A Mendelian Randomization Study Rules Out A Causal Relationship Between Inflammatory Bowel Disease And Colorectal Cancer

Background:Inflammatory bowel disease is a kind of intestinal autoimmune disease characterized by chronic,repeated recurrence,and is divided into two sub-categories:Crohn’s disease and ulcerative colitis.The incidence and prevalence of IBD has shifted over time in different regions of the world.The prevalence of inflammatory bowel disease in many countries exceeds 0.3%,indicating that it has become a global disease.Colorectal cancer is the second common cancer in women and men’s third common cancers,of which nearly 700,000 people die each year.With the gradual colonoscopy screening,the incidence of IBD in developed countries has becamesteady.The risk factors of colorectal cancer include age,eating habits,obesity,lack of physical exercise and smoking.With the gradual colonoscopy screening,the incidence of IBD in developed countries has became steady.The risk factors of colorectal cancer include age,eating habits,obesity,lack of physical exercise and smoking.It was found that the risk of IBD patients suffering from colorectal cancer(CRC)increased.In 2001,Eaden and others conducted the first large-scale meta analysis.the result of CRC risk in IBD patients shows that the CRC risk of 10 years after the diagnosis of UC is 2%,20 years 8%,and 30 years 18%,and the overall CRC prevalence is 3.7%.Most research on the relationship between inflammatory bowel disease and colorectal cancer is observational one,which may be affected by the confunding factors such as eating habits,age,and reverse causal relationships.Becaues of this,a new method exploring causality is needed.Because traditional observation research will be affected by the confunders such as food habits,age,and reverse causal relationships,a new method of exploring causality is needed.Mendellian randomization,using genetic variants,is a good way to estimate the relationships between exposures and outcomes.As the distribution of variants follows the law of Mendel and genetic variants is related to exposure,MR analysis is a natural randomization method,which is not affected by confunders.At the same time,as the accuracy of measuring genetic mutation is high,the measurement errors is also small.Therefore,compared with traditional observation research,Mendellian randomization research is more convincing and reliable.It is widely used in studying causality of diseases.Some MR studies even overthrow our general cognition,just as the MR conclusion that HDL is not a protection of coronary heart disease did.Objective: SNPs related to risk factors in this study is used as a instrumental variants for MR analysis between IBD and CRC,trying to unveil the casual relationship between IBD and colorectal cancer,to provide conclusions of preventing the onset of CRC in IBD patients.Methods:We use two sample Mendellian randomization study to estimate the two-way causal relationship between IBD(including UC and CD)and colorectal cancer.After screening the IEUGWAS database and SNPs,we conducted a variety of MR methods including IVW methods for qualified instrumental variants,and performed sensitive analyses to verify the heterogeneity and pleiotropy of instrumental variants.Result:1.The results of the use of three sets of SNP(CD: 106,UC: 113,IBD: 70)for IVW method MR analysis are not significant(P value: 0.58;CD results: OR [95%CI]:0.99962 [0.9912-1.00012],P value: 0.14;IBD results: or [95%CI]: 0.99959 [0.99869-1.00048],P value: 0.36).The MR-Egger regression,WM method,and MR-RAPS method have all concluded the same conclusion.No heterogeneity and pleiotropy was found in sensitive analysis.2.The same steps are used for bidirectional MR analysis.The results of the IVW method MR analysis are not significant(CD results: or [95%CI]: 1.07985 [0.00049-2372.38304],P value 0.98;UC results: or [95 %CI]: 0.27117 [0.00014-528.3707],P value: 0.74;IBD results: or [95%CI]: 0.47101 [0.0001-2242.94159],P value: 0.86).The MR-Egger regression,WM method,and MR-RAPS method have all concluded the same conclusion.No heterogeneity was found in sensitive analysis.Conclusion:Contrary to the conclusion of observation research,no causal relationship was found between IBD and CRC in two sample MR analysis.Sporadic CRC may be different in pathogenesis from IBD-related CRC.