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. 2026 Feb 13;105(7):e47590. doi: 10.1097/MD.0000000000047590

Oral health status and esophageal diseases: Univariate and multivariate Mendelian randomization analyses

Ziyuan Xu a,b, Xi Zou a,b, Shenlin Liu a,b,*
PMCID: PMC12908820  PMID: 41686600

Abstract

Emerging evidence suggests a profound connection between oral health status and esophageal diseases. Nevertheless, the causal relationship remains controversial. This Mendelian randomization (MR) study was performed to probe into the genetic causality between oral health status and esophageal diseases. Summary statistics from genome-wide association studies were obtained from the FinnGen project and the UK Biobank consortium. The number of instrumental single nucleotide polymorphisms per trait ranged from approximately 8.97 million to 16.38 million. The analyzed datasets included sample sizes of up to 4,63,010 individuals. Univariable MR analyses were conducted to explore the potential bidirectional causality between oral health status and esophageal diseases. Inverse-variance weighted method was primarily employed. To confirm the reliability of our findings, we conducted sensitivity analyses, including Cochran’s Q test, MR-Egger intercept test, and leave-one-out test. Furthermore, we conducted multivariable MR analysis to adjust for potential confounders. Mouth ulcers were strongly associated with esophageal carcinoma and Barrett’s esophagus. Toothache tended to increase the risk of Barrett’s esophagus. Excessive attrition of teeth was an increased risk for gastro-esophageal reflux. Patients with dental caries exhibited an increased susceptibility to ulcer of esophagus. In reverse, Barrett’s esophagus increased the risk of chronic periodontitis and excessive attrition of teeth. Ulcer of esophagus tended to increase the risk of excessive attrition of teeth. Sensitivity analysis yielded consistent results, indicating no heterogeneity or pleiotropy. This study suggests potential causal associations between oral health status and esophageal diseases.

Keywords: esophageal diseases, genome-wide association studies, inverse-variance weighted, Mendelian randomization, oral health status

1. Introduction

The oral cavity, which serves as the entrance to the digestive system, is essential for the initial processing of food and is a critical determinant of overall health and quality of life.[1] Highly prevalent oral conditions such as dental caries, periodontal disease, and tooth loss impose a substantial burden on individuals and health systems,[2]and can be influenced by factors including diet, hygiene, and substance use.[3]

The esophagus facilitates the transit of food to the stomach, and diseases affecting it – such as gastro-esophageal reflux, Barrett’s esophagus, and esophageal carcinoma – are globally widespread and increasing in prevalence.[4-6] Among these, roughly 10% to 15% of individuals with gastro-esophageal reflux will develop Barrett’s esophagus, which is a precursor to esophageal carcinoma.[7] Esophageal carcinoma is one of the most lethal malignancies around the world. Therefore, early screening for risk factors that may contribute to the development of esophageal diseases is important.

A growing body of evidence underscores a clinically important interplay between oral and esophageal health. Observational studies and meta-analyses have linked poor oral health, including dental caries and tooth loss, with a higher risk of esophageal cancer.[8-10] On the contrary, patients with esophageal diseases are more prone to suffer from tooth loss, possibly triggered by oral dysbiosis.[11,12] Gastro-esophageal reflux was closely associated with a higher incidence of erosive attrition of teeth, periodontal diseases, and dental caries.[13-17]

However, due to the limitations of traditional observational studies, the underlying bidirectional causal interplay between oral health status and esophageal diseases were not elucidated. Mendelian randomization (MR) can minimize confounding factors and reverse causality.[18] As an analytical method that uses genetic variants as instrumental variables, MR is particularly suited to address this question, because it can provide more robust causal evidence by mitigating biases inherent in observational epidemiology. This emerging method can facilitate the establishment of causal inference in the presumed exposure–outcome pathway. Previous MR studies have demonstrated that oral health is causally linked to various diseases, including hypertension, urolithiasis, psychiatric disorders, and nonalcoholic fatty liver disease 19-22. To the best of our knowledge, there is an absence of MR studies specifically delving into the causal connection between oral health status and esophageal diseases. Consequently, whether MR-derived genetic evidence supports a causal role of oral health in esophageal diseases has yet to be investigated.

In this study, based on univariate and multivariate MR approach, we explored the potential causation between oral health status and esophageal diseases. Further, it may provide an indication for primary disease prevention.

2. Methods

2.1. Study design

Figure 1 illustrated the overall design of the study. We performed univariate and multivariate MR analyses to elucidate the bidirectional causal associations between 10 oral health statuses and 5 esophageal diseases. This study fulfilled primary principles of the STROBE-MR statement: the single nucleotide polymorphisms (SNPs) are significantly associated with exposure; the SNPs should be independent of potential confounders; and the direct or indirect links between SNPs and outcome are not available.

Figure 1.

Figure 1.

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The flowchart of this study. Mendelian randomization (MR) analysis should fulfill the 3 primary assumptions: the single nucleotide polymorphisms (SNPs) are significantly associated with exposure; the SNPs should be independent of potential confounders; the direct or indirect links between SNPs and outcome are not available. SNP = single nucleotide polymorphism, MR = Mendelian randomization. The images of oral cavity and esophagus were provided by Servier Medical Art (https://smart.servier.com), licensed under CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/).

All data were obtained from publicly available genome-wide association studies (GWAS) databases; additional ethical approval was not required.

2.2. Data sources

FinnGen project provided the GWAS summary statistics for chronic periodontitis (GWAS ID “finn-b-K11_PERIODON_CHRON”), cysts of oral region (GWAS ID “finn-b-K11_ORALCYST”), excessive attrition of teeth (GWAS ID “finn-b-K11_ATTRITION”), erosion of teeth (GWAS ID “finn-b-K11_EROSION”), dental caries (GWAS ID “finn-b-K11_CARIES”), Barrett’s esophagus (GWAS ID “finn-b-K11_BARRET”) and gastro-esophageal reflux (GWAS ID “finn-b-K11_REFLUX”). Data on painful gums (GWAS ID “ukb-b-11161”), bleeding gums (GWAS ID “ukb-b-7872”), mouth ulcers (GWAS ID “ukb-b-6458”), toothache (GWAS ID “ukb-b-19191”), loose teeth (GWAS ID “ukb-b-12849”), esophageal carcinoma (GWAS ID “ieu-b-4960”), ulcer of esophagus (GWAS ID “ukb-b-13731”) and esophagitis (GWAS ID “ukb-b-19354”) were based on the UK Biobank consortium. All data used in this study were restricted to European populations. Detailed information on the data sources was comprehensively summarized in Table 1. Summary statistics on cigarettes and alcohol intake for used as confounders were extracted from the IEU Open GWAS with ID “ukb-b-20261” and “finn-b-F5_ALCOHOL_DEPENDENCE.”

Table 1.

Details of the GWAS included in the current study.

Exposure or outcome GWAS ID Year Ethnicity Sample size nCases nControl Number of SNPs Consortium
Painful gums ukb-b-11161 2018 European 4,61,113 13,314 4,47,799 98,51,867 MRC-IEU
Bleeding gums ukb-b-7872 2018 European 4,61,113 60,218 4,00,895 98,51,867 MRC-IEU
Mouth ulcers ukb-b-6458 2018 European 4,61,113 47,102 4,14,011 98,51,867 MRC-IEU
Toothache ukb-b-19191 2018 European 4,61,113 18,964 4,42,149 98,51,867 MRC-IEU
Loose teeth ukb-b-12849 2018 European 4,61,113 18,981 4,42,132 98,51,867 MRC-IEU
Chronic periodontitis finn-b-K11_PERIODON_CHRON 2021 European 1,98,441 3046 1,95,395 1,63,80,378 FinnGen
Cysts of oral region finn-b-K11_ORALCYST 2021 European 1,95,999 604 1,95,395 1,63,80,370 FinnGen
Excessive attrition of teeth finn-b-K11_ATTRITION 2021 European 1,95,687 292 1,95,395 1,63,80,370 FinnGen
Erosion of teeth finn-b-K11_EROSION 2021 European 1,95,538 143 1,95,395 1,63,80,370 FinnGen
Dental caries finn-b-K11_CARIES 2021 European 1,99,565 4170 1,95,395 1,63,80,411 FinnGen
Esophageal carcinoma ieu-b-4960 2021 European 3,72,756 740 3,72,016 89,70,465 UK Biobank
Barrett’s esophagus finn-b-K11_BARRET 2021 European 1,90,190 495 1,89,695 1,63,80,373 FinnGen
Ulcer of esophagus ukb-b-13731 2018 European 4,63,010 3251 4,59,759 98,51,867 MRC-IEU
Gastro-esophageal reflux finn-b-K11_REFLUX 2021 European 2,02,836 13,141 1,89,695 1,63,80,425 FinnGen
Esophagitis ukb-b-19354 2018 European 4,63,010 4931 4,58,079 98,51,867 MRC-IEU
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GWAS = genome-wide association studies, MRC-IEU = Medical Research Council Integrative Epidemiology Unit.

2.3. Selection of genetic instrumental variables

The SNPs were identified by the following steps: To enhance statistical efficacy and achieve an adequate number of instrumental variables, SNPs should be robustly associated with exposure factors (P < 5 × 10−6).[22] Linkage disequilibrium analysis were conducted (R2 < 0.001 and clustering distance = 10,000 kb). Pleiotropic SNPs associated with confounders and outcomes were discarded, as revealed by the PhenoScanner website. SNPs with F-statistic > 10 were selected, indicating the bias of weak instrumental variables can be ignored.[23] These steps were designed to satisfy the core MR assumptions: the significance threshold and F-statistic ensure the relevance of instruments; linkage disequilibrium clumping and pleiotropy screening support the independence assumption by minimizing confounder associations.

2.4. Statistical analyses

Univariable MR analyses were conducted to assess the potential bidirectional causality between oral health status and esophageal diseases. Inverse-variance weighted (IVW) method was primarily employed. MR-Egger and weighted median methods were utilized for complementary analyses. In sensitivity analysis, we utilized Cochran’s Q test to assess heterogeneity, MR-Egger intercept test to detect directional pleiotropy, and “leave-one-out test” to investigate results’ robustness. These sensitivity analyses were crucial for examining potential violations of the exclusion restriction assumption. Additionally, we conducted multivariable MR analysis to adjust for potential confounders (cigarette and alcohol intake). A Bonferroni correction was employed to adjust the P-values, thereby addressing the risk of data bias. Statistical analyses were conducted by R package “TwoSampleMR” version 0.6.24 and “MendelianRandomization” version 0.10.0.

3. Results

3.1. Univariable MR for the causal relationship between oral health statuses and esophageal diseases

In this study, we examined the causal relationships between oral health (painful gums, bleeding gums, mouth ulcers, toothache, loose teeth, chronic periodontitis, cysts of oral region, excessive attrition of teeth, erosion of teeth and dental caries) and esophageal diseases (esophageal carcinoma, Barrett’s esophagus, ulcer of esophagus, gastro-esophageal reflux and esophagitis) by analyzing each pair of traits using bidirectional MR. Tables S1 and S2, Supplemental Digital Content, https://links.lww.com/MD/R337 displayed detailed information on selected instrumental variables. In total, 11, 45, 100, 14, 17, 16, 8, 9, 9, and 10 SNPs were employed for MR analyses in painful gums, bleeding gums, mouth ulcers, toothache, loose teeth, chronic periodontitis, cysts of oral region, excessive attrition of teeth, erosion of teeth and dental caries. We screened 13 SNPs linked to esophageal carcinoma, 10 SNPs link to Barrett’s esophagus, 12 SNPs linked to ulcer of esophagus, 29 SNPs linked to gastro-esophageal reflux, and 3 SNPs linked to esophagitis. The F-statistic of the SNPs ranged from 20.86 to 1047.16, suggesting that weak instrument bias was implausible. Tables S3 and S4, Supplemental Digital Content, https://links.lww.com/MD/R337 provided the complete results.

Univariate MR analysis showed that mouth ulcers were negatively associated with esophageal carcinoma (IVW P-value = .009, odds ratio [OR] = 0.994, MR.Egger.Intercept.P = .72) and Barrett’s esophagus (IVW P-value = .043, OR = 0.047, MR.Egger.Intercept.P = .34). On the contrary, toothache tended to increase the risk of Barrett’s esophagus (IVW P-value = .042, OR > 1, MR.Egger.Intercept.P = .69). Excessive attrition of teeth was suggestively associated with an elevated risk of gastro-esophageal reflux (IVW P-value = .046, OR = 1.020, MR.Egger.Intercept.P = .27). Furthermore, patients with dental caries exhibited an increased susceptibility to ulcer of esophagus (IVW P-value = .024, OR = 1.002, MR.Egger.Intercept.P = .47). The IVW results show a direction consistent with those of the other MR methods (Fig. 2, Table S3, Supplemental Digital Content, https://links.lww.com/MD/R337).

Figure 2.

Figure 2.

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Causal effects for oral health status on esophageal diseases. CI = confidence interval, IVW = inverse-variance weighted, MR = Mendelian randomization, OR = odds ratio.

In a reverse MR analysis (Fig. 3, Table S4, Supplemental Digital Content, https://links.lww.com/MD/R337), we uncovered that Barrett’s esophagus tend to increase the risk of chronic periodontitis (IVW P-value = .026, OR = 1.056, MR.Egger.Intercept.P = .46) and excessive attrition of teeth (IVW P-value = .034, OR = 1.187, MR.Egger.Intercept.P = .38). Ulcer of esophagus tended to increase the risk of excessive attrition of teeth (IVW P-value = .050, OR > 1, MR.Egger.Intercept.P = .29). Furthermore, in bidirectional MR analyses, we did not find a significant causal effect of esophageal carcinoma on mouth ulcers, Barrett’s esophagus on mouth ulcers, Barrett’s esophagus on toothache, gastro-esophageal reflux on excessive attrition of teeth, and ulcer of esophagus on dental caries.

Figure 3.

Figure 3.

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Causal effects for esophageal diseases on oral health status. CI = confidence interval, IVW = inverse-variance weighted, MR = Mendelian randomization, OR = odds ratio.

Sensitivity analyses, including the Cochran’s Q test and the MR-Egger intercept test, revealed no significant evidence of heterogeneity or horizontal pleiotropy. This strengthens the validity of our causal inferences by supporting the core MR assumption that genetic instruments primarily influence the outcomes through the exposures of interest (Table 2). Scatter plots also corroborated these results. The distribution of the funnel plots displayed a near symmetry, indicating the absence of directional pleiotropy. The “leave-one-out” method showed little change in the overall error line after removing each SNP (Figs. S1–S7, Supplemental Digital Content, https://links.lww.com/MD/R336). Sensitivity analyses indicated the dependability of the above results.

Table 2.

Results of sensitivity analysis.

Exposure Outcome Cochran Q test MR-Egger
Q Q-Pval Intercept P
Mouth ulcers Esophageal carcinoma 94.48 0.38 0.00 .72
Barrett’s esophagus 79.63 0.82 −0.02 .34
Toothache Barrett’s esophagus 14.59 0.33 0.03 .69
Excessive attrition of teeth gastro-esophageal reflux 7.53 0.48 0.01 .27
Dental caries Ulcer of esophagus 1.76 0.62 0.00 .47
Barrett’s esophagus Chronic periodontitis 4.08 0.91 0.02 .46
Excessive attrition of teeth 9.48 0.39 −0.07 .38
Ulcer of esophagus Excessive attrition of teeth 3.84 0.97 −0.31 .29
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MR = Mendelian randomization.

3.2. Multivariable MR for the causal relationship between oral health statuses and esophageal diseases

Multivariate MR analyses were performed with the adjustment of smoking and alcohol consumption. Several exposures showed significant causal effects after Bonferroni correction. Specifically, mouth ulcers were significantly associated with a reduced risk of esophageal carcinoma (adjusted P = .014, OR = 0.993) and with a reduced risk of Barrett’s esophagus (adjusted P = .027, OR = 0.017). Additionally, excessive attrition of teeth was associated with an increased risk of gastro-esophageal reflux (adjusted P = .007, OR = 1.025). The independent causal estimates from the multivariate MR-Egger method were consistent with those from the multivariate IVW analysis.

In contrast, the following associations were not statistically significant after multiple testing correction: toothache on Barrett’s esophagus, dental caries on ulcer of esophagus, Barrett’s esophagus on chronic periodontitis, Barrett’s esophagus on excessive attrition of teeth, and ulcer of esophagus on excessive attrition of teeth. This suggests that smoking and alcohol consumption may partly mediate the causal effects. The results of the multivariate MR are shown in Table 3.

Table 3.

Multivariable MR analysis adjusted for cigarettes and alcohol intake.

Exposure Outcome MVMR-IVW
OR (95% CI)		 P-value Adjusted P-value (Bonferroni) MVMR-Egger
OR (95% CI)		 P-value Adjusted P-value (Bonferroni)
Mouth ulcers Esophageal carcinoma 0.993 (0.989, 0.998) .005 .014 0.993 (0.989, 0.998) .005 .015
Barrett’s esophagus 0.017 (0.001, 0.359) .009 .027 0.017 (0.001, 0.369) .009 .028
Toothache Barrett’s esophagus 121.333 (0.000, 21,40,02,680.304) .513 1.000 126.108 (0.000, 22,96,20,650.136) .511 1.000
Excessive attrition of teeth gastro-esophageal reflux 1.025 (1.009, 1.042) .002 .007 1.025 (1.009, 1.042) .003 .008
Dental caries Ulcer of esophagus 1.001 (1.000, 1.002) .027 .082 1.001 (1.000, 1.002) .034 .103
Barrett’s esophagus Chronic periodontitis 0.992 (0.951, 1.035) .711 1.000 0.994 (0.953, 1.036) .765 1.000
Excessive attrition of teeth 1.161 (1.015, 1.329) .029 .088 1.162 (1.015, 1.330) .030 .089
Ulcer of esophagus Excessive attrition of teeth 32,29,875.518 (0.000, 5,30,63,42,91,99,97,73,00,00,00,00,00,00,00,000.000) .613 1.000 12,40,969.935 (0.000, 2,41,21,82,89,95,26,24,00,00,00,00,00,00,00,000.000) .637 1.000
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CI = confidence interval, IVW = inverse-variance weighted, MVMR = multivariable Mendelian randomization, OR = odds ratio.

4. Discussion

In this study, utilizing publicly available GWAS summary statistics, we conducted univariable and multivariable MR analyses to elucidate the potential causal association between 10 oral diseases and 5 esophageal diseases. In this study, a suggestive causal relationship was observed between mouth ulcers and esophageal carcinoma, mouth ulcers and Barrett’s esophagus, toothache and Barrett’s esophagus, excessive attrition of teeth and gastro-esophageal reflux, dental caries and ulcer of esophagus, Barrett’s esophagus and chronic periodontitis, Barrett’s esophagus and excessive attrition of teeth, and ulcer of esophagus and excessive attrition of teeth.

Poor oral health can significantly impact an individual’s quality of life. Toothache is prevalent within the general population, with a considerable occurrence rate. It can be categorized into dentinal pain, pulpal pain, periodontal pain and atypical odontalgia.[24] Many endogenous and exogenous factors can cause bleeding gums, including periodontal diseases and Von Willebrand disease.[25] Mouth ulcers have self-limiting properties and recurrence, presenting as inflammation and pain.[26] From the aspects of etiology, mouth ulcers can stem from traumatic, infectious, or allergic factors, as well as autoimmune conditions and tumors.[27] Periodontitis is the inflammatory disorder triggered by dental plaque accumulation. It manifests as the gradual deterioration of the periodontal ligament and alveolar bone.[28] Cysts of oral region can be categorized as odontogenic cysts, non-odontogenic cysts and pseudocysts.[29] Tooth wear, characterized by the irreversible loss of enamel and dentin, can be divided into erosion, attrition and abrasion.[30] Tooth wear can result in functional or aesthetic impairments as well as pain. Dental caries arises from a complicated interplay between acid-producing bacteria, saliva, food, and teeth.[31]

Esophageal disease is garnering increasing concern as an important clinical problem. Esophagitis encompasses various types, including reflux esophagitis, eosinophilic esophagitis, lymphocytic esophagitis, sloughing esophagitis, pill esophagitis, and infectious esophagitis.[32] Gastro-esophageal reflux is identified as the nonphysiological aspiration of contents from the gastrointestinal tract. It can stem from various mechanisms, such as gastric composition and motility, impaired mucosal integrity, and symptom perception.[33,34] Barrett’s esophagus, a precursor to esophageal carcinoma, is defined by intestinal metaplasia in the distal esophagus.[35] Esophageal carcinoma ranks as the sixth leading fatal cancer globally. It comprises 2 primary subtypes: oesophageal squamous cell carcinoma (OSCC) and esophageal adenocarcinoma.[36] Risk factors for esophageal carcinoma include socioeconomic disadvantage, tobacco and alcohol consumption, intake of hot beverages and nitrosamines, and obesity.[37]

Earlier studies have variably yielded a bidirectional association between oral health status and esophageal diseases, but the connection was still tenuous for several reasons. Our MR study detected mouth ulcers was protective factors for esophageal carcinoma and Barrett’s esophagus. A nationwide nested case-control study indicated that oral cavity disease does not cause OSCC.[38] As indicated by a single-center study, tooth wear is often accompanied by oligosymptomatic gastro-esophageal reflux, which is in consistent with our results.[39] Hence, it is essential to consider the patient’s oral health status when preventing and treating associated esophageal diseases. In addition, we found a risk effect of Barrett’s esophagus on chronic periodontitis and excessive attrition of teeth. Similarly, in 57% of patients with Barrett’s esophagus, high levels of Campylobacter species, which were linked to periodontitis, were detected.[40] Our MR findings failed to indicate any link between periodontitis and gastro-esophageal reflux. Likewise, an observational study also yielded no evidence supporting their association.[41] Our observation corresponds to the outcomes of previous studies. Tobacco and alcohol consumption can have adverse effects on both oral and esophageal health.[42,43] After adjusting for smoking and alcohol consumption, the effects of mouth ulcers on esophageal carcinoma, excessive attrition of teeth on gastro-esophageal reflux, and dental caries on ulcer of esophagus remained significant.

Research has identified 3 mechanisms linking oral conditions with systemic disease: metastatic spread of infection via transient bacteremia, metastatic injury from circulating oral microbial toxins, and metastatic inflammation due to immunological injury induced by oral microorganisms.[44] These operate through direct pathways – such as systemic inflammatory responses, cytokine leakage, and endothelial invasion by pathogens – and indirect pathways involving common risk factors.[45] The inflammatory cascade begins when periodontitis produces mediators like IL-1, IL-6, and TNF-α, which enter systemic circulation once oral mucosal receptors are saturated. Key pathogens like Porphyromonas gingivalis, along with Treponema denticola and Tannerella forsythia, can enter the bloodstream during routine activities, carrying endotoxins such as lipopolysaccharides to distant organs.[46,47] The chronic systemic distribution of oral bacterial products alters immunity by subverting host defenses or prolonging inflammation, activating monocytes and vascular inflammation while priming immune cells at oral sites to exert detrimental effects distantly.[48] Inflammatory mediators including TNF-α and IL1β promote local recruitment and can trigger immune responses in distant tissues via hematogenous dissemination.[49,50]

Building upon these mechanisms, the oral-esophageal connection exemplifies how localized oral pathologies may influence specific organ systems. Several mechanisms have been proposed to elucidate the link between oral health status and esophageal diseases. First, oral microbiome patterns can be intricately associated with esophageal diseases.[51] Microbiota in the oral cavity and esophagus interact and swap nutrients to optimize their physiology and metabolism.[52] Bacteria can create extracellular matrix that products biofilm in our digestive system, which is mostly pathogenic in nature.[53] Second, oral inflammation entails the involvement of various immune cells and cytokines, which also play a role in esophageal diseases.[54,55] Third, patients with esophageal disorders could exhibit alterations in certain saliva parameters, such as pH levels, hemoglobin and buffering capacity.[56-58]

The present study had 3 strengths. First, as far as we know, this is the first comprehensive MR study to investigate the genetic causal relationship between oral health status and esophageal diseases. Second, sensitivity analyses validate the reliability of our results. Multivariable MR analyses were conducted to evaluate and adjust for potential confounders. Third, data sources primarily originated from multiple aggregated databases, minimizing the potential for sample overlap.

However, our study also has some limitations. First, as the GWAS datasets exclusively comprised individuals of European ancestry, caution is warranted when generalizing the results to other ethnicities. Second, due to the unavailability of information for individual histological subtypes, it is impossible to analyze the subtypes of esophageal diseases, such as esophageal adenocarcinoma and OSCC. Third, MR research can only provide a preliminary insight into the potential causality, the biological pathogenic mechanisms remain elusive and require further investigation. Moreover, we note that marginal effect magnitudes are a common feature of such analyses, stemming from the polygenic architecture of complex disorders and the liability threshold model. Statistically, even small effects (e.g., OR ≈ 1.01–1.02) can achieve significance in large-scale studies and remain valid for causal inference.[59-62] Indeed, estimates of this magnitude are primarily intended to shed light on potential causal mechanisms rather than to directly inform clinical risk stratification.[63] This distinction is important given the methodological context: MR demonstrates greater reliability in confirming the causality and its direction than in providing precise estimates of the effect magnitude, as accurately measuring effect size typically depends on additional evidence from cohort studies or clinical trials.[64] Therefore, a conservative interpretation is warranted, emphasizing the need to distinguish statistical significance from clinical or biological relevance, which typically demands independent validation. This will be the focus of our subsequent work.

5. Conclusion

In conclusion, based on the univariate and multivariate MR analyses, we initially identified bidirectional causality between oral health status and esophageal diseases. Future work is warranted to confirm these causal relationships, decipher the underlying mechanisms, and uncover therapeutic potential for oral health status and esophageal diseases. Specifically, further clinical and epidemiological studies are needed to replicate these findings in diverse populations across different ethnicities and geographic regions, which will help assess the generalizability and robustness of the observed associations. Additionally, functional validation studies are essential to elucidate the precise biological pathways linking oral conditions to esophageal pathophysiology. Ultimately, these efforts may guide the development of targeted preventive strategies and facilitate the translation of oral health interventions into clinical practice for esophageal disease management.

Author contributions

Conceptualization: Ziyuan Xu, Xi Zou, Shenlin Liu.

Data curation: Ziyuan Xu.

Formal analysis: Ziyuan Xu.

Funding acquisition: Shenlin Liu.

Writing – original draft: Ziyuan Xu.

Writing – review & editing: Xi Zou, Shenlin Liu.

Supplementary Material

medi-105-e47590-s001.xlsx (351.2KB, xlsx)

Abbreviations:

GWAS
genome-wide association studies
IVW
inverse variance-weighted
MR
Mendelian randomization
OR
odds ratio
OSCC
oesophageal squamous cell carcinoma
SNP
single nucleotide polymorphism

This work was supported by the Jiangsu University Advantage Discipline Construction Project (035062005006-05), State Administration of Chinese Medicine Project (20085-9-1), Project initiated by researchers from Jiangsu Province Hospital of Chinese Medicine (ZDXYS202208-1), Jiangsu Province Hospital of Chinese Medicine Peak Academic Talent Project (y2021rc19), Jiangsu Provincial Health and Medical Committee Key Projects (ZD2022070), Science and Technology Project of Affiliated Hospital of Nanjing University of Chinese Medicine (Y2020CX62), State Administration of Chinese Medicine Project (20085-9-3), Jiangsu Provincial Science and Technology Department Project (BE2019771).

Ethical approval was not required for the studies involving humans because our research relied on summary statistics from previously published studies, and no additional ethical approval or informed permission was required. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements because our research relied on summary statistics from previously published studies, and no additional ethical approval or informed permission was required.

The authors have no conflicts of interest to disclose.

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Supplemental Digital Content is available for this article.

How to cite this article: Xu Z, Zou X, Liu S. Oral health status and esophageal diseases: Univariate and multivariate Mendelian randomization analyses. Medicine 2026;105:7(e47590).

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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