The Effect of obesity on dental caries: A mendelian randomization study

The Effect of obesity on dental caries: A 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 Article The Effect of obesity on dental caries: A mendelian randomization study Li Tan, Mei Wang, Qiong Liu, Yun Chen, Ya-Qiong Zhao, Jie Zhao, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4739550/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 10 You are reading this latest preprint version Abstract Background Clinical and retrospective studies suggest obesity increases the risk of dental caries, but causal mechanisms remain unclear. We employed the Mendelian randomization (MR) method to explore obesity's potential causal link to dental caries. Methods We extracted body mass index (BMI) and waist circumference (WC) data from the IEU OpenGWAS project database. These data were used to identify single-nucleotide polymorphisms (SNPs) associated with obesity as instrumental variables. Additionally, dental caries data were extracted from the same database. Using the R package ‘TwoSampleMR’, we conducted inverse-variance weighted (IVW) analyses and various sensitivity analyses to assess the impact of obesity on dental caries. Results The IVW analysis indicated that every 1-SD increase in BMI was associated with a higher incidence of dental caries (odds ratio [OR] = 1.286; 95% confidence interval [CI] = 1.122–1.474; P = 2.94E-04), as was every 1-SD increase in WC (OR = 1.242; 95% CI = 1.032–1.496; P = 2.20E-02). These findings were consistent across additional MR sensitivity analyses. Conclusion Our results provide evidence of a probable causal relationship between genetic susceptibility to obesity and an increased risk of dental caries. Therefore, individuals with obesity should take preventive measures to reduce the risk of dental caries. Health sciences/Medical research Health sciences/Risk factors Health sciences/Diseases/Dental diseases/Dental caries Health sciences/Diseases/Endocrine system and metabolic diseases/Obesity Mendelian randomization Obesity Dental caries Figures Figure 1 Figure 2 Introduction Dental caries is a common chronic infectious disease that primarily affects the hard tissues of the teeth [ 1 ] . According to a recent report published in The Lancet, dental caries is one of the most prevalent diseases globally, ranking 11th in terms of prevalence among all diseases [ 2 ] . Both genetic and environmental factors influence the development and occurrence of dental caries, although these relationships have not been fully elucidated [ 3 , 4 ] . Moreover, dental caries and its complications can lead to or exacerbate systemic diseases that significantly diminish quality of life [ 5 ] . Therefore, understanding the causes of dental caries is essential, as they impose a considerable burden on public health and the economy [ 6 , 7 ] . Obesity is increasingly prevalent in modern societies, significantly impacting people’s quality of life and strongly correlating with various diseases, such as cardiovascular issues and type 2 diabetes mellitus [ 8 , 9 ] . The role of obesity as a risk factor for dental caries continues to be debated. Some observational studies have linked obesity to a notably higher risk of dental caries [ 10–12 ] , while contradictory results have been reported in other investigations [ 13 , 14 ] . Nearly all of the aforementioned findings about the linkage between obesity and dental caries rely on traditional observational studies, which may suffer from inherent limitations like reverse causality and residual confounding [ 15 , 16 ] . These studies often fail to account for lifestyle and dietary habits, which can influence both obesity and dental caries incidence, potentially leading to residual confounding [ 17–19 ] . To address these limitations, we utilized Mendelian randomization (MR) analysis to investigate the potential causal relationship between obesity and the risk of dental caries. Mendelian randomization leverages genetic variants as instrumental variables [ 20 ] , circumventing biases inherent in traditional observational studies such as reverse causality and residual confounding. By randomly allocating genotypes before conception, this approach simulates natural randomized controlled study conditions [ 21 ] . Within this study, we retrieved single-nucleotide polymorphisms (SNPs) associated with obesity traits—body mass index (BMI) and waist circumference (WC)—from the IEU OpenGWAS project database to serve as instrumental variables. Additionally, dental caries outcomes were extracted from the same database. Subsequently, using the R package ‘TwoSampleMR’, we conducted inverse-variance weighted (IVW) and several sensitivity analyses to investigate the impact of obesity on dental caries. Methods The STROBE-MR checklist of recommended items to address in reports of MR studies was followed in our study [ 22 ] . Instrumental variable selection Our study design, illustrated in Figure 1, adheres to Mendel’s randomized design principles [ 23 ] . As Figure 1 depicted, a valid Instrumental variable (IV) has to satisfy three assumptions: (1) Relevance: It must be associated with the exposure (commonly referred to as the relevancy assumption); (2) Independence: It should remain unaffected by measurable or unmeasurable confounding factors (the independence assumption); and (3) Exclusion Restriction: It can only influence the outcome through the exposure (the exclusion restriction assumption) [ 24 ] . Our IV selection will be described below and meet the above three assumptions. Regarding the exposures, we used summary statistics on the relationships between SNPs and BMI from the MRC Integrative Epidemiology Unit (MRC-IEU) of GWAS in European populations (https://gwas.mrcieu.ac.uk/datasets/ukb-b-19953/), which included a total sample size of 461,460. Subsequently, summary-level data on the relationships between SNPs and WC from GWAS conducted by the Neale Lab (NL) in European populations, involving a sample size of 336,639, were also employed. Finally, to satisfy the relevance assumption, SNPs meeting the genome-wide significant criteria ( P 10,000 kb by configuring the clump data function in the TwoSampleMR package, and constructed the R 2 of linkage disequilibrium (LD) relationship between genes <0.001, avoiding potential bias brought on by LD relationship between SNPs. GWAS summary statistics data for dental caries were acquired from MRC-IEU (https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_CARIES/) about the outcomes, and the results of these are summarized by the p values, standard errors (SE), and values. The analyses that produced the public information utilized in this study were restricted to demographic data from the European population, and Table 1 provides a summary of these topics. To further verify the relevance assumption, we computed the F statistic of BMC and WC (Supplementary Table S1, S2) by all SNPs. The 457 SNPs for BMC had a minimum F statistic of 29.8, and the 230 SNPs for WC had a minimum F statistic of 29.8, which both satisfied the commonly cited rule of thumb that F > 10 avoids bias in IV analysis is misleading [ 25 ] . Mendelian randomization analysis In this study, the primary analysis method was inverse variance weighted (IVW). Additionally, the MR Egger, the Simple mode, the Weighted mode, and the Median Weighted were employed as Supplementary Methods. Under the assumption that all instrumental factors were effective, the IVW principle used each instrumental variable's reciprocal variance as a weight in weighted computations. As a result, all instrumental variable effect values were weighted according to the variance where estimates with larger SE were weighted less in the IVW estimate. The TwoSampleMR package was used to carry out the analysis mentioned above. Sensitivity analysis To satisfy the independence assumption and exclusion restriction assumption, a sensitivity analysis was conducted [ 26 , 27 ] . In the beginning, using Cochran's Q test and the I2 statistic, we performed a heterogeneity test for the SNPs that were thought to be traits of obesity. In cases where the test findings indicated that there was heterogeneity, we next used the MR-PRESSO package to detect the outlier SNPs [ 27 ] . After that, the horizontal pleiotropy of the instrumental variables was determined using the MR-Egger method [ 28 ] . If the intercept term's p-value in the regression equation is greater than 0.05, there is no evidence of horizontal pleiotropy. Similar to this, we carried out a leave-one-out analysis using the TwoSampleMR package to confirm the stability of the analysis results [ 29 ] . The TwoSampleMR package also produced the forest plot and funnel plot. The statistical power analysis We calculated the statistical power using the mRnd website (https://shiny.cnsgenomics.com/mRnd/) [ 30 ] . First, we computed the R2 of BMC and WC (Supplementary Table S1, S2) by using the formula as in previous studies [ 31 ] . Then, the sample size =199,565 (Total population in the GWAS data of dental caries), α = 0.05 (Type-I error rate), K = 0.021 (Proportion of cases in the GWAS data of dental caries), OR (BMI = 1.286, WC =1.242), total R2 (BMI = 0.063, WC =0.037) were input to the power analysis of binary outcome in this website. According to the calculated results of the website, we found the statistical power to determine the causal relationship of BMI and WC to dental caries were 1 and 0.84 (The statistical power > 0.8 meant the study had sufficient power as the previous study presented [ 31 ] ) which suggest the result of our study is reliable. Ethical approval The GWAS summary data that were used in this analysis were taken from published publications whose pertinent research has been approved by institutional review boards. Results Effect of obesity on dental caries SNP of obesity features, comprising a total of 457 SNPs of BMI and 230 SNPs of WC, were selected as instrumental factors after reviewing the GERD GWAS summary statistics (Supplementary Table S1, S2). Following mendelian randomization analysis with the TwoSampleMR package, IVW outcomes revealed that every 1-SD increase in BMI (odds ratio, OR = 1.286; 95% confidence interval [CI] = 1.122-1.474; p = 2.94E-04) and WC (OR = 1.242; 95% CI = 1.032-1.496; p = 2.20E-02 ) were substantially linked to a greater incidence of dental caries. Additionally, practically all studies revealed consistent connections between BMI, WC, and dental caries, although the magnitudes of these associations varied among different analyses (Figure 2 and Table 2). The total effect of BMI and WC on dental caries was not significantly changed by any one SNP, according to stability analysis using the leave-one-out method (Supplementary Figures S1, S2). This demonstrated the consistency of our research. Additionally, the forest plots and funnel plots demonstrated that there was no discernible variability among the chosen SNPs for the instrumental variable (Supplementary Figures S3, S4, S5, S6). A heterogeneity analysis was then conducted, and the results revealed no significant heterogeneity between BMI and dental caries (MR Egger p = 0.438, IVW p = 0.434) (Supplementary Table S3). At the same time, there was also no powerful heterogeneity between WC and dental caries (MR Egger p = 0.978, IVW p = 0.976) (Supplementary Table S4). The egger-intercept and MR-PRESSO analysis both showed that nor was there any horizontal pleiotropy between BMI and dental caries (egger-intercept P = 0.312, Global Test p = 0.350) (Supplementary Tables S5). At the same time, there was also no horizontal pleiotropy between WC and dental caries (egger-intercept P = 0.479, Global Test p = 0.976) (Supplementary Tables S6). Discussion Numerous studies have suggested that Obesity may be one of the factors contributing to an increased risk of dental caries [ 10 , 32-35 ] . For instance, a cross-sectional study conducted in China revealed that obese individuals were three times more inclined to suffer dental caries than non-obese ones [ 10 ] . Similarly, a systematic review reported an increased risk of dental caries among obese individuals [ 34 ] . However, other studies have shown conflicting results, suggesting either no association or even a negative effect of obesity on the risk of dental caries [ 13 , 36-38 ] . The discrepancy in the aforementioned research findings likely arises from their reliance on observational or cross-sectional studies. These types of studies face inherent limitations in establishing a definitive causal relationship between obesity and dental caries, as they are unable to control for initial risk factors related to dental caries at the design stage. Such factors include behavioral and psychological factors, biological, sociodemographic, and cultural factors [ 39-41 ] . Moreover, recent research has suggested that genetic factors may also contribute significantly to the development of dental caries [ 42 ] . Therefore, to overcome the constraints in observational or cross-sectional studies, and to deeply comprehend the genetic factors that contribute to the progression of dental caries which will facilitate the dissection of etiology and support theoretical advancements in clinical intervention strategies. We utilized the MR analysis to investigate whether obesity could increase the risk of dental caries. Mendel's second law is utilized by Mendelian randomization analysis, which views gene variants as instrumental variables [ 20 ] . It is possible to circumvent biases of traditional research methods such as observational studies sometimes including reverse causality and residual confounding by randomly allocating genotypes before conception, which simulates natural, randomized, controlled study circumstances [ 21 ] . In this study, we selected BMI and WC as exposures, commonly used as surrogate measures for obesity [ 43 , 44 ] . Then, to explore the causal relationship between obesity and dental caries, we employed the ‘TwosampleMR’ method. As IVW outcomes revealed that every 1-SD increase in BMI (odds ratio, OR = 1.286; 95% confidence interval [CI] = 1.122-1.474; P = 2.94E-04) and WC (OR = 1.242; 95% CI = 1.032-1.496; P = 2.20E-02) were substantially linked to a higher incidence of dental caries. Therefore, our findings suggest a positive association between obesity and increased risk of dental caries in the European population. Sensitivity analyses confirmed the robustness and reliability of these results. Our research still has many limitations. Firstly, it is restricted to European populations, making its applicability to other racial groups uncertain. Secondly, there is a possibility that we have not accounted for all instrumental variables linked to potential confounding factors, which may violate the basic assumptions of MR analysis. Finally, the risk of dental caries is determined by both genetic and environmental factors [ 45 , 46 ] , and our findings partially address only the genetic influence of obesity on dental caries. Conclusion In conclusion, our study is the first MR analysis to evaluate the causal effect of obesity on dental caries. Moreover, given that obesity contributes to dental caries at the genetic level, it is necessary to take oral prevention and intervention measures for obese individuals to prevent the occurrence of dental caries. Declarations Ethical approval The GWAS summary data that were used in this analysis were taken from published publications whose pertinent research has been approved by institutional review boards. Competing interests The authors assert that they are uninterested in engaging in competing. Funding This research did not receive funding from any agency. Author Contribution L.T. and M.W. were in charge of task management and research conception. Q.L., Y.C., and Y.-Q.Z. were in charge of choosing the research topics and gathering the data. Y.F., Q.Y., J.H., Z.-Y.O.-Y., D.-M.A. and J.Z. conducted the statistical analyses. Y.G. and Y.-Z.F. supervised the project. Each author contributed to the analysis and writing of the manuscript. 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Supplementary Files STROBEMR.docx SupplementaryFiguresS1leaveoneoutplotofBMIdentalcaries.pdf SupplementaryFiguresS2leaveoneoutplotofWCdentalcaries.pdf SupplementaryFiguresS3funnelplotsofBMIdentalcaries.pdf SupplementaryFiguresS4funnelplotsofWCdentalcaries.pdf SupplementaryFiguresS5forestplotsofBMIdentalcaries.pdf SupplementaryFiguresS6forestplotsofWCdentalcaries.pdf SupplementaryTableS1230SNPswereselectedasinstrumentalvariablesofwaistcircumferenceCARIES.csv SupplementaryTableS2458SNPswereselectedasinstrumentalvariablesofBMIdentalcaries2.csv SupplementaryTableS3heterogeneityofBMIdentalcaries.csv SupplementaryTableS4heterogeneityofWCdentalcaries.csv SupplementaryTableS5horizontalpleiotropyofBMIdentalcaries.csv SupplementaryTableS6horizontalpleiotropyofWCdentalcaries.csv.csv Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 18 Sep, 2024 Reviews received at journal 17 Sep, 2024 Reviews received at journal 09 Sep, 2024 Reviewers agreed at journal 09 Sep, 2024 Reviewers agreed at journal 07 Sep, 2024 Reviewers invited by journal 07 Sep, 2024 Editor assigned by journal 01 Sep, 2024 Editor invited by journal 06 Aug, 2024 Submission checks completed at journal 05 Aug, 2024 First submitted to journal 14 Jul, 2024 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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University","correspondingAuthor":false,"prefix":"","firstName":"Yun-Zhi","middleName":"","lastName":"Feng","suffix":""}],"badges":[],"createdAt":"2024-07-14 18:29:04","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4739550/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4739550/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63616949,"identity":"70abf7ba-8e38-40a0-b574-0fe85b204a7c","added_by":"auto","created_at":"2024-08-30 08:07:53","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":32449,"visible":true,"origin":"","legend":"\u003cp\u003eCausal diagram of Mendelian randomization in whether obesity could affect dental caries.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4739550/v1/a016cb5f68baf6713780caf7.jpg"},{"id":63616942,"identity":"5eb31ba3-0ce7-4515-86f4-86657ba5b7a7","added_by":"auto","created_at":"2024-08-30 08:07:52","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":104653,"visible":true,"origin":"","legend":"\u003cp\u003eScatterplot of the effect size for each SNP on obesity (BMI\u0026amp;WC) and the risk of dental caries.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4739550/v1/e2ac1e64fdad6ca9d097283a.jpg"},{"id":63617958,"identity":"8e070f0a-7728-4fe7-8c64-44e008e065df","added_by":"auto","created_at":"2024-08-30 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08:15:52","extension":"csv","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":258,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS5horizontalpleiotropyofBMIdentalcaries.csv","url":"https://assets-eu.researchsquare.com/files/rs-4739550/v1/29763183b795a7d06f5879fa.csv"},{"id":63617388,"identity":"af726fc9-2261-40c6-88ea-ce7c658fb6bc","added_by":"auto","created_at":"2024-08-30 08:15:53","extension":"csv","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":252,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTableS6horizontalpleiotropyofWCdentalcaries.csv.csv","url":"https://assets-eu.researchsquare.com/files/rs-4739550/v1/c79fc424702c120668fe1dcb.csv"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Effect of obesity on dental caries: A mendelian randomization study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDental caries is a common chronic infectious disease that primarily affects the hard tissues of the teeth \u003csup\u003e[\u003c/sup\u003e1\u003csup\u003e]\u003c/sup\u003e. According to a recent report published in The Lancet, dental caries is one of the most prevalent diseases globally, ranking 11th in terms of prevalence among all diseases \u003csup\u003e[\u003c/sup\u003e2\u003csup\u003e]\u003c/sup\u003e. Both genetic and environmental factors influence the development and occurrence of dental caries, although these relationships have not been fully elucidated \u003csup\u003e[\u003c/sup\u003e3\u003csup\u003e,\u003c/sup\u003e 4\u003csup\u003e]\u003c/sup\u003e. Moreover, dental caries and its complications can lead to or exacerbate systemic diseases that significantly diminish quality of life \u003csup\u003e[\u003c/sup\u003e5\u003csup\u003e]\u003c/sup\u003e. Therefore, understanding the causes of dental caries is essential, as they impose a considerable burden on public health and the economy \u003csup\u003e[\u003c/sup\u003e6\u003csup\u003e,\u003c/sup\u003e 7\u003csup\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eObesity is increasingly prevalent in modern societies, significantly impacting people\u0026rsquo;s quality of life and strongly correlating with various diseases, such as cardiovascular issues and type 2 diabetes mellitus \u003csup\u003e[\u003c/sup\u003e8\u003csup\u003e,\u003c/sup\u003e 9\u003csup\u003e]\u003c/sup\u003e. The role of obesity as a risk factor for dental caries continues to be debated. Some observational studies have linked obesity to a notably higher risk of dental caries \u003csup\u003e[\u003c/sup\u003e10\u0026ndash;12\u003csup\u003e]\u003c/sup\u003e, while contradictory results have been reported in other investigations \u003csup\u003e[\u003c/sup\u003e13\u003csup\u003e,\u003c/sup\u003e 14\u003csup\u003e]\u003c/sup\u003e. Nearly all of the aforementioned findings about the linkage between obesity and dental caries rely on traditional observational studies, which may suffer from inherent limitations like reverse causality and residual confounding \u003csup\u003e[\u003c/sup\u003e15\u003csup\u003e,\u003c/sup\u003e 16\u003csup\u003e]\u003c/sup\u003e. These studies often fail to account for lifestyle and dietary habits, which can influence both obesity and dental caries incidence, potentially leading to residual confounding \u003csup\u003e[\u003c/sup\u003e17\u0026ndash;19\u003csup\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTo address these limitations, we utilized Mendelian randomization (MR) analysis to investigate the potential causal relationship between obesity and the risk of dental caries. Mendelian randomization leverages genetic variants as instrumental variables \u003csup\u003e[\u003c/sup\u003e20\u003csup\u003e]\u003c/sup\u003e, circumventing biases inherent in traditional observational studies such as reverse causality and residual confounding. By randomly allocating genotypes before conception, this approach simulates natural randomized controlled study conditions \u003csup\u003e[\u003c/sup\u003e21\u003csup\u003e]\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eWithin this study, we retrieved single-nucleotide polymorphisms (SNPs) associated with obesity traits\u0026mdash;body mass index (BMI) and waist circumference (WC)\u0026mdash;from the IEU OpenGWAS project database to serve as instrumental variables. Additionally, dental caries outcomes were extracted from the same database. Subsequently, using the R package \u0026lsquo;TwoSampleMR\u0026rsquo;, we conducted inverse-variance weighted (IVW) and several sensitivity analyses to investigate the impact of obesity on dental caries.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe STROBE-MR checklist of recommended items to address in reports of MR studies was followed in our study\u003csup\u003e[\u003c/sup\u003e22\u003csup\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInstrumental variable selection \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur study design, illustrated in Figure 1, adheres to Mendel’s randomized design principles \u003csup\u003e[\u003c/sup\u003e23\u003csup\u003e]\u003c/sup\u003e. As Figure 1 depicted, a valid Instrumental variable (IV) has to satisfy three assumptions: (1) Relevance: It must be associated with the exposure (commonly referred to as the relevancy assumption); (2) Independence: It should remain unaffected by measurable or unmeasurable confounding factors (the independence assumption); and (3) Exclusion Restriction: It can only influence the outcome through the exposure (the exclusion restriction assumption) \u003csup\u003e[\u003c/sup\u003e24\u003csup\u003e]\u003c/sup\u003e. Our IV selection will be described below and meet the above three assumptions.\u003c/p\u003e\n\u003cp\u003eRegarding the exposures, we used summary statistics on the relationships between SNPs and BMI from the MRC Integrative Epidemiology Unit (MRC-IEU) of GWAS in European populations (https://gwas.mrcieu.ac.uk/datasets/ukb-b-19953/), which included a total sample size of 461,460. Subsequently, summary-level data on the relationships between SNPs and WC from GWAS conducted by the Neale Lab (NL) in European populations, involving a sample size of 336,639, were also employed. Finally, to satisfy the relevance assumption, SNPs meeting the genome-wide significant criteria (\u003cem\u003eP\u003c/em\u003e\u0026lt; 5 × 10\u003csup\u003e−8\u003c/sup\u003e) were selected for this investigation \u003csup\u003e[\u003c/sup\u003e24\u003csup\u003e]\u003c/sup\u003e. Additionally, we determined the physical distance among SNPs \u0026gt;10,000 kb by configuring the clump data function in the TwoSampleMR package, and constructed the R\u003csup\u003e2 \u003c/sup\u003eof linkage disequilibrium (LD) relationship between genes \u0026lt;0.001, avoiding potential bias brought on by LD relationship between SNPs.\u003c/p\u003e\n\u003cp\u003eGWAS summary statistics data for dental caries were acquired from MRC-IEU (https://gwas.mrcieu.ac.uk/datasets/finn-b-K11_CARIES/) about the outcomes, and the results of these are summarized by the p values, standard errors (SE), and values. The analyses that produced the public information utilized in this study were restricted to demographic data from the European population, and Table 1 provides a summary of these topics.\u003c/p\u003e\n\u003cp\u003eTo further verify the relevance assumption, we computed the F statistic of BMC and WC (Supplementary Table S1, S2) by all SNPs. The 457 SNPs for BMC had a minimum F statistic of 29.8, and the 230 SNPs for WC had a minimum F statistic of 29.8, which both satisfied the commonly cited rule of thumb that F \u0026gt; 10 avoids bias in IV analysis is misleading \u003csup\u003e[\u003c/sup\u003e25\u003csup\u003e]\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMendelian randomization analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study, the primary analysis method was inverse variance weighted (IVW). Additionally, the MR Egger, the Simple mode, the Weighted mode, and the Median Weighted were employed as Supplementary Methods. Under the assumption that all instrumental factors were effective, the IVW principle used each instrumental variable's reciprocal variance as a weight in weighted computations. As a result, all instrumental variable effect values were weighted according to the variance where estimates with larger SE were weighted less in the IVW estimate. The TwoSampleMR package was used to carry out the analysis mentioned above.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo satisfy the independence assumption and exclusion restriction assumption, a sensitivity analysis was conducted \u003csup\u003e[\u003c/sup\u003e26\u003csup\u003e, \u003c/sup\u003e27\u003csup\u003e]\u003c/sup\u003e. In the beginning, using Cochran's Q test and the I2 statistic, we performed a heterogeneity test for the SNPs that were thought to be traits of obesity. In cases where the test findings indicated that there was heterogeneity, we next used the MR-PRESSO package to detect the outlier SNPs \u003csup\u003e[\u003c/sup\u003e27\u003csup\u003e]\u003c/sup\u003e. After that, the horizontal pleiotropy of the instrumental variables was determined using the MR-Egger method \u003csup\u003e[\u003c/sup\u003e28\u003csup\u003e]\u003c/sup\u003e. If the intercept term's p-value in the regression equation is greater than 0.05, there is no evidence of horizontal pleiotropy. Similar to this, we carried out a leave-one-out analysis using the TwoSampleMR package to confirm the stability of the analysis results \u003csup\u003e[\u003c/sup\u003e29\u003csup\u003e]\u003c/sup\u003e. The TwoSampleMR package also produced the forest plot and funnel plot.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe statistical power analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe calculated the statistical power using the mRnd website (https://shiny.cnsgenomics.com/mRnd/) \u003csup\u003e[\u003c/sup\u003e30\u003csup\u003e]\u003c/sup\u003e. First, we computed the R2 of BMC and WC (Supplementary Table S1, S2) by using the formula as in previous studies \u003csup\u003e[\u003c/sup\u003e31\u003csup\u003e]\u003c/sup\u003e. Then, the sample size =199,565 (Total population in the GWAS data of dental caries), α = 0.05 (Type-I error rate), K = 0.021 (Proportion of cases in the GWAS data of dental caries), OR (BMI = 1.286, WC =1.242), total R2 (BMI = 0.063, WC =0.037) were input to the power analysis of binary outcome in this website. According to the calculated results of the website, we found the statistical power to determine the causal relationship of BMI and WC to dental caries were 1 and 0.84 (The statistical power \u0026gt; 0.8 meant the study had sufficient power as the previous study presented \u003csup\u003e[\u003c/sup\u003e31\u003csup\u003e]\u003c/sup\u003e) which suggest the result of our study is reliable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe GWAS summary data that were used in this analysis were taken from published publications whose pertinent research has been approved by institutional review boards.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eEffect of obesity on dental caries\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSNP of obesity features, comprising a total of 457 SNPs of BMI and 230 SNPs of WC, were selected as instrumental factors after reviewing the GERD GWAS summary statistics (Supplementary Table S1, S2). Following mendelian randomization analysis with the TwoSampleMR package, IVW outcomes revealed that every 1-SD increase in BMI (odds ratio, OR = 1.286; 95% confidence interval [CI] = 1.122-1.474; p = 2.94E-04) and WC (OR = 1.242; 95% CI = 1.032-1.496; p = 2.20E-02 ) were substantially linked to a greater incidence of dental caries. Additionally, practically all studies revealed consistent connections between BMI, WC, and dental caries, although the magnitudes of these associations varied among different analyses (Figure 2 and Table 2).\u003c/p\u003e\n\u003cp\u003eThe total effect of BMI and WC on dental caries was not significantly changed by any one SNP, according to stability analysis using the leave-one-out method (Supplementary Figures S1, S2). This demonstrated the consistency of our research. Additionally, the forest plots and funnel plots demonstrated that there was no discernible variability among the chosen SNPs for the instrumental variable (Supplementary Figures S3, S4, S5, S6). A heterogeneity analysis was then conducted, and the results revealed no significant heterogeneity between BMI and dental caries (MR Egger p = 0.438, IVW p = 0.434) (Supplementary Table S3). At the same time, there was also no powerful heterogeneity between WC and dental caries (MR Egger p = 0.978, IVW p = 0.976) (Supplementary Table S4). The egger-intercept and MR-PRESSO analysis both showed that nor was there any horizontal pleiotropy between BMI and dental caries (egger-intercept P = 0.312, Global Test p = 0.350) (Supplementary Tables S5). At the same time, there was also no horizontal pleiotropy between WC and dental caries (egger-intercept P = 0.479, Global Test p = 0.976) (Supplementary Tables S6).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eNumerous studies have suggested that Obesity may be one of the factors contributing to an increased risk of dental caries \u003csup\u003e[\u003c/sup\u003e10\u003csup\u003e, \u003c/sup\u003e32-35\u003csup\u003e]\u003c/sup\u003e. For instance, a cross-sectional study conducted in China revealed that obese individuals were three times more inclined to suffer dental caries than non-obese ones \u003csup\u003e[\u003c/sup\u003e10\u003csup\u003e]\u003c/sup\u003e. Similarly, a systematic review reported an increased risk of dental caries among obese individuals \u003csup\u003e[\u003c/sup\u003e34\u003csup\u003e]\u003c/sup\u003e. However, other studies have shown conflicting results, suggesting either no association or even a negative effect of obesity on the risk of dental caries \u003csup\u003e[\u003c/sup\u003e13\u003csup\u003e, \u003c/sup\u003e36-38\u003csup\u003e]\u003c/sup\u003e. \u003c/p\u003e\n\u003cp\u003eThe discrepancy in the aforementioned research findings likely arises from their reliance on observational or cross-sectional studies. These types of studies face inherent limitations in establishing a definitive causal relationship between obesity and dental caries, as they are unable to control for initial risk factors related to dental caries at the design stage. Such factors include behavioral and psychological factors, biological, sociodemographic, and cultural factors \u003csup\u003e[\u003c/sup\u003e39-41\u003csup\u003e]\u003c/sup\u003e. Moreover, recent research has suggested that genetic factors may also contribute significantly to the development of dental caries\u003csup\u003e[\u003c/sup\u003e42\u003csup\u003e]\u003c/sup\u003e. \u003c/p\u003e\n\u003cp\u003eTherefore, to overcome the constraints in observational or cross-sectional studies, and to deeply comprehend the genetic factors that contribute to the progression of dental caries which will facilitate the dissection of etiology and support theoretical advancements in clinical intervention strategies.\u003c/p\u003e\n\u003cp\u003eWe utilized the MR analysis to investigate whether obesity could increase the risk of dental caries. Mendel\u0026apos;s second law is utilized by Mendelian randomization analysis, which views gene variants as instrumental variables \u003csup\u003e[\u003c/sup\u003e20\u003csup\u003e]\u003c/sup\u003e. It is possible to circumvent biases of traditional research methods such as observational studies sometimes including reverse causality and residual confounding by randomly allocating genotypes before conception, which simulates natural, randomized, controlled study circumstances \u003csup\u003e[\u003c/sup\u003e21\u003csup\u003e]\u003c/sup\u003e. In this study, we selected BMI and WC as exposures, commonly used as surrogate measures for obesity \u003csup\u003e[\u003c/sup\u003e43\u003csup\u003e, \u003c/sup\u003e44\u003csup\u003e]\u003c/sup\u003e. Then, to explore the causal relationship between obesity and dental caries, we employed the \u0026lsquo;TwosampleMR\u0026rsquo; method. As IVW outcomes revealed that every 1-SD increase in BMI (odds ratio, OR = 1.286; 95% confidence interval [CI] = 1.122-1.474; \u003cem\u003eP \u003c/em\u003e= 2.94E-04) and WC (OR = 1.242; 95% CI = 1.032-1.496; \u003cem\u003eP\u003c/em\u003e = 2.20E-02) were substantially linked to a higher incidence of dental caries. Therefore, our findings suggest a positive association between obesity and increased risk of dental caries in the European population. Sensitivity analyses confirmed the robustness and reliability of these results. \u003c/p\u003e\n\u003cp\u003eOur research still has many limitations. Firstly, it is restricted to European populations, making its applicability to other racial groups uncertain. Secondly, there is a possibility that we have not accounted for all instrumental variables linked to potential confounding factors, which may violate the basic assumptions of MR analysis. Finally, the risk of dental caries is determined by both genetic and environmental factors \u003csup\u003e[\u003c/sup\u003e45\u003csup\u003e, \u003c/sup\u003e46\u003csup\u003e]\u003c/sup\u003e, and our findings partially address only the genetic influence of obesity on dental caries.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn conclusion, our study is the first MR analysis to evaluate the causal effect of obesity on dental caries. Moreover, given that obesity contributes to dental caries at the genetic level, it is necessary to take oral prevention and intervention measures for obese individuals to prevent the occurrence of dental caries.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthical approval\u003c/h2\u003e \u003cp\u003eThe GWAS summary data that were used in this analysis were taken from published publications whose pertinent research has been approved by institutional review boards.\u003c/p\u003e \u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors assert that they are uninterested in engaging in competing.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis research did not receive funding from any agency.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eL.T. and M.W. were in charge of task management and research conception. Q.L., Y.C., and Y.-Q.Z. were in charge of choosing the research topics and gathering the data. Y.F., Q.Y., J.H., Z.-Y.O.-Y., D.-M.A. and J.Z. conducted the statistical analyses. Y.G. and Y.-Z.F. supervised the project. Each author contributed to the analysis and writing of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgments\u003c/h2\u003e \u003cp\u003eNA\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eThis article has all the data created or analyzed during this investigation.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCheng L, Zhang L, Yue L, Ling J, Fan M, Yang D, et al. Expert consensus on dental caries management. Int J Oral Sci 2022; 14: 17.\u003c/li\u003e\n\u003cli\u003eGlobal, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. 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Association between BMI and Dental Caries among School Children and Adolescents in Jiangsu Province, China. Biomed Environ Sci 2017; 30: 758-761.\u003c/li\u003e\n\u003cli\u003eKopycka-Kedzierawski DT, Auinger P, Billings RJ, Weitzman M. Caries status and overweight in 2- to 18-year-old US children: findings from national surveys. Community Dent Oral Epidemiol 2008; 36: 157-167.\u003c/li\u003e\n\u003cli\u003eAlves LS, Susin C, Dam\u0026eacute;-Teixeira N, Maltz M. Overweight and obesity are not associated with dental caries among 12-year-old South Brazilian schoolchildren. Community Dent Oral Epidemiol 2013; 41: 224-231.\u003c/li\u003e\n\u003cli\u003eda Silva RA, Barreiros D, Oliveira S, da Silva LA, Nelson-Filho P, K\u0026uuml;chler EC. Association Between Body Mass Index and Caries Experience in Brazilian Children and Adolescents. J Dent Child (Chic) 2016; 83: 146-151.\u003c/li\u003e\n\u003cli\u003eRodriguez JL, Thakkar-Samtani M, Heaton LJ, Tranby EP, Tiwari T. Caries risk and social determinants of health: A big data report. J Am Dent Assoc 2022.\u003c/li\u003e\n\u003cli\u003eNakano R, Ohshima T, Mukai Y, Tsurumoto A, Maeda N. Association Between Dental Caries Prevalence and Stress Levels in Japanese Children. Cureus 2022; 14: e31074.\u003c/li\u003e\n\u003cli\u003eDo LG, Song YH, Du M, Spencer AJ, Ha DH. Socioecological determinants of child oral health-A scoping review. Community Dent Oral Epidemiol 2022.\u003c/li\u003e\n\u003cli\u003eBretz WA, Corby PM, Schork NJ, Robinson MT, Coelho M, Costa S, et al. Longitudinal analysis of heritability for dental caries traits. J Dent Res 2005; 84: 1047-1051.\u003c/li\u003e\n\u003cli\u003eBoden BP, Ahmed AE, Fine KM, Craven MJ, Deuster PA. Baseline Aerobic Fitness in High School and College Football Players: Critical for Prescribing Safe Exercise Regimens. Sports Health 2022; 14: 490-499.\u003c/li\u003e\n\u003cli\u003eLow NY, Chan CY, Subramaniam S, Chin KY, Ima Nirwana S, Muhammad N, et al. Comparing the performance of body mass index, waist circumference and waist-to-height ratio in predicting Malaysians with excess adiposity. Ann Hum Biol 2022: 1-6.\u003c/li\u003e\n\u003cli\u003eGiacaman RA, Fern\u0026aacute;ndez CE, Mu\u0026ntilde;oz-Sandoval C, Le\u0026oacute;n S, Garc\u0026iacute;a-Manr\u0026iacute;quez N, Echeverr\u0026iacute;a C, et al. Understanding dental caries as a non-communicable and behavioral disease: Management implications. Front Oral Health 2022; 3: 764479.\u003c/li\u003e\n\u003cli\u003eKnapp R, Marshman Z, Gilchrist F, Vettore M, Rodd H. Clinical, individual and environmental factors related to children\u0026apos;s health-related quality of life following treatment under general anaesthetic for dental caries: a path analysis. Eur Arch Paediatr Dent 2022; 23: 399-408.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Mendelian randomization, Obesity, Dental caries","lastPublishedDoi":"10.21203/rs.3.rs-4739550/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4739550/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eClinical and retrospective studies suggest obesity increases the risk of dental caries, but causal mechanisms remain unclear. We employed the Mendelian randomization (MR) method to explore obesity's potential causal link to dental caries.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe extracted body mass index (BMI) and waist circumference (WC) data from the IEU OpenGWAS project database. These data were used to identify single-nucleotide polymorphisms (SNPs) associated with obesity as instrumental variables. Additionally, dental caries data were extracted from the same database. Using the R package \u0026lsquo;TwoSampleMR\u0026rsquo;, we conducted inverse-variance weighted (IVW) analyses and various sensitivity analyses to assess the impact of obesity on dental caries.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe IVW analysis indicated that every 1-SD increase in BMI was associated with a higher incidence of dental caries (odds ratio [OR]\u0026thinsp;=\u0026thinsp;1.286; 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;1.122\u0026ndash;1.474; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.94E-04), as was every 1-SD increase in WC (OR\u0026thinsp;=\u0026thinsp;1.242; 95% CI\u0026thinsp;=\u0026thinsp;1.032\u0026ndash;1.496; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.20E-02). These findings were consistent across additional MR sensitivity analyses.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eOur results provide evidence of a probable causal relationship between genetic susceptibility to obesity and an increased risk of dental caries. Therefore, individuals with obesity should take preventive measures to reduce the risk of dental caries.\u003c/p\u003e","manuscriptTitle":"The Effect of obesity on dental caries: A mendelian randomization study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-30 08:07:47","doi":"10.21203/rs.3.rs-4739550/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2024-09-18T08:55:05+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-17T14:46:38+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-09-09T16:53:54+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"120459552851617498814185956233392109041","date":"2024-09-09T16:21:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"292388078804009629458876257416960202445","date":"2024-09-07T14:13:23+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-09-07T09:58:05+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-09-01T07:35:47+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2024-08-06T12:37:38+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-08-05T06:58:05+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2024-07-14T18:27:12+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c41159e7-a341-46a3-aa02-acda3b7e26bd","owner":[],"postedDate":"August 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":36743105,"name":"Health sciences/Medical research"},{"id":36743106,"name":"Health sciences/Risk factors"},{"id":36743107,"name":"Health sciences/Diseases/Dental diseases/Dental caries"},{"id":36743108,"name":"Health sciences/Diseases/Endocrine system and metabolic diseases/Obesity"}],"tags":[],"updatedAt":"2024-10-03T07:38:42+00:00","versionOfRecord":[],"versionCreatedAt":"2024-08-30 08:07:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4739550","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4739550","identity":"rs-4739550","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}