GRN is a prognostic biomarker and correlated with immune infiltration in glioma: A study based on TCGA data.

Background: Among primary brain tumors, gliomas are associated with a poor prognosis and a median survival that varies depending on the tumor grade and subtype. As the most malignant form of glioma, glioblastoma (GBM) constitutes a significant health concern. Alteration in granulin(GRN) has been proved to be accountable for several diseases. However, the relationship between GRN and GBM remains unclear. We evaluated the role of GRN in GBM through The Cancer Genome Atlas (TCGA) database. Methods: First, we assessed the relationship between GRN and GBM through the GEPIA database. Next, the relationship between GRN and GBM prognosis was analyzed by logistic regression and multivariate cox methods. Using CIBERSORT and the GEPIA correlation module, we also investigated the link between GRN and immune infiltrates in cancer. Using the TCGA data, a gene set enrichment analysis (GSEA) was performed. We also employed Tumor Immune Estimation Resource (TIMER) to examine the data set of GRN expression and immune infiltration level in GBM and investigate the cumulative survival in GBM. We also validated tissues from GBM patients by Western blotting, RT-qPCR, and immunohistochemistry. Results: Increased GRN expression was shown to have a significant relationship to tumor grade in a univariate study utilizing logistic regression. Furthermore, multivariate analysis disclosed that GRN expression down-regulation is an independent predictive factor for a favorable outcome. GRN expression level positively correlates with the number of CD4+ T cells, neutrophils, macrophages, and dendritic cells (DCs) that infiltrate a GBM. The GSEA also found that the high GRN expression phenotype pathway was enriched for genes involved in immune response molecular mediator production, lymphocyte-mediated immunity, cytokine-mediated signaling pathway, leukocyte proliferation, cell chemotaxis, and CD4+ alpha beta T cell activation. Differentially enriched pathways in the Kyoto Encyclopedia of Genes and Genomes (KEGG) include lysosome, apoptosis, primary immunodeficiency, chemokine signaling pathway, natural killer cell-mediated cytotoxicity, and B cell receptor signaling pathway. Validated result showed that GRN was upregulated in GBM tissues. These results suggested that GRN was a potential indicator for the status of GBM. Conclusion: GRN is a prognostic biomarker and correlated with immune infiltrates in GBM.

Genetic variation of rs12918566 affects GRIN2A expression and is associated with spontaneous movement response during sevoflurane anesthesia induction.

N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the nervous system and are preferentially inhibited by general anesthetics such as sevoflurane. Spontaneous movement is a common complication during sevoflurane anesthesia induction and seriously affects operations. In this study, we investigated the relationship between NMDA polymorphisms and spontaneous movement during sevoflurane induction. This prospective clinical study enrolled 393 patients undergoing sevoflurane anesthesia as part of their surgical routine. In the GRIN1, GRIN2A, and GRIN2B genes, 13 polymorphisms that form a heteromeric complex as part of the NMDA receptor were selected using Haploview and genotyped using matrix-assisted laser desorption ionization-time of flight mass spectrometry MassARRAY. Both RNAfold and Genotype-Tissue Expression portals were used to identify gene expression profiles. Our data showed that 35.8% of subjects exhibited spontaneous movement. The GRIN2A rs12918566 polymorphism was associated with spontaneous movement during sevoflurane induction. A logistic regression analysis of additive, dominant, and recessive models indicated a significant association (odds ratio [OR] (95% confidence limit [CI]): 0.58 (0.42-0.80), p = .00086; OR (95% CI): 0.51 (0.31-0.84), p = .0075, and OR (95% CI): 0.47 (0.27-0.81), p = .0060, respectively). After false discovery rate (FDR) correction, the additive model was still significant with a PFDR =0.010. Bioinformatics demonstrated that the rs12918566 genomic variation affected GRIN2A expression in brain tissue. We also revealed that GRIN2A rs12918566 was significantly associated with spontaneous movement during sevoflurane induction. We believe the NMDA receptor plays an important role in regulating the anesthetic effects of sevoflurane.

Association between well-characterized gene polymorphisms and the hypnosis response caused by sevoflurane-induced anaesthesia.

WHAT IS KNOWN AND OBJECTIVE: Sevoflurane is the most widely used volatile anaesthetic in clinical practice. It exhibits a hypnotic (unconsciousness) effect and causes a loss of reaction to noxious stimuli (immobility). However, to date, the mechanism of action of sevoflurane is poorly understood. In this study, we explored the effects of genetic variations on sevoflurane-induced hypnosis. METHODS: Sixty-six SNPs in 18 candidate genes were genotyped using MALDI-TOF MassARRAY in a discovery cohort containing 161 patients administered sevoflurane. Significant polymorphisms were assessed in a validation cohort containing 265 patients. RESULTS AND DISCUSSION: Three polymorphisms (GRIN1 rs28681971, rs79901440 and CHRNA7 rs72713539) were significantly associated with the time to loss of consciousness in patients treated with sevoflurane in the discovery cohort; among them, GRIN1 rs28681971 showed a significant association even after false discovery rate (FDR) correction (pFDR  = 0.039). Following the validation analysis, GRIN1 rs28681971 and rs79901440 showed statistical efficacy (pFDR  = 0.027, 0.034). Combined assessments and meta-analysis of the results of the two cohorts indicated that the C carriers of rs28681971 and T carriers of rs79901440 in GRIN1 require a longer time to achieve unconsciousness. WHAT IS NEW AND CONCLUSION: These findings suggest that GRIN1 polymorphisms are associated with sevoflurane-induced unconsciousness. Thus, the genotypes of GRIN1 may serve as novel and meaningful biomarkers for sevoflurane-induced unconsciousness.