Genetically predicted Vascular endothelial growth factor A mediates the association between CD3+ CD8+ TD T cell and Colorectal cancer: A Mendelian randomization analysis

Abstract Background: The association between CD3 on Terminally Differentiated CD8+ T cell (CD3+CD8+ TD T cell) and colorectal cancer (CRC) risk remained uncertain. The study aimed to investigate the causal relationship between CD3+CD8+ TD T cell and CRC, as well as to quantify the role of Vascular Endothelial Growth Factor A (VEGF-A) as a potential mediator in this relationship. Methods: The summary statistics dataset for the association of genetic variants with CD3+CD8+ TD T cell was obtained from the published IEU GWAS (N = 2911). The FennGenn consortium datasets R9, which included 293706 participants (6509 cases and 287137 controls), were used to identify genetic variants related to CRC. The odds ratio (OR) with 95% confidence intervals (CIs) of a two-sample Mendelian randomization analysis was used to assess this association. Additionally, a two-step MR analysis was conducted to estimate the proportion of the effect of VEGF-A mediated CD3+CD8+ TD T cell on CRC. Results: The results of IVW indicated that CD3+CD8+ TD T cell was associated with CRC (OR=1.053, 95% CI=1.004–1.104, P=0.032).The Cochran heterogeneity test showed no significant heterogeneity among SNPs of CD3+CD8+ TD T cell ( Q = 14.9807, P=0.7238, I 2 =0.2683), and no considerable pleiotropy was detected for the association of CD3+CD8+ TD T cell with CRC( intercept = 0.015; p = 0.2917)，There was no evidence that genetically predicted CRC had an effect on CD3+CD8+ TD T cell risk (OR=0.943, 95% CI=0.851-1.044,P=0.259). There was evidence that genetically predicted CD3+CD8+ TD T cell had an effect on VEGF-A risk (OR=1.038, 95% CI=1.006-1070,P=0.021) and VEGF-A had an effect on CRC risk (OR=1.09, 95% CI=1.019-1.167,P=0.012).The proportion of genetically predicted CD3+CD8+ TD T cell mediated by VEGF-A was 6.17%. Conclusion: In conclusion, our study identified a causal relationship between CD3+CD8+ TD T cell and CRC, with a small proportion of the effect mediated by VEGF-A, but a majority of the effect remains unclear. Further research is needed on additional risk factors as potential mediators. In clinical practice, more attention should be given to the Tumor immune microenvironment in the biological behavior of colorectal cancer.