\u003cp\u003eGeneral workflow of Mendelian randomization (MR) study. Fifteen micronutrients (vitamins A, B9, B6, B12, C, D, E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc) were used as exposures, while thirteen oral diseases (dental caries, chronic periodontitis, acute periodontitis, diseases of pulp and periapical tissues, impacted teeth, cleft lip and cleft palate, oral cavity cancer, oropharyngeal cancer, mouth ulcers, toothache, loose teeth, bleeding gums, and painful gums) served as outcomes. Utilizing single nucleotide polymorphisms (SNPs) as instrumental variables, we aimed to explain and mitigate the effects of confounding factors (such as smoking and alcohol consumption) to investigate the causal relationships between micronutrient levels and oral disease risks.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6332891/v1/1a3029e0fe8a97d27323e2f2.jpg"},{"id":82354297,"identity":"9fa9b1c8-efbb-44f2-96ba-020e7553f18d","added_by":"auto","created_at":"2025-05-09 11:09:50","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3651472,"visible":true,"origin":"","legend":"\u003cp\u003eMendelian randomization analysis of micronutrients and oral diseases. A total of 10 significant causal associations were observed. The IVW results were presented as the primary reference. P \u0026lt; 0.05 indicated a significant causal association. OR, odds ratio. OR \u0026gt; 1, risk factor. OR \u0026lt; 1, protective factor.\u003c/p\u003e","description":"","filename":"figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6332891/v1/4a2ca37ea87b9c78bd8923fc.jpg"},{"id":82354301,"identity":"923e22dc-b5fc-4d12-b733-1b3189beae7c","added_by":"auto","created_at":"2025-05-09 11:09:50","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":3246561,"visible":true,"origin":"","legend":"\u003cp\u003eMendelian randomization analysis of oral diseases and micronutrient levels. A total of 9 significant causal relationships were observed. The IVW results were presented as the primary reference. P \u0026lt; 0.05 indicated a significant causal association. Ironferritin, ironserum and irontsat were three important measures of iron levels. Ironferritin, serum ferritin; Ironserum, serum iron; Irontsat, transferrin saturation. OR, odds ratio. OR \u0026gt; 1, risk factor. OR \u0026lt; 1, protective factor.\u003c/p\u003e","description":"","filename":"figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6332891/v1/07366045774f8cba0bed8096.jpg"},{"id":85541685,"identity":"c16d7e21-6019-4cdb-87e4-5adcd7f85a2a","added_by":"auto","created_at":"2025-06-27 06:54:01","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2437382,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6332891/v1/fe8fbe7f-b373-4ab4-809b-7c1f757b1b58.pdf"},{"id":82354322,"identity":"95a8236d-2d3b-4cf5-ac61-858ca91aa965","added_by":"auto","created_at":"2025-05-09 11:09:51","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":12305154,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS16.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6332891/v1/42002182dbde80a713754497.xlsx"},{"id":82354295,"identity":"0544ae2a-5ef3-4e97-be8c-766cde0569b0","added_by":"auto","created_at":"2025-05-09 11:09:50","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":98756,"visible":true,"origin":"","legend":"","description":"","filename":"STROBEMRchecklistfillable.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6332891/v1/caf122d76bda0bfd01ab5290.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Causal association between micronutrients and oral diseases: a bidirectional two-sample Mendelian randomization study","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eOral health is an indispensable indicator for evaluating the quality of life. However, oral diseases, as common health issues, significantly impair patients' quality of life [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Oral diseases encompass a range of pathological conditions affecting the oral and facial structures, primarily resulting from microbial imbalance leading to tissue destruction [\u003cspan additionalcitationids=\"CR4 CR5\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. These diseases include dental caries, periodontal diseases, oral cancer, and other mucosal-related disorders, imposing a substantial global health burden that affects approximately 3.9\u0026nbsp;billion people worldwide [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This study encompassed 13 common oral diseases, including dental caries, chronic periodontitis, acute periodontitis, diseases of pulp and periapical tissues, impacted teeth, cleft lip and cleft palate, oral cavity cancer, oropharyngeal cancer, mouth ulcers, toothache, loose teeth, bleeding gums, and painful gums. These oral diseases are typically caused by the interplay of multiple factors, involving biological susceptibility and social determinants, necessitating targeted public health interventions.\u003c/p\u003e \u003cp\u003eMicronutrients are essential minerals that constitute only 0.01% of the body weight but play crucial physiological roles [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Their metabolic homeostasis is directly related to core biological processes such as immune regulation, redox balance, and enzyme catalytic activity [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Previous research has shown a strong association between micronutrient deficiencies and the occurrence of oral diseases [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. For instance, vitamin D plays a crucial role in facilitating the absorption of calcium and phosphorus, essential nutrients for healthy dental development [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. Deficiencies in vitamin D during pregnancy and early childhood can impact dental development [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A lack of vitamin C can lead to gingival bleeding and necrosis, triggering a series of periodontal diseases [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Additionally, micronutrients like iron and magnesium are also relevant to oral health, with deficiencies potentially causing unstable teeth or other oral issues [\u003cspan additionalcitationids=\"CR21 CR22\" citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In summary, the intake of these micronutrients is crucial for maintaining good oral health, as both deficiencies and excesses can lead to oral diseases. Therefore, this study included 15 micronutrients, including vitamins A, B9, B6, B12, C, D, E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc, to investigate the causal associations between micronutrient levels and oral diseases.\u003c/p\u003e \u003cp\u003eExisting research has revealed potential links between micronutrient and the risk of oral diseases [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. However, these associations are influenced by numerous confounding factors, such as smoking and alcohol consumption. Therefore, comprehensively understanding the relationship between micronutrients and oral disease risk is crucial for developing effective prevention and management strategies. Mendelian randomisation (MR) uses genetic variation as instrumental variables (IVs) for causal inferences, which can overcome the confounding biases and reverse causality issues present in traditional epidemiological studies [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. This new approach provides more robust genetic associations [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. In line with this objective, we used a two-sample MR (TSMR) approach to evaluate the causal relationships between 15 micronutrients and the risk of 13 oral diseases, considering the potential impact of reverse causality. These findings aim to provide valuable insights that can inform clinical decision-making for preventive interventions.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Study design\u003c/h2\u003e \u003cp\u003eFigure \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e illustrated the general flowchart of this study. In brief, we conducted a TSMR method using publicly available summary statistics and data collected from previous literature. Fifteen micronutrients were used as exposures and thirteen oral diseases as outcomes. To reduce demographic bias, both the exposure and outcome cohorts were restricted to individuals of European ancestry. The data used in this study were obtained from publicly available sources with participant consent and ethical approval, thus no additional institutional review board (IRB) ethical approval was required. Notably, all MR analyses were based on three core assumptions: (1) IVs must be strongly associated with the exposure; (2) IVs should be unrelated to confounding factors; and (3) IVs must not have a direct relationship with the outcome, influencing it only through the exposure.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Exposure data\u003c/h2\u003e \u003cp\u003eThe genome-wide association studies (GWAS) data for the micronutrients included in our study comprised the following 15 elements: vitamins A, B9, B6, B12, C, D, E, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc. Specifically, GWAS data for vitamins A and B9 were obtained from the GWAS Catalog (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ebi.ac.uk/gwas/\u003c/span\u003e\u003cspan address=\"https://www.ebi.ac.uk/gwas/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) database, with accession numbers GCST90200405 and GCST90012742, respectively. GWAS data for vitamins B12, D, and E were accessed from the OpenGWAS project (\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), with corresponding GWAS IDs as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Comprehensive data information was provided in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e. The GWAS data for vitamin C consisted of 11 SNPs reported in a GWAS study [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], from which we selected 10 SNPs after excluding one (rs174547). This excluded SNP was reported to have pleiotropic effects on the FADS1 gene and was associated with numerous glycerophospholipids or sphingolipids, hence its exclusion. Furthermore, available genetic instrumental variables for vitamins B6, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc were obtained from published literature [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Detailed information regarding the instrumental variables for the nutrients obtained from the literature was provided in Supplementary Table \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 Outcome data\u003c/h2\u003e \u003cp\u003eGWAS data on oral diseases were publicly available through the IEU OpenGWAS project online database (\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). The study encompassed 13 oral diseases: dental caries, chronic periodontitis, acute periodontitis, diseases of pulp and periapical tissues, impacted teeth, cleft lip and cleft palate, oral cavity cancer, oropharyngeal cancer, mouth ulcers, toothache, loose teeth, bleeding gums, and painful gums. The corresponding GWAS IDs for each disease were detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Additional relevant data information was provided in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e.\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\u003eDetailed information of the GWAS data in our analysis\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=\"char\" char=\".\" 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 \u003cp\u003eExposure/Outcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eID\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePopulation\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eSample size\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCase\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDental caries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-d-K02\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\u003e361,194\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e359,084\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2,110\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efinn-b-K11_PERIODON_CHRON\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\u003e198,441\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e195,395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3,046\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efinn-b-K11_PERIODON_ACUTE\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\u003e195,764\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e195,395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e367\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiseases of pulp and periapical tissues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efinn-b-K11_PULP_PERIAPICAL\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\u003e200,749\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e195,395\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e5,354\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eImpacted teeth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-7534\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\u003e463,010\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e461,414\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1,596\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCleft lip and cleft palate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003efinn-b-Q17_CLEFT_LIP_CLEFT_PALATE\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\u003e218,792\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e218,611\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e181\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOral cavity cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eieu-b-4961\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\u003e372,373\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e372,016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e357\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOropharyngeal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eieu-b-4968\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\u003e372,510\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e372,016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e494\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouth ulcers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-6458\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\u003e461,113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e414,011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e47,102\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToothache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-19191\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\u003e461,113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e442,149\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18,964\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLoose teeth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-12849\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\u003e461,113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e442,132\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e18,981\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding gums\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-7872\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\u003e461,113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e400,895\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e60,218\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePainful gums\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-11161\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\u003e461,113\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e447,799\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e13,314\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGCST90200405\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\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin B9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGCST90012742\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\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin B12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-19524\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\u003e64,979\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-18593\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\u003e64,979\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eukb-b-6888\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\u003e64,979\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Selection of instrumental variables\u003c/h2\u003e \u003cp\u003eIVs for vitamin D, vitamin B6, β-carotene, calcium, copper, iron, magnesium, phosphorus, selenium, and zinc were obtained from literature and had undergone rigorous screening in previous studies. For other exposures, we also employed stringent criteria to select IVs. The criteria for choosing IVs were as follows: (1) SNPs with a genome-wide significance threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;5e-08 were selected as IVs, while a more relaxed threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;5e-06 was used for exposures with few associated genetic loci [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]; (2) SNPs were clumped to exclude the effects of linkage disequilibrium (r\u0026sup2; = 0.001, allele distance\u0026thinsp;=\u0026thinsp;10,000 kb); (3) An \u003cem\u003eF-statistic\u003c/em\u003e was used to test for weak instruments, with SNPs having an \u003cem\u003eF-statistic\u003c/em\u003e below 10 being excluded [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]; (4) SNPs with palindromic structures and incompatible were removed. Finally, SNPs identified as outliers by MR-PRESSO testing and those closely associated with confounding factors (such as smoking and alcohol consumption) were also excluded.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 Analysis of MR\u003c/h2\u003e \u003cp\u003eWe conducted MR analyses using five regression models: MR-Egger regression, inverse variance weighted (IVW), weighted median, weighted mode, and simple mode, with the IVW serving as the primary analysis [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Initially, we performed forward MR analyses to comprehensively investigate the causal relationships between the levels of 15 micronutrients and the risk of 13 oral diseases. Additionally, considering that oral disease patients might experience impaired chewing and swallowing functions, which could affect food selection and intake, potentially leading to deficiencies in essential micronutrients [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e], we performed reverse MR analyses using the same workflow to assess whether oral diseases as exposure factors causally influence micronutrient levels.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 Sensitivity analysis\u003c/h2\u003e \u003cp\u003eWe performed sensitivity analyses, including heterogeneity tests, horizontal pleiotropy tests, and leave-one-out methods, to validate the reliability and robustness of our findings. We assessed heterogeneity using Cochran's Q tests for both IVW and MR-Egger, where P\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated the presence of heterogeneity, prompting the use of a random-effects IVW model; otherwise, a fixed-effects model was applied. The MR-Egger intercept was used to evaluate pleiotropy, with a significant intercept (P\u0026thinsp;\u0026lt;\u0026thinsp;0.05) indicating overall directional pleiotropy [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. Additionally, we employed MR-PRESSO to identify outlier SNPs and performed a global test to confirm pleiotropy [\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. Finally, to assess whether individual SNPs influenced the causal estimates, we performed leave-one-out analyses to evaluate the impact of each SNP on the observed causal relationships.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Statistical analyses\u003c/h2\u003e \u003cp\u003eWe conducted TSMR analyses using R software (version 4.3.1) and the R packages \"TwoSampleMR\" (version 0.6.8) and \"MR-PRESSO\" (version 1.0). In the MR analyses, a P-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 indicated a significant causal relationship between exposure and outcome.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Causal association between micronutrients and oral diseases\u003c/h2\u003e \u003cp\u003eWe conducted MR analyses to investigate the causal relationships between 15 micronutrients and 13 oral diseases. The results from the IVW method were presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, revealing a total of 10 significant causal associations. Our study found that higher levels of micronutrients generally acted as protective factors of the risk of oral diseases. Specifically, high levels of vitamin B6 were negatively associated with the risk of mouth ulcers and loose teeth. High levels of vitamin B9 were negatively associated with the risk of cleft lip and cleft palate. High levels of vitamin D were negatively associated with chronic periodontitis. High levels of vitamin E were negatively associated with diseases of pulp and periapical tissues. High levels of vitamin C were negatively associated with dental caries. Calcium levels were negatively associated with diseases of pulp and periapical tissues and loose teeth. Iron levels were negatively associated with bleeding gums. Zinc levels were negatively associated with oropharyngeal cancer. No causal relationships were observed between other micronutrients and oral diseases. Additional MR analysis results were provided in Supplementary Table S3.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.2 Reverse Mendelian randomisation analysis results\u003c/h2\u003e \u003cp\u003eTo evaluate whether oral diseases as exposure factors causally influence micronutrient levels, we conducted reverse MR analyses. The IVW results were presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The findings indicated that the genetic susceptibility to bleeding gums was negatively associated with vitamin B12 levels. The genetic susceptibility to dental caries and acute periodontitis was negatively associated with vitamin D levels. The genetic susceptibility to disease of pulp and periapical tissues and painful gums was positively associated with serum ferritin levels. The genetic susceptibility to dental caries was positively associated with serum iron levels. The genetic susceptibility to toothache was negatively associated with transferrin saturation levels. The genetic susceptibility to mouth ulcers was positively associated with calcium levels. The genetic susceptibility to chronic periodontitis was positively associated with vitamin B6 levels. No other reverse causal associations were observed. Additional MR analysis results were provided in Supplementary Table S4.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003e3.3 Sensitivity analysis results\u003c/h2\u003e \u003cp\u003eWe conducted multiple sensitivity analyses, comprising Cochran's Q tests, MR-Egger intercept tests, and MR-PRESSO global tests, to strengthen the robustness and reliability of our results. In most cases, Cochran's Q test for heterogeneity yielded P-values greater than 0.05, suggesting that significant heterogeneity was not observed. Although heterogeneity was detected in some results, it did not render the MR estimates invalid using the random-effects IVW model in this study, which can balance the aggregated heterogeneity. Furthermore, we used MR-Egger intercept tests and MR-PRESSO global tests to detect pleiotropy, with P\u0026thinsp;\u0026gt;\u0026thinsp;0.05 indicating no significant pleiotropy observed. The results of the sensitivity analyses are presented in Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, and Supplementary Tables S5 and S6. Leave-one-out analyses, scatter plots, and funnel plots further validated the stability of our findings (Supplementary Figures \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e and S2). In summary, the sensitivity analyses ensured that our results were reliable.\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\u003eSensitivity analysis of causal relationship between Micronutrients and Oral Disease\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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=\"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 \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003emethod\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_pvalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMR_egger_intercept\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePvalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMR.PRESSO\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eForward MR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin B9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCleft lip and cleft palate\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\u003e2.6022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.6264\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.3106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.3064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.545\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin B9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCleft lip and cleft palate\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.975\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.553\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic periodontitis\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\u003e12.4291\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0058\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.933\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.178\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin D\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.4426\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1325\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiseases of pulp and periapical tissues\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\u003e2.4545\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9821\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.9267\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.998\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin E\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiseases of pulp and periapical tissues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.4635\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9914\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDental caries\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\u003e12.0743\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0981\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-1.00E-04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5704\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.192\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitamin C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDental caries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.6856\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.1231\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecalcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiseases of pulp and periapical tissues\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\u003e177.0089\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9142\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0048\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.1792\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.767\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecalcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eDiseases of pulp and periapical tissues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e178.8257\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecalcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoose teeth\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\u003e307.5934\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.29e-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1e-04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.2311\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.201\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ecalcium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoose teeth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e309.7064\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e1.106e-5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eiron\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBleeding gums\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.3825\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0659\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eselenium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic periodontitis\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\u003e0.3871\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9429\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0615\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.5906\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.920\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eselenium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eChronic periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7475\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9453\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eselenium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMouth ulcers\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\u003e2.0118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.7336\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.002\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.193\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.589\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eselenium\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMouth ulcers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.4566\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.4857\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitaminB6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMouth ulcers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.7595\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.3835\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVitaminB6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLoose teeth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.0218\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8827\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezinc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOropharyngeal cancer\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\u003e0.0268\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.8699\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1e-04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.7638\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e/\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ezinc\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOropharyngeal cancer\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.1782\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.9147\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\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=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSensitivity analysis of reverse MR\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\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=\"left\" 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=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eExposure\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003emethod\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_pvalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eMR_egger_intercept\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePvalue\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eMR.PRESSO\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"8\" nameend=\"c8\" namest=\"c1\"\u003e \u003cp\u003eReverse MR\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding gums\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminB12\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\u003e53.2444\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0513\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.6846\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.05\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBleeding gums\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminB12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e53.4792\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0612\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDental caries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminD\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\u003e8.0668\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.8392\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.7436\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.886\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDental caries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e8.1784\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.8798\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminE\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\u003e3.8204\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.701\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.7469\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.801\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAcute periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminE\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.9345\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.7873\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiseases of pulp and periapical tissues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eironferritin\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\u003e12.8798\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1681\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0044\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.3467\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.176\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiseases of pulp and periapical tissues\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eironferritin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.2906\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1601\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePainful gums\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eironferritin\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\u003e9.5526\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1448\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0067\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.4368\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.208\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePainful gums\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eironferritin\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e10.6571\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1543\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDental caries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eironserum\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\u003e15.1521\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.3678\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-0.0025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.4899\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.426\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDental caries\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eironserum\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e15.6963\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.4025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToothache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eirontsat\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\u003e12.1898\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.3495\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e-2.00E-04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.9759\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.445\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eToothache\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eirontsat\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.1909\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.4305\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouth ulcers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCa\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\u003e18.6666\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0969\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0013\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.3974\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.167\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMouth ulcers\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCa\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e19.8648\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0986\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminB6\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\u003e12.7006\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.1766\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.0034\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.6099\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0.249\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic periodontitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eVitaminB6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIVW\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e13.0949\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.2184\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eOral diseases are a global health issue affecting millions of people. Our study aimed to investigate the causal associations between micronutrients and oral diseases. Our findings revealed that elevated levels of eight micronutrients were inversely associated with the risk of eight oral diseases. Notably, vitamin B9 was significantly negatively associated with the risk of cleft lip and cleft palate. Vitamin D was significantly negatively associated with the risk of chronic periodontitis. Vitamin E was significantly negatively associated with the risk of diseases of pulp and periapical tissues. The OR value between the remaining micronutrients and other oral diseases was relatively weak. Considering that oral health issues might limit patients' intake of certain foods, such as hard or high-fiber foods, which were often rich in essential micronutrients [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], we performed reverse MR analyses to investigate the causal associations between the genetic susceptibility to oral diseases and micronutrient levels. The results showed that eight oral diseases had causal associations with five micronutrient levels. In summary, this study systematically analyzed the causal associations between multiple oral diseases and micronutrients, revealing the importance of these nutrients in oral disease.\u003c/p\u003e \u003cp\u003eVitamin B9 has a strong biological association with the development of cleft lip and palate. It is essential for embryonic development, especially in the formation and closure of the neural tube [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. A deficiency in vitamin B9 may lead to developmental abnormalities, including cleft lip and palate [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Additionally, research indicates that prenatal supplementation with vitamin B9 can reduce the incidence of cleft lip and palate [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In summary, vitamin B9 has a significant biological role in preventing cleft lip and palate by ensuring normal embryonic development and reducing the risk of these conditions. Regarding the association between vitamin D and the risk of chronic periodontitis, numerous studies have been conducted, but no definitive consensus has been reached. Vitamin D is vital for the absorption of calcium and phosphorus, which are essential for maintaining healthy periodontal bone structure [\u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e]. A deficiency in vitamin D may lead to reduced bone density, increasing the risk of periodontal diseases [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Furthermore, vitamin D possesses immunomodulatory and anti-inflammatory effects, which can mitigate inflammatory responses in the oral cavity, thereby decreasing the severity of periodontitis [\u003cspan additionalcitationids=\"CR50\" citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. Some studies suggest that vitamin D levels are associated with the severity of periodontitis, and a deficiency may increase the risk of developing the disease [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e]. However, the results are inconsistent, with some studies failing to find a direct link between vitamin D levels and the risk of periodontitis [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. Our study supports a protective role of vitamin D in reducing the risk of chronic periodontitis, although additional studies are required to clarify its specific role in periodontitis. As for the relationship between vitamin E and diseases of pulp and periapical tissues, fewer studies have been conducted. Vitamin E can protect cells from oxidative stress, which may help maintain the health of oral tissues, including the gums and surrounding tissues [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e, \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. Vitamin E also promotes cellular regeneration and healing, which may aid in the repair and maintenance of oral tissues [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. Additionally, the anti-inflammatory properties of vitamin E help to reduce inflammatory responses in the oral cavity, potentially influencing the health of pulp and periapical tissues indirectly [\u003cspan additionalcitationids=\"CR59\" citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e]. In summary, these findings provide important information regarding the role of micronutrients in oral diseases.\u003c/p\u003e \u003cp\u003eReverse MR analyses revealed that micronutrients play multifaceted roles in oral diseases. The genetic susceptibility to diseases of pulp and periapical tissues, painful gums, and dental caries was positively associated with increased iron levels. This may be attributed to iron metabolic imbalance, as iron overload can lead to increased oxidative stress by promoting the production of reactive oxygen species (ROS), disrupting the intracellular redox balance [\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. This could exacerbate inflammatory responses and damage in oral tissues, affecting the health of pulp and periapical tissues [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e, \u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e]. Additionally, abnormal iron metabolism can enhance inflammatory reactions within the oral cavity, such as the oxidative stress caused by ferritin autophagy in periodontitis, which may be related to the occurrence of gingival pain and other oral diseases [\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e64\u003c/span\u003e, \u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e]. Furthermore, the genetic susceptibility to mouth ulcers was positively associated with calcium levels. This may be because calcium is involved in maintaining the health of oral mucosa, and changes in calcium levels could affect the integrity and repair capacity of oral mucosa [\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e, \u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. However, this association requires further research for confirmation. The association between vitamin B6 and chronic periodontitis may be related to vitamin B6's role in regulating the immune system and influencing the intensity of inflammatory responses [\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e68\u003c/span\u003e, \u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e69\u003c/span\u003e]. Vitamin B6 serves as a coenzyme for various enzymes involved in the metabolism of carbohydrates, proteins, and fats [\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e70\u003c/span\u003e]. Chronic periodontitis is an inflammatory disease triggered by bacterial infection, and studies have shown that vitamin B6 metabolic pathways are significantly elevated in periodontitis patients [\u003cspan additionalcitationids=\"CR72\" citationid=\"CR71\" class=\"CitationRef\"\u003e71\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR73\" class=\"CitationRef\"\u003e73\u003c/span\u003e]. All in all, these findings provide new insights for nutritional interventions in oral diseases.\u003c/p\u003e \u003cp\u003eIn summary, our study systematically analyzed the causal relationships between various micronutrients and oral diseases, revealing the roles of micronutrients in oral diseases and highlighting their importance in oral health. However, this study also has certain limitations. Firstly, our study population comprised individuals of European ancestry, which restricts the generalizability of our results to other populations. Future studies should include GWAS data from diverse populations and ethnicities to validate these discoveries. Secondly, the sample size of the available GWAS data for the selected oral diseases is limited, necessitating future research with larger GWAS datasets to further confirm these associations. Lastly, although we pioneered a comprehensive analysis of the causal relationships between multiple micronutrients and oral disease risks, additional studies are required to uncover the precise mechanisms through which micronutrients impact the development of oral diseases. Nevertheless, our study provide new perspectives and useful insights into potential strategies for alleviating pathological symptoms in oral disease patients.\u003c/p\u003e"},{"header":"5. Conclusion","content":"\u003cp\u003eOur study systematically analyzed the causal associations between micronutrients and oral diseases. By highlighting the importance of micronutrients in oral health, our research provided valuable references and guidance for the prevention and management of oral diseases. Future research needs to explore the specific mechanisms by which micronutrients influence oral diseases and to validate these findings across different populations, thereby advancing oral health.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare that they have no potential conflicts of interest.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eConsent for publication\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e \u003c/p\u003e\u003cp\u003e \u003ch2\u003eClinical trial number\u003c/h2\u003e \u003cp\u003eNot applicable\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eNone.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eC.Y.L. contributed to the study design. C.Y.L. conducted the literature search. C.Y.L. and W.L. acquired the data. W.L. and C.Y.L. wrote the article. C.Y.L. performed data analysis. W.L. drafted. C.Y.L. and W.L. revised the article and gave the final approval of the version to be submitted. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eNot applicable.\u003c/p\u003e\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e \u003cp\u003eThe data and materials in the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eM.A. Peres, L.M.D. Macpherson, R.J. Weyant, B. Daly, R. Venturelli, M.R. Mathur, S. Listl, R.K. Celeste, C.C. Guarnizo-Herre\u0026ntilde;o, C. Kearns, H. Benzian, P. Allison, R.G. Watt, Oral diseases: a global public health challenge, Lancet (London, England) 394(10194) (2019) 249-260.\u003c/li\u003e\n\u003cli\u003eL. 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Song, Vitamin B6 status, type 2 diabetes mellitus, and periodontitis: evidence from the NHANES database 2009-2010, BMC oral health 25(1) (2025) 299.\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":"Mendelian randomization, Micronutrients, Oral diseases","lastPublishedDoi":"10.21203/rs.3.rs-6332891/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6332891/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003ePrevious studies had shown that multivitamin and mineral deficiencies increase the risk of oral diseases. To this end, we conducted a Mendelian randomization (MR) analysis to assess the causal relationship between micronutrients and oral diseases.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe performed bidirectional MR analyses utilizing publicly available summary statistics from independent European-ancestry cohorts. The study investigated potential causal associations between 15 micronutrients levels and the risk of 13 oral diseases. Five distinct MR methods were employed for analysis, with the inverse variance weighted (IVW) method serving as the primary approach for causal inference. Furthermore, sensitivity analyses were conducted to assess potential horizontal pleiotropy and heterogeneity in the results, demonstrating the robustness of the findings.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eMR analyses revealed significant associations between the levels of 7 micronutrients and the risk of 8 oral diseases. Notably, vitamin B9 demonstrated a protective effect against cleft lip and palate (IVW, OR\u0026thinsp;=\u0026thinsp;0.2584; 95% CI, 0.0919\u0026ndash;0.7267; P\u0026thinsp;=\u0026thinsp;0.0103), vitamin D showed a protective effect against chronic periodontitis (IVW, OR\u0026thinsp;=\u0026thinsp;0.4595; 95% CI, 0.2455\u0026ndash;0.8598; P\u0026thinsp;=\u0026thinsp;0.0150), and vitamin E exhibited a protective effect against pulp and periapical diseases (IVW, OR\u0026thinsp;=\u0026thinsp;0.6927; 95% CI, 0.4801\u0026ndash;0.9993; P\u0026thinsp;=\u0026thinsp;0.0496). Reverse MR analyses indicated causal associations between 8 oral diseases and 5 micronutrient levels. These findings were robust across extensive sensitivity analyses.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur results strongly supported the important role of micronutrients in oral diseases. These findings provided a valuable reference for better management of oral diseases.\u003c/p\u003e","manuscriptTitle":"Causal association between micronutrients and oral diseases: a bidirectional two-sample Mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-09 11:09:46","doi":"10.21203/rs.3.rs-6332891/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":"3041aec1-0ca3-4d2c-86f3-1378015d5fd9","owner":[],"postedDate":"May 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-06-27T06:53:22+00:00","versionOfRecord":[],"versionCreatedAt":"2025-05-09 11:09:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6332891","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6332891","identity":"rs-6332891","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}