Diagnostic Values of METTL1-Related Genes and Immune Characteristics in Systemic Lupus Erythematosus

Yu Liu; Enyi Zhu; Yan Lei; Ailing Luo; Yaping Yan; Mansi Cai; Shanshan Liu; Yan Huang; Hui Guan; Ming Zhong; Weinian Li; Lian Lin; Michael Hultstöm; Enyin Lai; Zhihua Zheng; Xiaoping Liu; Chun Tang

doi:10.2147/JIR.S431628

Diagnostic Values of METTL1-Related Genes and Immune Characteristics in Systemic Lupus Erythematosus

J Inflamm Res. 2023 Nov 17:16:5367-5383. doi: 10.2147/JIR.S431628. eCollection 2023.

Authors

Yu Liu^#¹, Enyi Zhu^#¹, Yan Lei^#¹, Ailing Luo², Yaping Yan², Mansi Cai², Shanshan Liu², Yan Huang³, Hui Guan¹, Ming Zhong¹, Weinian Li⁴, Lian Lin¹, Michael Hultstöm^{5

6}, Enyin Lai⁷, Zhihua Zheng¹, Xiaoping Liu², Chun Tang¹

Affiliations

¹ Department of Nephrology, Center of Kidney and Urology, the Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, People's Republic of China.
² Department of Hematology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangdong Provincial Clinical Research Center for Child Health, Guangzhou, 510623, People's Republic of China.
³ The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, 421001, People's Republic of China.
⁴ Department of Rheumatology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, 510623, People's Republic of China.
⁵ Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden.
⁶ Department of Medical Cell Biology, Unit for Integrative Physiology, Uppsala University, Uppsala, Sweden.
⁷ Department of Physiology, School of Basic Medical Sciences, Zhejiang University School of Medicine, Hangzhou, 310058, People's Republic of China.

^# Contributed equally.

Abstract

Purpose: Methyltransferase like 1 (METTL1) regulates epitranscriptomes via the m7G modification in mammalian mRNA and microRNA. Systemic lupus erythematosus (SLE) is caused by abnormal immune reactivity and has diverse clinical manifestations. RNA methylation as a mechanism to regulate gene expression is widely implicated in immune regulation. However, the role of m7G in immune response of SLE has not been extensively studied.

Patients and methods: Expression of METTL1 was identified in the public dataset GSE122459 and validated in an independent cohort of SLE patients. We investigated the association between METTL1-expression and clinical manifestations of SLE. Subsequently, differentially expressed genes (DEG) that were correlated with METTL1-expression in GSE122459 were used for functional enrichment analysis. The correlation between infiltrating immune cells and METTL1, as well as candidate biomarkers identified to be correlated with either METTL1 or immune cell infiltration were assessed by single-sample GSEA. Potential mechanisms were explored with Gene ontology and KEGG pathway enrichment. Diagnostic performances of candidate biomarkers in SLE were analyzed.

Results: The mRNA and protein expression of METTL1 in SLE patients were significantly decreased in both datasets. METTL1-coexpressed DEGs were enriched in several key immune-related pathways. Activated CD8 T cells, activated CD4 T cells, memory B cells and type 2 helper T cells were different between patients with high and low METTL1 expression. Further, activated CD8 T-cells, activated CD4 T-cells, memory B-cells were correlated with METTL1. The genes of LAMP3, CD83, PDCD1LG2, IGKVD3D-20, IGKV5-2, IGKV2D-30, IGLV3-19 and IGLV4-60 were identified as candidate targets that were correlated with immune cell proportion. Moreover, LAMP3, CD83, and PDCD1LG2 expression were of diagnostic value in SLE as indicated by ROC analysis.

Conclusion: Our findings suggested that METTL1 and its candidate targets LAMP3, CD83, PDCD1LG2 may be used for diagnosing SLE and could be explored for developing targeted molecular therapy for SLE.

Keywords: biomarker; immunity; methyltransferase like 1; single sample gene set enrichment analysis; systemic lupus erythematosus.

Grants and funding

The research was supported by Shenzhen Municipal Science and Technology Innovation Commission (JCYJ20210324123414040), and Guangdong Basic and Applied Basic Research Foundation (2019A1515110488 and 2020A1515110306).