Impact of alterations in X-linked IRAK1gene and miR-146a on susceptibility and clinical manifestations in patients with systemic sclerosis

• Published in: Immunology letters 2018-12, Vol.204, p.1-8
• Main Authors: Vreca, Misa, Andjelkovic, Marina, Tosic, Natasa, Zekovic, Ana, Damjanov, Nemanja, Pavlovic, Sonja, Spasovski, Vesna
• Format: Article
• Language: English
• Subjects: Biomarker; Gene expression; IRAK1; miR-146a; SNV; Systemic sclerosis
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/j.imlet.2018.10.002

•IRAK1 gene expression could be a marker for better stratification of SSc patients.•Carriers CC genotype of miR-146a rs2910164 C > G have 10 times more chances to develop lung fibrosis and active form of SSc.•Reduced miR-146a expression is a risk factor for development and progression of SSc. Systemic sclerosis (SSc) is a heterogeneous multisystem autoimmune disease with unknown etiology. Numerous studies have indicated that the disease heterogeneity implies various genetic abnormalities. Considering that SSc is characterized by a strong sex bias and that the position of IRAK1 gene is on the X chromosome, we assume that variations in IRAK1 gene could explain female predominance of SSc. It was previously described that miR-146a has a role in ‘fine-tuning’ regulation of the TLR/NF-kB signaling pathway through down-regulation of IRAK1 gene. The aim of the present study was to analyze both variants and expression level of IRAK1 and miR-146a genes in terms of susceptibility to SSc and clinical presentation of SSc patients. We analyzed variants IRAK1 rs3027898 C > A and miR-146a rs2910164 C > G in 102 SSc patients and 66 healthy subjects. Genotyping was performed by Sanger sequencing. Expression level of IRAK1 mRNA and miR-146a in PBMCs was performed in subset of 50 patients and 13 healthy controls by RT-qPCR. Our results showed that there was no association between IRAK1 rs3027898 and the risk of SSc in women. However, the analysis of genotype distribution of the mir-146a rs2910164 C > G variant indicated that CC genotype shows strong association with lung fibrosis and active form of the disease. When expression level of IRAK1 gene was analyzed, we detected significant downregulation of IRAK1 mRNA in SSc patients compared to controls, as well as in male compared to female patients, in patients with ACAs autoantibodies and in patients with severe skin involvement. Regarding the expression level of miR-146a, we have found significantly reduced expression in SSc patients, in patients with skin involvement and in male SSc patients. The results from this study indicate that expression of IRAK1 gene could explain phenotypic heterogeneity of SSc and may be involved in the pathogenesis of SSc due to its differential expression in certain subgroups. Our results also suggested that miR-146a rs2910164 CC genotype may be predisposing factor for development lung fibrosis and more progressive form of SSc. Results from relative expression analysis of miR-146a demonstrated tha