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ORIGINAL RESEARCH article

Front. Oncol.
Sec. Cancer Epidemiology and Prevention
Volume 14 - 2024 | doi: 10.3389/fonc.2024.1418283
This article is part of the Research Topic Understanding Molecular Mechanisms to Facilitate the Development of Biomarkers for Therapeutic Intervention in Gastrointestinal Diseases and Sepsis View all 10 articles

Elucidating the causal relationship between 486 genetically predicted blood metabolites and the risk of gastric cancer: A comprehensive Mendelian randomization analysis

Provisionally accepted
Lei Qian Lei Qian 1*Jiawei Song Jiawei Song 2Xiaoqun Zhang Xiaoqun Zhang 3*Yihuan Qiao Yihuan Qiao 4Zhaobang Tan Zhaobang Tan 5*Shisen Li Shisen Li 5Jun Zhu Jun Zhu 6*Jipeng Li Jipeng Li 1,5*
  • 1 Department of Experiment Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
  • 2 School of Clinical Medicine, Xi’an Medical University, Xi’an, China
  • 3 Department of Pharmacy, Shaanxi Provincial Hospital of Chinese Medicine, Xi’an, China
  • 4 Department of Digestive Surgery, Xi'an Honghui Hospital, Xi’an, China
  • 5 Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
  • 6 Xijing Hospital, Air Force Medical University, Xi’an, China

The final, formatted version of the article will be published soon.

    Background: Previous epidemiological studies have yielded inconclusive results regarding the causality between blood metabolites and the risk of gastric cancer (GC). Methods: MR analysis and metabolomics techniques such as ultra-high performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) and gas chromatography/tandem mass spectrometry (GC-MS/MS) technologies were employed to assess the causality of 486 genetically predicted blood metabolites on the risk of GC. The genome-wide association study (GWAS) summary data for 486 blood metabolites from 7,824 individuals. The GWAS summary data for GC (ebi-a-GCST90018849) were obtained from the IEU Open GWAS project, including 1,029 GC cases and 474,841 controls. Primary causality estimates were obtained using inverse variance weighting (IVW), supplemented with the weighted median, MR-Egger, weighted mode, and simple mode. In addition, we conducted sensitivity analyses （including Cochran’s Q, MR-Egger intercept, MR-PRESSO, and leave-one-out tests），Steiger’s test, linked disequilibrium score regression, and multivariate MR (MVMR) to improve the assessment of causality between GC and blood metabolite.. Finally, we recruited a total of 11 patients diagnosed with gastric cancer from the First Affiliated Hospital of Air Force Military Medical University between September and October 2024. The control group comprised 11 healthy individuals. Plasma samples were collected from both groups for the evaluation of blood-related metabolite expression levels using advanced techniques such as ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and gas chromatography-mass spectrometry (GC-MS/MS). Results: The MVMR analysis revealed a significant association between genetically predicted elevated levels of tryptophan (odds ratio [OR] = 0.523, 95% confidence interval [CI] = 0.313–0.872, p = 0.013), nonadecanoate (19:0) (odds ratio [OR] = 0.460, 95% confidence interval [CI] = 0.225–0.943, p = 0.034), and erythritol (odds ratio [OR] = 0.672, 95% confidence interval [CI] = 0.468–0.930, p = 0.016) with a decreased risk of gastric cancer. Based on metabolomic techniques such as UPLC-MS/MS and GC-MS/MS analyses, it has been demonstrated that the expression levels of tryptophan, nonadecanoate (19:0), and erythritol are reduced in patients with gastric cancer. Conclusions: These findings indicate that three blood metabolites are causally related to GC and provide new perspectives for combining genomics and metabolomics to study the mechanisms of metabolite-mediated GC development.

    Keywords: Blood metabolites, gastric cancer, Mendelian randomization, causality, genomewide association study

    Received: 16 Apr 2024; Accepted: 18 Nov 2024.

    Copyright: © 2024 Qian, Song, Zhang, Qiao, Tan, Li, Zhu and Li. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence:
    Lei Qian, Department of Experiment Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
    Xiaoqun Zhang, Department of Pharmacy, Shaanxi Provincial Hospital of Chinese Medicine, Xi’an, China
    Zhaobang Tan, Department of Gastrointestinal Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
    Jun Zhu, Xijing Hospital, Air Force Medical University, Xi’an, China
    Jipeng Li, Department of Experiment Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China

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