Associations of IRAK1 Gene Polymorphisms and mRNA Expression With NMOSD Risk in the Northern Chinese Han Population.

Hongjing Yan,Bin Li,Ruoyi Guo,Lianchang Wang,Xutao Xi,Weifeng Chen,Jianxun Ma

doi:10.3389/fneur.2021.661791

Abstract

Objectives: Interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) is a very important immunomodulatory gene for autoimmune diseases located on the X chromosome. However, there was little study about the correlation of IRAK1 functional single nucleotide polymorphisms with mRNA expression in neuromyelitis optica spectrum disorder (NMOSD) patients. In this study, we aimed to investigate the plausible association of IRAK1 polymorphism, IRAK1 mRNA expression, and NMOSD risk in the northern Chinese Han population.Methods: Four loci of IRAK1 gene (rs1059702, rs7061789, rs1059703, and rs3027898) were genotyped using multiplex SNaPshot technique in 102 NMOSD patients and 213 healthy subjects. Allele, genotype, and haplotype frequencies were compared. Stratified analyses were conducted by age, sex, AQP4 status, and age of onset. IRAK1 mRNA levels in the peripheral blood mononuclear cells of 30 NMOSD patients (of active phase) and 15 healthy control subjects were detected using qPCR. The correlations between the SNP polymorphisms and mRNA expression levels of genes were tested using non-parametric tests.Results: The minor allele frequencies (MAF) of these four locis were significantly lower in NMOSD cases than that of the controls. The frequencies of rs1059703G/G genotype, rs1059702A/A genotype, rs3027898 C/C genotype, and rs7061789G/G genotype were higher in the case group than that of the control group. Haplotype analysis revealed that the major haplotype “G-A-C-G” (alleles in the order of SNPs rs1059703, rs1059702, rs3027898, and rs7061789), containing the risk alleles, conferred an adverse effect on NMOSD. The level of IRAK1mRNA was markedly higher in NMOSD when compared to the healthy control groups. The IRAK1mRNA levels of female patients with the major haplotype were significantly higher compared to those with other haplotypes and to the male patients with the same genotype.Conclusion: IRAK1 polymorphisms were highly correlated with NMOSD susceptibility. Its haplotype G-A-C-G (rs1059703-rs1059702-rs3027898-rs7061789) confers increasing the risk of NMOSD in female patients. The IRAK1 risk haplotype G-A-C-G upregulated IRAK1 mRNA expression in female NMOSD patients. Our study provides a novel insight into the molecular mechanism of the pathogenesis of NMOSD and reveals that IRAK1 is the potential mechanism-specific druggable target in NMOSD disease.

Highlights

Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating autoimmune disease primarily affecting the spinal cord and optic nerve
Some studies have shown that toll-like receptor (TLR) signaling, which has been implicated in various neuroimmune processes, may play a relevant role in the pathogenesis of NMOSD [1, 2, 8]
Our study identifies that IRAK1 polymorphisms are correlated with NMOSD risk in northern Chinese Han populations and contribute to the up-regulated expression level of IRAK1 mRNA in female NMOSD patients

Summary

Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating autoimmune disease primarily affecting the spinal cord and optic nerve. Neuromyelitis optica occurs more frequently in women than in men, by as much as [1, 2]: 1 [3]. The exact molecular mechanisms behind the pathogenesis of NMOSD remain unclear. Some studies have shown that toll-like receptor (TLR) signaling, which has been implicated in various neuroimmune processes, may play a relevant role in the pathogenesis of NMOSD [1, 2, 8]

Objectives

Methods

Results

Discussion

Conclusion