A mendelian randomization study with populations of European ancestry rules out a causal relationship between inflammatory bowel disease and colorectal cancer

Abstract

Background: Ulcerative colitis (UC), a subtype of inflammatory bowel disease (IBD), has been found to be associated with colorectal cancer (CRC) in observational studies, but there is no evidence to support a causal relationship or reverse causality between the two diseases.Methods: We employed two-sample bidirectional Mendelian randomization to estimate an unconfounded bidirectional causal relationship between IBD (including UC and Crohn’s disease (CD)) and colorectal cancer. After searching IEU GWAS database and filtering SNPs, we applied a variety of MR methods including IVW method using qualified instrumental variables, and conducted sensitivity analysis to detect the heterogeneity and pleiotropy of instrumental variables.Results: After using three groups of SNPs (CD: 106, UC: 113, IBD: 70), the IVW method MR analysis showed that the results were not significant (result for UC: odds ratio (OR) [95% Confidence Interval (CI)]: 0.9998 [0.9991–1.0005], p value: 0.58; result for CD: OR [95%CI]: 0.99962 [0.99912–1.00012], p value: 0.14; results for IBD: OR [95%CI]: 0.99959 [0.99869–1.00048], p value: 0.36). MR-Egger regression, WM method and MR-RAPS method reached the same conclusion. Sensitivity analysis did not reveal heterogeneity and pleiotropy. Bidirectional MR analysis was performed using the same procedure, and the results of IVW MR analysis were also not significant (result for CD: OR [95%CI]: 1.07985 [0.00049–2372.38304], p value 0.98; result for UC: OR [95%CI]: 0.27117 [0.00014–528.3707], p value: 0.74; result for IBD: OR [95%CI]: 0.47101 [0.0001–2242.94159], p value: 0.86). MR-Egger regression, WM method and MR-RAPS method also reached the same conclusion. Sensitivity analysis did not find any evidence of heterogeneity and pleiotropy.Conclusion: Contrary to the conclusions of previous observational studies, a two-sample MR analysis did not find a causal relationship or reverse causal relationship between IBD and CRC. Sporadic CRC (sCRC) may differ in pathogenesis from IBD-related CRC.

Association of inflammatory bowel disease in first‐degree relatives with risk of colorectal cancer: A nationwide case‐control study in Sweden

“…In a recent mendelian randomization study applying 289 instrumental SNPs of IBD, no significant relationship between the SNPs and CRC was found. 34 This finding is consistent with our study, supporting that IBD and CRC share no horizontal pleiotropy. Therefore, our current study, which had a much better power, represents a timely revisit to this research question by comprehensively assessing the association between family history of IBD…”

“…Given the high heritability of IBD, 33 mendelian randomization design provides another good approach to detect pleiotropy between IBD and CRC. In a recent mendelian randomization study applying 289 instrumental SNPs of IBD, no significant relationship between the SNPs and CRC was found 34 . This finding is consistent with our study, supporting that IBD and CRC share no horizontal pleiotropy.…”

Unraveling the mystery: a Mendelian randomized exploration of gut microbiota and different types of obesity

“…MR-PRESSO was utilized to detect and eliminate SNPs with levels of horizontal pleiotropy outliers. MR-Steiger analysis was conducted on all SNPs to verify the direction of causal estimates, and SNPs with erroneous directions were removed according to the method described by ( Li et al., 2022 ). Subsequently, a Bonferroni correction ( P <0.05/n, where n represents the number of remaining SNPs) was applied to remove SNPs directly correlated with outcomes.…”

Exploring the intestinal ecosystem: from gut microbiota to associations with subtypes of inflammatory bowel disease

“…We applied the MR-PRESSO test to identify and exclude outlier SNPs due to horizontal pleiotropy. To satisfy the exclusion assumption, we employed MR-Steiger analysis to determine the causal direction of all SNPs and removed SNPs with incorrect directions ( Li F. et al., 2022 ). Finally, we employed Bonferroni correction (P<0.05/n, where n represents the number of remaining SNPs) to remove SNPs directly associated with outcomes.…”