FCGR2C: An Emerging Immune Gene for Predicting Sepsis Outcome

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2022 Dec 19

PMID 36532072

Authors

Si Liu

Yao Lu Zhang

Lu Yao Zhang

Guang Ju Zhao

Zhong Qiu Lu

Affiliations

Soon will be listed here.

Abstract

Background: Sepsis is a life-threatening disease associated with immunosuppression. Immunosuppression could ultimately increase sepsis mortality. This study aimed to identify the prognostic biomarkers related to immunity in sepsis.

Methods: Public datasets of sepsis downloaded from the Gene Expression Omnibus (GEO) database were divided into the discovery cohort and the first validation cohort. We used R software to screen differentially expressed genes (DEGs) and analyzed DEGs' functional enrichment in the discovery dataset. Immune-related genes (IRGs) were filtered from the GeneCards website. A Lasso regression model was used to screen candidate prognostic genes from the intersection of DEGs and IRGs. Then, the candidate prognostic genes with significant differences were identified as prognostic genes in the first validation cohort. We further validated the expression of the prognostic genes in the second validation cohort of 81 septic patients recruited from our hospital. In addition, we used four immune infiltration methods (MCP-counter, ssGSEA, ImmuCellAI, and CIBERSORT) to analyze immune cell composition in sepsis. We also explored the correlation between the prognostic biomarker and immune cells.

Results: First, 140 genes were identified as prognostic-related immune genes from the intersection of DEGs and IRGs. We screened 18 candidate prognostic genes in the discovery cohort with the lasso regression model. Second, in the first validation cohort, we identified 4 genes (CFHR2, FCGR2C, GFI1, and TICAM1) as prognostic immune genes. Subsequently, we found that FCGR2C was the only gene differentially expressed between survivors and non-survivors in 81 septic patients. In the discovery and first validation cohorts, the AUC values of FCGR2C were 0.73 and 0.67, respectively. FCGR2C (AUC=0.84) had more value than SOFA (AUC=0.80) and APACHE II (AUC=0.69) in evaluating the prognosis of septic patients in our recruitment cohort. Moreover, FCGR2C may be closely related to many immune cells and functions, such as B cells, NK cells, neutrophils, cytolytic activity, and inflammatory promotion. Finally, enrichment analysis showed that FCGR2C was enriched in the phagosome signaling pathway.

Conclusion: FCGR2C could be an immune biomarker associated with prognosis, which may be a new direction of immunotherapy to reduce sepsis mortality.

References

Hotchkiss R, Monneret G, Payen D . Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. Lancet Infect Dis. 2013; 13(3):260-8. PMC: 3798159. DOI: 10.1016/S1473-3099(13)70001-X. View

Rooney M, Shukla S, Wu C, Getz G, Hacohen N . Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell. 2015; 160(1-2):48-61. PMC: 4856474. DOI: 10.1016/j.cell.2014.12.033. View

Hoffman L, Tomalin L, Schultz G, Howell M, Anandasabapathy N, Alavi A . Integrating the skin and blood transcriptomes and serum proteome in hidradenitis suppurativa reveals complement dysregulation and a plasma cell signature. PLoS One. 2018; 13(9):e0203672. PMC: 6162087. DOI: 10.1371/journal.pone.0203672. View

Xie J, Wang H, Kang Y, Zhou L, Liu Z, Qin B . The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey. Crit Care Med. 2019; 48(3):e209-e218. DOI: 10.1097/CCM.0000000000004155. View

Breunis W, Van Mirre E, Bruin M, Geissler J, de Boer M, Peters M . Copy number variation of the activating FCGR2C gene predisposes to idiopathic thrombocytopenic purpura. Blood. 2007; 111(3):1029-38. DOI: 10.1182/blood-2007-03-079913. View

Napoli A, Fast L, Gardiner F, Nevola M, Machan J . Increased granzyme levels in cytotoxic T lymphocytes are associated with disease severity in emergency department patients with severe sepsis. Shock. 2011; 37(3):257-62. DOI: 10.1097/SHK.0b013e31823fca44. View

Lin A, Qi C, Li M, Guan R, Imyanitov E, Mitiushkina N . Deep Learning Analysis of the Adipose Tissue and the Prediction of Prognosis in Colorectal Cancer. Front Nutr. 2022; 9:869263. PMC: 9131178. DOI: 10.3389/fnut.2022.869263. View

Lassauniere R, Tiemessen C . Variability at the FCGR locus: characterization in Black South Africans and evidence for ethnic variation in and out of Africa. Genes Immun. 2015; 17(2):93-104. DOI: 10.1038/gene.2015.60. View

Deng Y, Ren E, Yuan W, Zhang G, Wu Z, Xie Q . GRB10 and E2F3 as Diagnostic Markers of Osteoarthritis and Their Correlation with Immune Infiltration. Diagnostics (Basel). 2020; 10(3). PMC: 7151213. DOI: 10.3390/diagnostics10030171. View

10.

Metes D, Ernst L, CHAMBERS W, Sulica A, Herberman R, Morel P . Expression of functional CD32 molecules on human NK cells is determined by an allelic polymorphism of the FcgammaRIIC gene. Blood. 1998; 91(7):2369-80. View

11.

Chen R, Qin S, Zhu H, Chang G, Li M, Lu H . Dynamic monitoring of circulating CD8 T and NK cell function in patients with septic shock. Immunol Lett. 2022; 243:61-68. DOI: 10.1016/j.imlet.2022.02.004. View

12.

Newman A, Steen C, Liu C, Gentles A, Chaudhuri A, Scherer F . Determining cell type abundance and expression from bulk tissues with digital cytometry. Nat Biotechnol. 2019; 37(7):773-782. PMC: 6610714. DOI: 10.1038/s41587-019-0114-2. View

13.

Singer M . Biomarkers in sepsis. Curr Opin Pulm Med. 2013; 19(3):305-9. PMC: 4222798. DOI: 10.1097/MCP.0b013e32835f1b49. View

14.

Ayvat P, Kayhan Omeroglu S . Mortality estimation using APACHE and CT scores with stepwise linear regression method in COVID-19 intensive care unit: A retrospective study. Clin Imaging. 2022; 88:4-8. PMC: 9067018. DOI: 10.1016/j.clinimag.2022.04.017. View

15.

Delano M, Ward P . The immune system's role in sepsis progression, resolution, and long-term outcome. Immunol Rev. 2016; 274(1):330-353. PMC: 5111634. DOI: 10.1111/imr.12499. View

16.

Patil N, Guo Y, Luan L, Sherwood E . Targeting Immune Cell Checkpoints during Sepsis. Int J Mol Sci. 2017; 18(11). PMC: 5713381. DOI: 10.3390/ijms18112413. View

17.

Wang L, Gao B, Wu M, Yuan W, Liang P, Huang J . Profiles of Immune Cell Infiltration in Carotid Artery Atherosclerosis Based on Gene Expression Data. Front Immunol. 2021; 12:599512. PMC: 8027089. DOI: 10.3389/fimmu.2021.599512. View

18.

Beppler J, Koehler-Santos P, Pasqualim G, Matte U, Alho C, Dias F . Fc Gamma Receptor IIA (CD32A) R131 Polymorphism as a Marker of Genetic Susceptibility to Sepsis. Inflammation. 2015; 39(2):518-25. DOI: 10.1007/s10753-015-0275-1. View

19.

Smeding L, Plotz F, Groeneveld A, Kneyber M . Structural changes of the heart during severe sepsis or septic shock. Shock. 2012; 37(5):449-56. DOI: 10.1097/SHK.0b013e31824c3238. View

20.

Nagelkerke S, Schmidt D, de Haas M, Kuijpers T . Genetic Variation in Low-To-Medium-Affinity Fcγ Receptors: Functional Consequences, Disease Associations, and Opportunities for Personalized Medicine. Front Immunol. 2019; 10:2237. PMC: 6786274. DOI: 10.3389/fimmu.2019.02237. View