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Interferon Regulatory Factor 5 Gene Polymorphisms and mRNA Expression Levels Are Associated with Neuromyelitis Optica Spectrum Disorder

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Abstract

Interferon regulatory factor 5 (IRF5) is a critical transcription factor in the toll-like receptor signaling pathway. It is associated with autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. However, the relationship between the functional single nucleotide polymorphisms (SNPs) of IRF5 and its mRNA expression level in patients with neuromyelitis optica spectrum disorder remains unclear. The present study aimed to investigate the relationship between polymorphisms and mRNA expression levels of the IRF5 gene with the incidence of neuromyelitis optica spectrum disorder (NMOSD) in northern Chinese Han people. Two loci of the IRF5 gene (rs2004640 and rs2280714) of 164 patients with NMOSD and 269 healthy subjects were genotyped using the multiple SNaPshot technique. The frequencies of alleles, genotypes, and haplotypes were compared. Stratified analysis was performed according to age, sex, AQP4 status, onset age, and Expanded Disability Status Scale (EDSS) score. The IRF5 mRNA levels in peripheral blood mononuclear cells (PBMCs) of 64 NMOSD patients (32 patients in the acute stage and 32 patients in the remission stage) and 35 healthy subjects were detected by real-time PCR. The association of SNP polymorphisms with the mRNA expression level was determined by nonparametric tests. Allele and genotype frequency distributions of rs2004640 showed significant differences between both groups. Compared to healthy controls, the frequency of rs2004640 T allele markedly increased in patients (OR = 1.51, 95% CI = 1.09–2.08, P = 0.005). Minor allele T and GT genotype of rs2004640 that significantly increases the risk of NMOSD were discovered using genetic inheritance models (codominant, dominant, and overdominant) and haplotype analyses. Subsequent haplotype analyses revealed that the major haplotype “T-A” containing the risk alleles (the SNP sequence of the alleles was rs2004640 and rs2280714) had adverse effects on NMOSD. Based on the stratification analysis according to the EDSS score, the GT genotype frequency in the EDSS ≥ 4 group (38.2%) was markedly lower than that in the EDSS < 4 group (61.8%) (OR = 0.32, 95% CI = 0.15–0.68, P = 0.0054), with a significant difference. The IRF5 mRNA expression level was increased in NMOSD patients compared to that in normal subjects. IRF5 gene polymorphisms may be tightly associated with the genesis and progression of NMOSD in northern Chinese Han people. IRF5 mRNA expression was increased in patients with NMOSD and significantly increased in patients with acute phase. Perhaps IRF5 expression levels can be used as a predictor of disease activity in the future.

Highlights

IRF5 gene (rs2004640) shows significant differences between both NMOSD and healthy controls.

Minor allele T and GT genotype of rs2004640 significantly increase the risk of NMOSD.

IRF5 mRNA expression level increases in NMOSD patients compared to normal subjects.

The rs2004640 polymorphism of the IRF5 gene is highly correlated with susceptibility to NMOSD.

Significance Statement

NMOSD is a relatively rare inflammatory, autoimmune, and demyelinating disorder of the CNS, which predominantly affects the optic nerve and spinal cord. IRF5 gene plays a crucial role in regulating immune responses and has been implicated in various autoimmune diseases. This study investigated the association of IRF5 gene polymorphisms and mRNA expression levels with NMOSD. The findings reveal a significant correlation between specific IRF5 gene polymorphisms and increased susceptibility to NMOSD. To the best of our knowledge, the association of IRF5 gene polymorphisms and mRNA expression levels with NMOSD has not been investigated. Our study provides a genetic perspective on the importance of IRF5 in NMOSD pathogenesis and promotes the development of screening strategies that target the alleles susceptible to NMOSD for early control.

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Data Availability

All processed data used in this study can be obtained from the corresponding author upon reasonable request.

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Acknowledgements

The authors are grateful to the NMOSD patients and healthy volunteers for participating in this study. Also, we would like to thank Mr. Arshad Mehmood for assisting with professional editing and proofreading for this manuscript.

Funding

This study was supported by the Hebei Natural Science Foundation (No. H2022206483) and the S&T Program of Hebei (No. 22377711D).

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Authors and Affiliations

  1. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China

    Gaoning Wang, Liu Jing, Ying Wang, Arshad Mehmood, Huining Zhang, Ruoyi Guo, Lu Zhang & Bin Li

  2. Key Laboratory of Neurology of Hebei Province, Shijiazhuang, Hebei, China

    Gaoning Wang, Liu Jing, Ying Wang, Arshad Mehmood, Huining Zhang, Ruoyi Guo, Lu Zhang & Bin Li

  3. Department of Neurology, The First Hospital of Qinhuangdao, Qinhuangdao, Hebei, China

    Gaoning Wang & Liu Jing

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  1. Gaoning Wang
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Contributions

Gaoning Wang: Conceptualization. Liu Jing and Ying Wang: Data curation. Arshad Mehmood: Writing-review & editing. Huining Zhang: Validation. Ruoyi Guo and Lu Zhang: Software. Bin Li: Supervision. All the authors have approved the submission.

Corresponding author

Correspondence to Bin Li.

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Ethical Approval

The experiments were performed at the Key Laboratory of Neurology of Hebei Province and were approved by the Experimental Ethics Committee of the Second Hospital of Hebei Medical University.

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Wang, G., Jing, L., Wang, Y. et al. Interferon Regulatory Factor 5 Gene Polymorphisms and mRNA Expression Levels Are Associated with Neuromyelitis Optica Spectrum Disorder. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04072-0

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