The causal effect of inflammatory bowel disease on diffuse large B-cell lymphoma: two-sample Mendelian randomization study

BACKGROUND: It has been reported that inflammatory bowel disease (IBD) is associated with an increased risk of malignancies, including lymphoma. A number of large observational studies have been devoted to exploring the causal link between IBD and malignant lymphoma. However, no consensus exists on whether there is a causal relationship between IBD and malignant lymphoma. METHODS: The summary dataset of the IBD and lymphoma genome-wide association studies (GWAS) was obtained from the OPEN GWAS website. Single-nucleotide polymorphisms (SNPs) were selected as genetic instrumental variants (IVs) for fulling P < 5 × 10(-8) and linkage disequilibrium (LD) of r(2) = 0.001 in the IBD GWAS. The proxy SNPs with LD of r(2) > 0.8 were identified. Palindromic SNPs and outlier SNPs were excluded. The assessments of sensitivity employed the Cochran’s Q test, Mendelian randomization (MR)-Egger intercept test, and leave-one-out analysis. RESULTS: The MR analysis results proved the causality of IBD on diffuse large B-cell lymphoma (DLBCL). The risk of developing DLBCL is increased by 28.6% in patients with IBD [odds ratio (OR)(IVW) = 1.286, 95% confidence interval (CI) 1.066–1.552, P = 0.009]. The results of the subgroup analysis showed that Crohn’s disease (OR(IVW) = 1.218, 95% CI 1.030–1.441, P = 0.021) rather than ulcerative colitis (OR(IVW) = 1.206, 95% CI 0.984–1.478, P = 0.072) had a causal effect on DLBCL. No horizontal and directional pleiotropy was observed in the MR studies. CONCLUSIONS: The above MR study concluded that IBD itself is causally responsible for DLBCL, especially Crohn’s disease. Further investigations are needed to elucidate the mechanism underlying this direct causal link.