Functional prediction and comparative population analysis of variants in genes for proteases and innate immunity related to SARS-CoV-2 infection

Abstract

New coronavirus SARS-CoV-2 is capable to infect humans and cause a novel disease COVID-19. Aiming to understand a host genetic component of COVID-19, we focused on variants in genes encoding proteases and genes involved in innate immunity that could be important for susceptibility and resistance to SARS-CoV-2 infection. Analysis of sequence data of coding regions of FURIN, PLG, PRSS1, TMPRSS11a, MBL2 and OAS1 genes in 143 unrelated individuals from Serbian population identified 22 variants with potential functional effect. In silico analyses (PolyPhen-2, SIFT, MutPred2 and Swiss-Pdb Viewer) predicted that 10 variants could impact the structure and/or function of proteins. These protein-altering variants (p.Gly146Ser in FURIN ; p.Arg261His and p.Ala494Val in PLG ; p.Asn54Lys in PRSS1 ; p.Arg52Cys, p.Gly54Asp and p.Gly57Glu in MBL2 ; p.Arg47Gln, p.Ile99Val and p.Arg130His in OAS1 ) may have predictive value for inter-individual differences in the response to the SARS-CoV-2 infection. Next, we performed comparative population analysis for the same variants using extracted data from the 1000 Genomes project. Population genetic variability was assessed using delta MAF and Fst statistics. Our study pointed to 7 variants in PLG, TMPRSS11a, MBL2 and OAS1 genes with noticeable divergence in allelic frequencies between populations worldwide. Three of them, all in MBL2 gene, were predicted to be damaging, making them the most promising population-specific markers related to SARS-CoV-2 infection. Comparing allelic frequencies between Serbian and other populations, we found that the highest level of genetic divergence related to selected loci was observed with African, followed by East Asian, Central and South American and South Asian populations. When compared with European populations, the highest divergence was observed with Italian population. In conclusion, we identified 4 variants in genes encoding proteases ( FURIN, PLG and PRSS1 ) and 6 in genes involved in the innate immunity ( MBL2 and OAS1 ) that might be relevant for the host response to SARS-CoV-2 infection.

Markers Associated with COVID-19 Susceptibility, Resistance, and Severity

“…Therefore, the correlation between HLA variants and COVID-19 needs to be further studied to pinpoint the effect of genetic factors. In relation, a study of sequence analysis has identified 22 variants in the coding regions of some proteases (FURIN, PLG, PRSS1, TMPRSS11a) and innate immune-related genes (MBL2 and OAS1) in a Serbian population [55]. Using in silico analyses, 10 of these variants were predicted to be proteinaltering variants, possibly affecting the protein's function.…”

“…On the other hand, the mutations in innate immune-related genes are hypothesized to be disadvantageous to the host, allowing the virus to escape the immune response. These variants include p.Gly146Ser in FURIN; p.Arg261His and p.Ala494Val in PLG; p.Asn54Lys in PRSS1; p.Arg52Cys, p.Gly54Asp and p.Gly57Glu in MBL2; p.Arg47Gln, p.Ile99Val and p.Arg130His in OAS1 [55]. Additional population genetics studies have shown that seven variants in PLG, TMPRSS11a, MBL2 and OAS1 genes experienced genetic divergence (i.e., different allelic frequencies) among different populations worldwide [55].…”

“…These variants include p.Gly146Ser in FURIN; p.Arg261His and p.Ala494Val in PLG; p.Asn54Lys in PRSS1; p.Arg52Cys, p.Gly54Asp and p.Gly57Glu in MBL2; p.Arg47Gln, p.Ile99Val and p.Arg130His in OAS1 [55]. Additional population genetics studies have shown that seven variants in PLG, TMPRSS11a, MBL2 and OAS1 genes experienced genetic divergence (i.e., different allelic frequencies) among different populations worldwide [55]. It is also interesting to note that cytokine secretion is modulated through genetics and epigenetics regulations.…”

Evidence of a dysregulated Vitamin D pathway in SARS-CoV-2 infected patient’s lung cells

“…Examples of such upregulated genes included 2'-5'-oligoadenylate synthetase 1 (OAS1), an interferon-responsive gene [48][49][50] , interferon regulatory factor 2 (IRF2), interferon-induced transmembrane protein 2 (IFITM2), secretory leukocyte peptidase inhibitor (SLP1), max dimerization protein 1 (MXD1), tissue inhibitor of metalloproteinase-1 (TIMP1), PH domain-containing adaptor Bam32/DAPP1, and T helper type 1 (Th1)/monocyte-associated chemokine CCL2, which have been shown to also participate in SARS-CoV-2-AEC2 signaling in lung cells 51 . In fact, upregulation of OAS1 and IFITM2 has been recently noticed as a common feature in patients infected with SARS-CoV-2 41 , and certain variants of OAS1 have been predicted to influence SARS-CoV-2 infection 52 . These observations suggest that the noticed reduced expression of the vitamin D pathway in lung cells of patients infected with SARS-CoV-2 could be associated with both down-and upregulation of cellular genes because vitamin D is known to regulate gene expression both positively and negatively.…”

The impact of certain genetic variants (single nucleotide polymorphisms) on incidence and severity of COVID‐19

“…Indeed, four genetic variants identified in certain protease genes that alter the structure and function of the encoded protease proteins, which consequently cleave SARS-CoV-2 protein to facilitate viral cell entry, could be protective against and decrease the severity of COVID-19 infection. 18 In conclusion, SNPs in ACE2, TMPRSS2, cytokines, TLR-7, androgen receptor and protease genes could have a significant impact on incidence and severity of COVID-19. Performing genetic analysis in patients with COVID-19 to detect these variants could help in risk stratification of patients to plan their management accordingly.…”