1. Introduction
Globally, coronavirus disease 2019 (COVID-19) remains one of the newest and most widespread respiratory viral infections affecting humanity, with millions of cases and deaths recorded. The disease is associated with a wide range of clinical manifestations, from asymptomatic to mild to moderate and may progress to severe pneumonia requiring intensive care (Lamers and Haagmans, 2022). The causative agent of COVID-19 is a novel coronavirus (severe acute respiratory syndrome coronavirus-2; SARS-CoV-2), a single-strand positive RNA virus belonging to the Coronaviridae family (Li et al., 2021). The virus infects lung alveolar cells by attaching its spikes to a receptor on host cell, angiotensin-converting enzyme 2 (ACE2). This leads to hyperactivity of the angiotensin II receptor axis and facilitates virus entry into the cell (Beyerstedt et al., 2021). As an outcome, pro-fibrotic, pro-apoptotic and pro-inflammatory signal pathways are activated to mediate the pathogenesis of SARS-CoV-2 infection, which is characterized by an exacerbated host inflammatory response known as a cytokine storm that may lead to the development of acute respiratory distress syndrome (Lamers and Haagmans, 2022).
Pattern recognition receptors (PRRs) are the first line of host defense system response against viral attack, and interferon-induced helicase C domain-containing protein 1 (IFIH1, also known as MDA5; melanoma differentiation associated gene 5 protein) is one of the main PRRs that first sense viral RNA and activate host cells to produce interferon (IFN) in order to mount an effective antiviral immunity (Brisse and Ly, 2019). In vitro analysis showed that IFIH1 protein was effective in restricting replication of human respiratory syncytial virus and rhinoviruses, and in children with IFIH1 deficiency increased susceptibility to common respiratory RNA viruses was indicated (Asgari et al., 2017).
The IFIH1 protein is encoded by IFIH1 , a gene located in the long arm of human chromosome 2 at position 2q24.2. Naturally occurring single nucleotide polymorphisms (SNPs) of the IFIH1 gene have been studied worldwide, and some have shown an association with susceptibility to a number of autoimmune diseases (type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, and others) as well as infectious diseases such as COVID-19 (Muñiz-Banciella et al., 2023; Xiao et al., 2023). Among the IFIH1 SNPs that have attracted attention in the topic of COVID-19 susceptibility is rs1990760. Although the evidence is not conclusive, studies have linked rs1990760 to the risk of developing this respiratory infection, especially in cases where the disease is severe (Dieter et al., 2023; Feizollahi et al., 2023; Maiti, 2020). The rs1990760 SNP is a missense variant and there is evidence to suggest that this SNP is in strong linkage disequilibrium (LD) with an intergenic variant located between the FAP(fibroblast activation protein alpha) and IFIH1 genes; it is rs2111485. Studies have revealed that rs2111485 is associated with susceptibility to type 1 diabetes, vitiligo, and hepatitis C virus infection (Gootjes et al., 2022; Jiang et al., 2019; Onan et al., 2019). In addition, a protective role of rs2111485 in spontaneous hepatitis B virus clearance has also been suggested (Yao et al., 2021). In the context of COVID-19 susceptibility and to the researchers’ best knowledge, rs2111485 has not been investigated.
Although the wave of COVID-19 has subsided worldwide, there are surged in reported cases among few countries in January 2024 as infection of mutational variances becoming more common, there is still a need to understand the factors that may influence the development of the viral respiratory infection. In this study, two SNPs of the IFIH1 gene, rs1990760 and rs2111485, were genotyped in patients with mild/moderate COVID-19 with the aim of understanding their role in disease susceptibility. In addition, serum IFIH1 levels were also determined. The impact of rs1990760 and rs2111485 genotypes on IFIH1 levels was also evaluated.