A Mendelian randomization study of the causal relationships between immune cells and colorectal cancer

Abstract

Background: The incidence of colorectal cancer (CRC) is increasing steadily. This is corroborated by increasing evidence that establishes a connection between the regulation of immunocytes and the advancement of CRC. However, the exact underlying mechanisms remain unclear. Hence, this study aimed to elucidate the link between immune cells and vulnerability to CRC through the application of Mendelian randomization (MR) analysis. Methods Existing genome-wide association studies (GWAS) have provided summary data on immune cells and CRC in European populations. The ebi-a-GCST90018808 cohort was designated the discovery cohort, while the finn-b-C3_COLORECTAL cohort was the validation cohort. Only single nucleotide polymorphisms (SNPs) that satisfied the following conditions were selected as instrumental variables (IVs): a p-value less than 1×10^–5, a linkage disequilibrium coefficient (r2) less than 0.001, and a linkage disequilibrium region width of 10000 kb. The cornerstone analytical methodology used was inverse variance weighting (IVW), which was reinforced by the MR-Egger method to assess the causality of effects. Heterogeneity analysis was performed utilizing I² and Cochran's Q tests. To assess pleiotropy, the MR-Egger method's intercept was utilized, complemented by sensitivity evaluation through a leave-one-out approach. The two datasets were combined for meta-analysis to further validate whether the two immune cell traits were consistent between the two cohorts. Results In the discovery and validation cohorts, a causal association was found between CD25 expression on unswitched memory B cells and CD25⁺⁺ CD45RA^- CD4 not regulatory T cell absolute count, resulting in a decreased risk of CRC. Heterogeneity analysis indicated I² < 50% and P >0.05 according to Cochran's Q test, suggesting no heterogeneity among the IVs. The intercept obtained from the MR‒Egger analysis showed no significant difference from zero, suggesting a negligible influence of horizontal pleiotropy on the IVs. A meta-analysis was conducted to amalgamate the aggregated data from both datasets, further corroborating the influence of the two immune cell traits in mitigating CRC risk. Conclusion The results from MR analysis reveal that CD25 expression on unswitched memory B cells and CD25⁺⁺ CD45RA^- CD4 not regulatory T cell absolute count are intricately associated with a reduced risk of CRC.