Glioma is the most common malignant tumor in the central nervous system, and patients generally have a poor prognosis. In this article, we conducted a Mendelian randomization analysis between plasma proteins and glioma to explore the causal relationship between them. The results showed that 10 plasma proteins had a causal relationship with glioma, with five being risk factors (SIRPB1, RACGAP1, MLN, CHST9, TPST2) and five being protective factors (IL18R1, FCRL3, TAPBPL, ERAP1, TDGF1). Many of these are reported for the first time. Our study reports multiple biomarkers for glioma, which may provide reference for the diagnosis and treatment of glioma.

Zhihao Xie, Wentao Wang, Jiacong Chen, Chufeng Feng, Hongzheng Zhai. Systematic Mendelian Randomization Using the Human Plasma Proteome to Discover Potential Biomarkers for Glioma. Academic Journal of Medicine & Health Sciences (2025), Vol. 6, Issue 1: 23-30. https://doi.org/10.25236/AJMHS.2025.060104.

[1] Ostrom QT, Gittleman H, Farah P, Ondracek A, Chen Y, Wolinsky Y, et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2006-2010. Neuro Oncol. 2013;15 Suppl 2(Suppl 2): ii1–ii56.

[2] Louis DN, Perry A, Wesseling P, Brat DJ, Cree IA, Figarella-Branger D, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol. 2021;23(8):1231-1251.

[3] Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg. 2001;95(2):190-198.

[4] Krex D, Klink B, Hartmann C, von Deimling A, Pietsch T, Simon M, et al. Long-term survival with glioblastoma multiforme. Brain. 2007;130(Pt 10):2596-2606.

[5] Nabors LB, Portnow J, Ammirati M, Baehring J, Brem H, Butowski N, et al. NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017. J Natl Compr Canc Netw. 2017;15(11):1331-1345.

[6] Peeters MCM, Dirven L, Koekkoek JAF, Gortmaker EG, Fritz L, Vos MJ, et al. Prediagnostic symptoms and signs of adult glioma: the patients' view. J Neurooncol. 2020;146(2):293-301.

[7] Omuro A, DeAngelis LM. Glioblastoma and other malignant gliomas: a clinical review. JAMA. 2013;310(17):1842-1850.

[8] Kalinina J, Peng J, Ritchie JC, Van Meir EG. Proteomics of gliomas: initial biomarker discovery and evolution of technology. Neuro Oncol. 2011;13(9):926-942.

[9] Sejda A, Grajkowska W, Trubicka J, Szutowicz E, Wojdacz T, Kloc W, et al. WHO CNS5 2021 classification of gliomas: a practical review and road signs for diagnosing pathologists and proper patho-clinical and neuro-oncological cooperation. Folia Neuropathol. 2022;60(2):137-152.

[10] Huang Z, Ma L, Huang C, Li Q, Nice EC. Proteomic profiling of human plasma for cancer biomarker discovery. Proteomics. 2017;17(6).

[11] Peng L, Cantor DI, Huang C, Wang K, Baker MS, Nice EC. Tissue and plasma proteomics for early stage cancer detection. Mol Omics. 2018;14(6):405-423.

[12] Carlsson A, Persson O, Ingvarsson J, Widegren B, Salford L, Borrebaeck CA, et al. Plasma proteome profiling reveals biomarker patterns associated with prognosis and therapy selection in glioblastoma multiforme patients. Proteomics Clin Appl. 2010;4(6-7):591-602.

[13] Gupta V, Walia GK, Sachdeva MP. 'Mendelian randomization': an approach for exploring causal relations in epidemiology. Public Health. 2017;145:113-119.

[14] Zhong S, Yang W, Zhang Z, Xie Y, Pan L, Ren J, et al. Association between viral infections and glioma risk: a two-sample bidirectional Mendelian randomization analysis. BMC Med. 2023;21(1):487.

[15] Kitazawa T, Kaiya H. Motilin Comparative Study: Structure, Distribution, Receptors, and Gastrointestinal Motility. Front Endocrinol (Lausanne). 2021;12:700884.

[16] Xu HL, Hsing AW, Koshiol J, Chu LW, Cheng JR, Gao J, et al. Variants in motilin, somatostatin and their receptor genes and risk of biliary tract cancers and stones in Shanghai, China. Meta Gene. 2014;2:418-426.

[17] Smak P, Tvaroska I, Koca J. The catalytic reaction mechanism of tyrosylprotein sulfotransferase-1. Phys Chem Chem Phys. 2021;23(41):23850-23860.

[18]  Xu J, Deng X, Tang M, Li L, Xiao L, Yang L, et al. Tyrosylprotein sulfotransferase-1 and tyrosine sulfation of chemokine receptor 4 are induced by Epstein-Barr virus encoded latent membrane protein 1 and associated with the metastatic potential of human nasopharyngeal carcinoma. PLoS One. 2013;8(3):e56114.

[19] Esmailbeig M, Ghaderi A. Interleukin-18: a regulator of cancer and autoimmune diseases. Eur Cytokine Netw. 2017;28(4):127-140.

[20] Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 regulates both Th1 and Th2 responses. Annu Rev Immunol. 2001;19:423-474.

[21] Takashima Y, Kawaguchi A, Kanayama T, Hayano A, Yamanaka R. Correlation between lower balance of Th2 helper T-cells and expression of PD-L1/PD-1 axis genes enables prognostic prediction in patients with glioblastoma. Oncotarget. 2018;9(27):19065-19078.

[22] Zhong XY, Zhang LH, Jia SQ, Shi T, Niu ZJ, Du H, et al. Positive association of up-regulated Cripto-1 and down-regulated E-cadherin with tumour progression and poor prognosis in gastric cancer. Histopathology. 2008;52(5):560-568.