免疫细胞与乳腺癌风险的因果关系及脑脊液代谢物的中介机制:基于孟德尔随机化的研究

Objective Mendelian randomization (MR) analysis was used to explore the genetic link between immunophenotype and breast cancer (BC) risk and how cerebrospinal fluid (CSF) metabolites play a part in mediating this. Methods We used MR to assess the genetic associations between immune cells and BC risk and their possible mediators. Genetic statistics for immune cells and CSF metabolites were obtained from the Genome-Wide Association Study (GWAS) catalog, whereas those for BC were obtained from the Japan Biobank, the UK Biobank, and FinnGen's cross-ethnic meta-analysis. We performed a two-sample MR analysis using inverse variance weighting (IVW) to investigate the genetic association between immunoepidemiology and BC. We also analyzed CSF metabolites as mediators between them. Heterogeneity was tested using the Cochran's Q statistic, horizontal pleiotropy was tested using the MR Egger intercept, and sensitivity analysis was performed using the "leave-one-out" method. Results MR analysis by the IVW method showed that HLA DR⁺ CD4⁺ T cells were associated with a reduced risk of BC (OR =0.972, 95% CI:0.955-0.990, P = 0.003), and there was a negative genetic association between HLA DR⁺ CD4⁺ T cells and methylsuccinimidyl carnitine level (OR=0.922, 95% CI :0.861 - 0.986, P = 0.018), but there was a positive genetic association between the latter and BC risk (OR = 1.029, 95% CI: 1.012 - 1.047, P<0.001). Mediation analysis showed that the direct effect remained significant after correction for CSF methylsuccinylcarnitine level (β=-0.026, SE = 0.008, P = 0.002). And the indirect effect (β=-0.002, Delta Method SE = 0.001) suggested that this CSF metabolite might mediate 8.36% of the association in the protective effect of immune cells against BC risk (95% CI: -12.4% -29.1%). Conclusion Genetically predicted HLA DR⁺ CD4⁺ T cells may reduce the risk of BC development by modulating the level of methylsuccinylcarnitine, the CSF metabolite.