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.