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.