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

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关键词：免疫表型；脑脊液（CSF）代谢介质；乳腺癌（BC）；孟德尔随机化；肿瘤模拟

中图分类号：R737.9；R392.3 文献标志码：A

DOI：10.7652/jdyxb202504011

ABSTRACT： 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 playa part in mediating this.MethodsWe used MR to assessthe genetic associations between immune cels and BC risk and their posible mediators.Genetic statistics for immune cels 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 cros-thnic meta-analysis. We performed atwo-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’sQ 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+ （204号 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= O.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（ Δβ=-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+ （20 CD4+ Tcells may reduce the risk of BC development by modulating the level of methylsuccinylcarnitine，the CSF metabolite.

KEY WORDS： immunophenotype；cerebrospinal fluid （CSF） metabolism mediator； breast cancer（BC）;Mendelian randomization（MR）；tumor mimicry

乳腺癌（breastcancer，BC）是女性发病率最高的恶性肿瘤之一，发病率仅次于肺癌。（剩余17588字）