Genetically predicted blood metabolites mediate the association between circulating immune cells and pancreatic cancer: A Mendelian randomization study

IF 3.2 4区医学 Q2 BIOTECHNOLOGY & APPLIED MICROBIOLOGY Journal of Gene Medicine Pub Date : 2024-05-16 DOI:10.1002/jgm.3691

Guo Zhao, Yuanting Cai, Yuning Wang, Yuan Fang, Shuhang Wang, Ning Li

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Abstract

Background

Pancreatic cancer is characterized by metabolic dysregulation and unique immunological profiles. Nevertheless, the comprehensive understanding of immune and metabolic dysregulation of pancreatic cancer remains unclear. In the present study, we aimed to investigate the causal relationship of circulating immune cells and pancreatic cancer and identify the blood metabolites as potential mediators.

Methods

The exposure and outcome genome-wide association studies (GWAS) data used in the present study were obtained from the GWAS open-access database (https://gwas.mrcieu.ac.uk). The study used 731 circulating immune cell features, 1400 types of blood metabolites and pancreatic cancer from GWAS. We then performed bidirectional Mendelian randomization (MR) analyses to explore the causal relationships between the circulating immune cells and pancreatic cancer, and two-step MR to discover potential mediating blood metabolites in this process. All statistical analyses were performed in R software. The STROBE-MR (i.e. Strengthening the Reporting of Observational Studies in Epidemiology using Mendelian Randomization) checklist for the reporting of MR studies was also used.

Results

MR analysis identified seven types of circulating immune cells causally associated with pancreatic cancer. Furthermore, there was no strong evidence that genetically predicted pancreatic cancer had an effect on these seven types of circulating immune cells. Further two-step MR analysis found 10 types of blood metabolites were causally associated with pancreatic cancer and the associations between circulating CD39⁺CD8⁺ T cells and pancreatic cancer were mediated by blood orotates with proportions of 5.18% (p = 0.016).

Conclusions

The present study provides evidence supporting the causal relationships between various circulating immune cells, especially CD39⁺CD8⁺ T cells, and pancreatic cancer, with a potential effect mediated by blood orotates. Further research is needed on additional risk factors as potential mediators and establish a comprehensive immunity-metabolism network in pancreatic cancer.

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基因预测的血液代谢物介导了循环免疫细胞与胰腺癌之间的关联：孟德尔随机化研究

背景胰腺癌的特点是代谢失调和独特的免疫学特征。然而，对胰腺癌的免疫和代谢失调的全面了解仍不清楚。本研究旨在探讨循环免疫细胞与胰腺癌的因果关系，并确定血液代谢物作为潜在的介导因素。方法本研究使用的暴露和结局全基因组关联研究（GWAS）数据来自 GWAS 开放存取数据库（https://gwas.mrcieu.ac.uk）。研究使用了 GWAS 中的 731 个循环免疫细胞特征、1400 种血液代谢物和胰腺癌。然后，我们进行了双向孟德尔随机化（MR）分析，以探索循环免疫细胞与胰腺癌之间的因果关系，并进行了两步MR分析，以发现这一过程中潜在的介导血液代谢物。所有统计分析均在 R 软件中进行。同时还使用了STROBE-MR（即利用孟德尔随机化加强流行病学观察性研究的报告）核对表来报告MR研究。结果 MR 分析确定了七种与胰腺癌有因果关系的循环免疫细胞。此外，没有强有力的证据表明基因预测的胰腺癌会对这七种类型的循环免疫细胞产生影响。进一步的两步磁共振分析发现，有 10 种血液代谢物与胰腺癌存在因果关系，循环 CD39+CD8+ T 细胞与胰腺癌之间的关系由血液乳清酸介导，比例为 5.18%（P = 0.016）。结论本研究为各种循环免疫细胞（尤其是 CD39+CD8+ T 细胞）与胰腺癌之间的因果关系提供了证据支持，而血液中的乳清酸可能是其中介效应。需要进一步研究作为潜在介质的其他风险因素，并建立胰腺癌的全面免疫-代谢网络。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Journal of Gene Medicine 医学-生物工程与应用微生物

CiteScore

6.40

自引率

0.00%

发文量

审稿时长

6-12 weeks

期刊介绍： The aims and scope of The Journal of Gene Medicine include cutting-edge science of gene transfer and its applications in gene and cell therapy, genome editing with precision nucleases, epigenetic modifications of host genome by small molecules, siRNA, microRNA and other noncoding RNAs as therapeutic gene-modulating agents or targets, biomarkers for precision medicine, and gene-based prognostic/diagnostic studies. Key areas of interest are the design of novel synthetic and viral vectors, novel therapeutic nucleic acids such as mRNA, modified microRNAs and siRNAs, antagomirs, aptamers, antisense and exon-skipping agents, refined genome editing tools using nucleic acid /protein combinations, physically or biologically targeted delivery and gene modulation, ex vivo or in vivo pharmacological studies including animal models, and human clinical trials. Papers presenting research into the mechanisms underlying transfer and action of gene medicines, the application of the new technologies for stem cell modification or nucleic acid based vaccines, the identification of new genetic or epigenetic variations as biomarkers to direct precision medicine, and the preclinical/clinical development of gene/expression signatures indicative of diagnosis or predictive of prognosis are also encouraged.