To unveil the causal relationship between immunophenotypes and colorectal cancer using two-sample bidirectional Mendelian randomization and mediation analyses

Colorectal cancer (CRC) is a leading cause of cancer-related death worldwide. The mechanisms underlying this trend are not yet fully understood. This study aimed to examine the potential role of genetically predicted immunophenotypes in the development of CRC. A two-sample bidirectional Mendelian randomization study was conducted to explore the relationship between 731 genetically predicted immune cells and CRC. Furthermore, a two-step Mendelian randomization approach was employed to assess the possible mediating effect of immune cells on CRC. The inverse-variance weighted method identified 5 immunophenotypes as significantly inversely associated with CRC risk: the odds ratios for CRC risk associated with activated CD4 regulatory T cells (%CD4 regulatory T cells), CD25++ CD45RA- CD4 nonregulatory T cells (%CD4 + T cells), CD25++ CD45RA- CD4 nonregulatory T cells (%T cells), CD25++ CD8 + T cells (%T cells), and CD64 + CD16 + monocytes were 0.925 (95% CI = 0.874–0.978, P = 6.516 × 10 −3 ), 0.935 (95% CI = 0.878–0.995, P = .035), 0.936 (95% CI = 0.889–0.985, P = .011), 0.863 (95% CI = 0.786–0.948, P = 2.142 × 10 −3 ), and 0.636 (95% CI = 0.519–0.778, P = 1.18 × 10 −5 ), respectively. The mediation analysis indicated that the absolute count of CD25++ CD8 + T cells led to a 33.9% decrease in the risk associated with the percentage of activated CD4 regulatory T cells within CD4 regulatory T cells and CRC. Our analysis revealed that 5 immunophenotypes may be risk factors for CRC. Since other complementary methods have yielded inconsistent results, however, further investigation is necessary.