Introduction
Since December 2019, a new form of severe acute respiratory syndrome
(SARS) from a new strain of coronavirus (SARS coronavirus 2
[SARS-CoV-2]) has been spreading worldwide 1. The
disease caused by SARS-CoV-2 was named COVID-19 and was declared a
pandemic by the World Health Organization (WHO) in March 20202. The signs and symptoms of COVID-19 disease are
diverse in different patients 3. A combination of
genetic and non-genetic factors between the genome of the invading virus
and the host may interact in the process of virus infection and
determine the severity of the disease outcome 4.
Potential genetic and epigenetic factors of the host are associated with
increased severity of COVID-19 infection 5,6. So far,
genetic variants of human genes related to the entry mechanism of
SARS-CoV-2 and genes related to the host’s innate immune response have
been identified as essential host determinants in the severity of
COVID-19 7. The advent of the Next-Generation
Sequencing (NGS) technique has opened a new path for variant screening,
also Whole-Exome Sequencing (WES) offers a promising approach to
identify causative variants in known genes as well as in novel
disease-related candidate genes 8,9. Through the
technique of WES, the frequency of exonic variants of genes concerning
the severity of SARS-CoV-2 infectivity in patients can be tracked10. It is expected that this technique will be the
first choice of clinical services in the near future because it provides
useful information for genetic counseling 11,
treatment 12, and disease management13. Host genetic factors contributing to severe
COVID-19 have been investigated mainly in adults by Genome-Wide
Association Studies (GWAS) and Whole-Exome Sequencing (WES)/Whole-Genome
Sequencing (WGS) 14,15. The first detailed insight
into host genetics associated with severe COVID-19 infection was
provided by GWAS 16. GWAS is ideal for identifying
variants with a relatively high allelic frequency (>5%
minor allelic frequency) associated with specific Single Nucleotide
Polymorphisms (SNPs) 17. While the overall relative
risk of these SNPs is mostly small 18, they can
highlight specific genes that may have key pathogenic roles in the
disease 19. Several GWAS have investigated host
genetic variants in clinical phenotypes of severity/susceptibility to
COVID-19 20. The COVID-19 Host Genetics Initiative
(HGI) is constantly updating its GWAS meta-analysis (latest HGI version
6 available at https://www.covid19hg.org/results/r6/)21. GWAS have identified various loci associated with
susceptibility to infection or severity of COVID-1922, which were later confirmed by colocalization
analysis 23 or Mendelian Randomization (MR)24. The most consistent region identified among
several GWAS associated with severe COVID-19 is at 3p21.31 chromosomal
region, which includes several genes, including SLC6A2025. Several studies that also considered gene
expression data have shown alleles with low expression of the IFNAR2
gene are associated with an increased risk of severe COVID-1926,27. Finally, there is evidence that genetic
polymorphisms may influence the risk of SARS-CoV-2 infection through
viral entry 28, including ACE2 and TMPRSS2 genes29,30. Several studies have used a gene-based approach
to identify functional variants of these proteins associated with the
disease and severity of COVID-19 31. Overall, GWAS in
adults with severe COVID-19 has identified genes associated with
antiviral functions such as TYK2 32. The present study
was designed to identify variants of human genes that are the cause of
severe COVID-19 and investigate the effect of variants on the
three-dimensional structure of the relevant proteins. An advanced
understanding of host genetic and epigenetic factors and SARS-CoV-2
virus interactions is critical for improved prognostic tools and
innovative therapies 33. This research not only
contributes to our better understanding of the disease and accurate
identification of genetic differences; Rather, it facilitates the
process of predicting the severity of the disease and, as a result,
prompt and timely treatment of patients. In this study, Whole‐Exome
Sequencing is used to analyze variants in ACE2, TMPRSS2, TYK2, SLC6A20,
and IFNAR2 in a cohort of 100 patients with a history of COVID-19 from
Iran.