DataSheet_5_Plasma metabolites as mediators in immune cell-pancreatic cancer risk: insights from Mendelian randomization.docx

BackgroundImmune 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.MethodsThe 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.ResultsOur 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.ConclusionThis 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.

免疫细胞在胰腺癌的发生与发展中扮演着至关重要的角色，然而，由于复杂的免疫微环境和研究结果的不一致性，其因果关系尚不明确。本研究旨在通过孟德尔随机化（MR）方法，揭示免疫细胞与胰腺癌之间的因果关联，并识别潜在的中间因素。方法上，本研究从公共数据库中获取了关于免疫细胞、胰腺癌和血浆代谢物的全基因组关联研究（GWAS）数据。采用逆方差加权（IVW）作为主要分析方法，以探究暴露与结果之间的因果联系。此外，本研究还纳入了MR-Egger、简单模式、加权中位数和加权众数等补充分析方法。为确保结果的可靠性，我们进一步评估了横向多效性和异质性，并利用留一法对MR结果的稳定性进行了评估。总结而言，本研究通过中介分析阐明了血浆代谢物在潜在中介效应中的作用。结果显示，本研究揭示了免疫细胞与胰腺癌之间的因果联系，突出了CD11c+单核细胞（ORIVW=1.105；95%置信区间，95%CI：1.002–1.218；P=0.045）、HLA DR+ CD4+抗原呈递细胞（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（在总效应中的中介效应比例：-11.6%，95%CI：-89.7%，66.6%）和甘露糖与反-4-羟基脯氨酸比值（-19.4，95%CI：-136%，96.8%）在HLA DR+ CD8br T细胞与胰腺癌之间的自然关系中起到了部分中介作用。此外，我们的分析还表明，肾上腺素（-8.39%，95%CI：-18.3%，1.54%）在CD11c+单核细胞与胰腺癌之间的关联中起到部分中介作用，而皮质酮（-26.6%，95%CI：138%，-84.8%）则作为HLA DR+ CD4+抗原呈递细胞与胰腺癌之间的部分中介因子。结论上，本MR研究为免疫细胞与胰腺癌之间的因果关联提供了证据支持，血浆代谢物在其中充当了中介角色。识别出对胰腺癌具有潜在因果效应的免疫细胞表型，有助于揭示其潜在的发病机制，并为进一步治疗靶点的发现提供了新思路。