Bidirectional Causal Association Between Inflammatory Bowel Disease And Periodontitis:A Two-sample Mendelian Randomization Study

Purpose:Periodontitis(PD)is a chronic multifactorial inflammatory disease that occurs in periodontal tissues,characterized by progressive destruction of tooth supporting tissues including periodontal ligaments and alveolar bone,and its pathogenic factors involve complex dynamic interactions between specific bacterial pathogens,destructive host immune responses,bad habits such as smoking,and environmental factors.Inflammatory bowel disease(IBD)is a class of chronic inflammatory diseases of the gastrointestinal tract.In clinical classification,it is divided into: ulcerative colitis(UC),Crohn’s disease(CD)and unclassified inflammatory bowel disease(IBD-unclassified).The commonly accepted pathogenesis of IBD is the interaction of the susceptible host of the disease with the gut microbiome and abnormal activation of the autoimmune system.Studies in recent years have found that periodontitis is significantly associated with the occurrence and development of IBD in inflammatory bowel disease.Compared with healthy people,IBD patients are significantly more likely to develop periodontitis,their clinical attachment loss is more severe,the average probe depth of periodontal pockets is increased,and the need for periodontal treatment is higher.At present,the causal relationship between the two and the direction of the association are still controversial.This study aims to apply the Mendelian randomization method to genetically perform two-way causal inference of periodontitis and inflammatory bowel disease,including ulcerative colitis and Crohn’s disease,through genetic tools for periodontitis and inflammatory bowel disease.Methods:This study performed a two-sample bidirectional Mendelian randomization(MR)analysis using genetic variables and pooled statistics from genome-wide association studies(GWAS)of inflammatory bowel disease(6376 patients,including 4320 ulcerative colitis,2056 patients with Crohn’s disease,and 210,300 controls)and periodontitis(12,289 patients,and 22,326 controls).Firstly,the antivariance weighted(IVW)method was used to summarize and combine the causal effect estimates of each single nucleotide polymorphism(SNP)as the main statistical results.Then,the results of the IVW method were verified by MR-Egger method,weighted median method,weighted MBE method and other methods.The heterogeneity test is based on the MR-Egger model and IVW model and verified by Q-test,which is visually displayed by funnel chart;The pleiotropy test combined with MR-Egger intercept and outlier method to test quantitative judgment;The sensitivity analysis is based on the one-for-one method and visualized through the forest plot.All statistical analyses used R software,were two-sided tests,with P≤0.05 as the test level,and the main effect measures included Beta,P,Se,odds ratio OR,and 95% confidence intervals(CI)for OR.Results:MR studies showed that genetically determined periodontitis had no causal effect on ulcerative colitis(OR=0.998,95% CI: 0.902-1.104,P=0.97)and Crohn’s disease(OR=0.890,95% CI: 0.77-1.52,P=0.20)in IVW analysis,MR-Egger method,weighted median method,Similar results were obtained by the weighted MBE method(P was greater than 0.05),which proved the stability of the IVW method.In addition,no significant causal effects of ulcerative colitis on periodontitis(OR=0.937,95% CI:0.859-1.022,P=0.14)and Crohn’s disease on periodontitis(OR=1.026,95% CI:0.955-1.102,P=0.48)were also found in reverse MR analysis,and the results of MR-Egger regression,weighted median,and weighted mode methods were consistent with those of the IVW method.Tests for heterogeneity,pleiotropy,and sensitivity analyses showed that instrumental variables were not biased into the results.Conclusions:Although observational studies reported a significant association between periodontitis and inflammatory bowel disease,no bidirectional causal association between periodontitis and inflammatory bowel disease was found.