作为免疫细胞-胰腺癌风险介质的血浆代谢物:孟德尔随机化的启示

Ke Zhang, Jie Zhu, Peng Wang, Yuan Chen, Zhengwang Wang, Xinyu Ge, Junqing Wu, Long Chen, Yipin Lu, Peng Xu, Jie Yao
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引用次数: 0

摘要

免疫细胞在胰腺癌的发生和发展过程中起着至关重要的作用,但由于复杂的免疫微环境和相互矛盾的研究结果,其因果关系仍不确定。关于免疫细胞、胰腺癌和血浆代谢物的全基因组关联研究(GWAS)数据来自公共数据库。在这项研究中,反方差加权(IVW)是研究暴露与结果之间因果关系的主要分析方法。此外,本研究还采用了 MR-Egger、简单模式、加权中位数和加权模式作为辅助分析方法。为确保研究结果的可靠性,我们还进一步评估了水平多向性和异质性,并使用留一法(Leave-one-out method)评估了 MR 结果的稳定性。总之,本研究采用了中介分析来阐明血浆代谢物的潜在中介效应。我们的调查揭示了免疫细胞与胰腺癌之间的因果关系,突出了 CD11c+ 单核细胞的关键作用(几率比,ORIVW=1.105;95%置信区间,95%CI:1.002-1.218;P=0.045)、HLA DR+ CD4+抗原递呈细胞(ORIVW=0.920;95%CI:0.873-0.968;P=0.001)和HLA DR+ CD8br T细胞(ORIVW=1.058;95%CI:1.002-1.117;P=0.041)在胰腺癌进展中的关键作用。进一步的中介分析表明,草酸盐(中介效应占总效应的比例:-11.6%,95%CI:-89.7%,66.6%)和甘露糖与反式-4-羟脯氨酸的比率(-19.4,95%CI:-136%,96.8%)部分中介了 HLA DR+ CD8br T 细胞与胰腺癌之间的关系。此外,我们的分析表明,肾上腺素(-8.39%,95% CI:-18.3%,1.54%)在 CD11c+ 单核细胞与胰腺癌的关系中起部分中介作用,而可的松(-26.6%,95% CI:138%,-84.8%)在 HLA DR+ CD4+ AC 与胰腺癌的关系中起部分中介作用。确定对胰腺癌具有潜在因果效应的免疫细胞表型有助于了解胰腺癌的潜在机制,并提出新的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Plasma metabolites as mediators in immune cell-pancreatic cancer risk: insights from Mendelian randomization
Immune cells play a crucial role in the development and progression of pancreatic cancer, yet the causal relationship remains uncertain due to complex immune microenvironments and conflicting research findings. Mendelian randomization (MR), this study aims to delineate the causal relationships between immune cells and pancreatic cancer while identifying intermediary factors.The genome-wide association study (GWAS) data on immune cells, pancreatic cancer, and plasma metabolites are derived from public databases. In this investigation, inverse variance weighting (IVW) as the primary analytical approach to investigate the causal relationship between exposure and outcome. Furthermore, this study incorporates MR-Egger, simple mode, weighted median, and weighted mode as supplementary analytical approaches. To ensure the reliability of our findings, we further assessed horizontal pleiotropy and heterogeneity and evaluated the stability of MR results using the Leave-one-out method. In conclusion, this study employed mediation analysis to elucidate the potential mediating effects of plasma metabolites.Our investigation revealed a causal relationship between immune cells and pancreatic cancer, highlighting the pivotal roles of CD11c+ monocytes (odds ratio, ORIVW=1.105; 95% confidence interval, 95%CI: 1.002–1.218; P=0.045), HLA DR+ CD4+ antigen-presenting cells (ORIVW=0.920; 95%CI: 0.873–0.968; P=0.001), and HLA DR+ CD8br T cells (ORIVW=1.058; 95%CI: 1.002–1.117; P=0.041) in pancreatic cancer progression. Further mediation analysis indicated that oxalate (proportion of mediation effect in total effect: -11.6%, 95% CI: -89.7%, 66.6%) and the mannose to trans-4-hydroxyproline ratio (-19.4, 95% CI: -136%, 96.8%) partially mediate the relationship between HLA DR+ CD8br T cells and pancreatic cancer in nature. In addition, our analysis indicates that adrenate (-8.39%, 95% CI: -18.3%, 1.54%) plays a partial mediating role in the association between CD11c+ monocyte and pancreatic cancer, while cortisone (-26.6%, 95% CI: 138%, -84.8%) acts as a partial mediator between HLA DR+ CD4+ AC and pancreatic cancer.This MR investigation provides evidence supporting the causal relationship between immune cell and pancreatic cancer, with plasma metabolites serving as mediators. Identifying immune cell phenotypes with potential causal effects on pancreatic cancer sheds light on its underlying mechanisms and suggests novel therapeutic targets.
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