key: cord-1034951-z0zcfk6g
authors: Hashemi, Seyed Mohammad Ali; Thijssen, Marijn; Hosseini, Seyed Younes; Tabarraei, Alijan; Pourkarim, Mahmoud Reza; Sarvari, Jamal
title: Human gene polymorphisms and their possible impact on the clinical outcome of SARS-CoV-2 infection
date: 2021-05-02
journal: Arch Virol
DOI: 10.1007/s00705-021-05070-6
sha: fdcd4ff7f25553239c13c56069558fe5e8fcd599
doc_id: 1034951
cord_uid: z0zcfk6g

The SARS-CoV-2 pandemic has become one of the most serious health concerns globally. Although multiple vaccines have recently been approved for the prevention of coronavirus disease 2019 (COVID-19), an effective treatment is still lacking. Our knowledge of the pathogenicity of this virus is still incomplete. Studies have revealed that viral factors such as the viral load, duration of exposure to the virus, and viral mutations are important variables in COVID-19 outcome. Furthermore, host factors, including age, health condition, co-morbidities, and genetic background, might also be involved in clinical manifestations and infection outcome. This review focuses on the importance of variations in the host genetic background and pathogenesis of SARS-CoV-2. We will discuss the significance of polymorphisms in the ACE-2, TMPRSS2, vitamin D receptor, vitamin D binding protein, CD147, glucose‐regulated protein 78 kDa, dipeptidyl peptidase-4 (DPP4), neuropilin-1, heme oxygenase, apolipoprotein L1, vitamin K epoxide reductase complex 1 (VKORC1), and immune system genes for the clinical outcome of COVID-19.

In March 2020, the World Health Organization (WHO) declared a pandemic caused by an emerging coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The pathogen rapidly surged across the globe, causing havoc on all continents and severely destabilizing healthcare systems. An infection with this virus can cause a variety of mild to severe symptoms, which are collectively named coronavirus disease-2019 (COVID-19) [1] . SARS-CoV-2 is a member of the genus Betacoronavirus, family Coronaviridae. This enveloped virus has a positive single-stranded RNA genome with a length of 29.8 to 29.9 kb, making it the largest amongst all human RNA viruses [2] [3] [4] . SARS-CoV-2 is primarily transmitted through respiratory droplets and contact routes [2, 5] . With unprecedented speed, multiple vaccines have recently been approved, and many others are currently under development to prevent COVID-19. However, with regard to antiviral drugs, specific treatments for SARS-CoV-2 are not yet available.

The course of disease can differ greatly among individuals, ranging from an asymptomatic infection to mild or severe disease and death. The mortality rate for SARS-CoV-2 is still under debate and is affected by multiple variables [2, [5] [6] [7] . From the start of the COVID-19 pandemic, there have been numerous publications about the pathogenesis of the virus, but much still remains to be elucidated. For instance, it is still not clear why some people remain asymptomatic while others develop severe disease. Furthermore, viral respiratory infections are usually more serious in children than in adults, but for SARS-CoV-2 infection this seems to be reversed. Answering these questions and finding the factors that affect the virulence of SARS-CoV-2 will contribute to the development of suitable treatment strategies and better infection control.

Age is an important factor in the outcome of viral respiratory infections. During the Spanish flu pandemic in 1918, the mean death rate was high in people aged younger than five years, 20-40 years old, and older than 65 years [8] . Similarly, at the start of the H1N1 influenza pandemic in 2009, severe pneumonia was observed in 5-to 59-year-old individuals [9] . With other coronaviruses, such as SARS-CoV and human cronavirus-NL63 (HCoV-NL63), it has been observed that children are relatively resistant to infection, similar to the current observations for SARS-CoV-2 [10, 11] .

It has been demonstrated that viral factors such as the number of viral particles in the inoculum, duration of exposure to the virus, and mutations in the virus genome can influence the severity and outcome of the disease [12] . Similarly, host factors such as health condition, age, gender, smoking, immune status, diabetes, hypertension, cardiovascular disease, chronic respiratory disease, cancer, and, more importantly, the genetic background, might determine the clinical manifestations and outcome of infection [13] [14] [15] [16] [17] . Based on the data, it appears that the genetic background of the host influences the severity of the infection and disease outcome [18, 19] . In this review, we provide a comprehensive overview of the current data regarding host gene polymorphisms that might be associated with the pathogenesis and outcome of SARS-CoV-2 infection.

The human ACE or ACE-1 gene is located on chromosome 17q23.3 and is made up of 26 exons. It contains some polymorphisms including insertions (I) or deletions (D) as well as a repetitive sequence of 287 base pairs of Alu sequence in intron 16 [20] . It has been reported that polymorphisms in this gene are associated with SARS-CoV infection outcome [21] . The serum level of ACE in people with the DD genotype is almost twice that of genotype II [22] . The D allele might affect renin-angiotensin pathway activity by increasing the serum or local level of ACE, leading to damage of the vascular endothelium and lung epithelium [23] . Studies have shown that some ACE polymorphisms are associated with Alzheimer's disease (the II and ID ACE genotypes), cardiovascular disease (DD), hepatitis C virus (HCV) infection (DD), and cancers (ACE A240T polymorphism) [24] [25] [26] [27] [28] [29] (Table 1) . Itoyama et al. found that the frequency of the D allele in SARS patients (with and without hypoxemia) was significantly higher than in healthy controls [21] . Also, they suggested that ACE-1 insertions/ deletions (I/D) could probably accelerate the development of pneumonia in SARS-CoV infection [21] . Another study in Caucasian individuals demonstrated that the presence of the D allele was accompanied by an increased rate of acute respiratory distress syndrome (ARDS) [30] . Yamamoto et al. reported that the frequency of SARS-CoV-2 infections and mortality strongly correlated with the ACE-1 I/D genotype, which might serve as a predictive marker for the severity of COVID-19 [31] . On the other hand, Chan et al. reported that in the Chinese population, the ACE I/D polymorphism was not associated with SARS-CoV infection [32] ( Table 2 ). The reason for this discrepancy in the Chinese population is unknown, but it might be related to the lower frequency of the DD genotype and the D allele in the Chinese population than in people with a Caucasian background [30, 33] .

Angiotensin-converting enzyme 2 (ACE-2) is a close homolog of ACE (or ACE-1), exhibiting 61% amino acid similarity and 40% sequence identity. ACE-2 acts as a carboxyl peptidase [34] and has been recognized as the main entry receptor for both SARS-CoV and SARS-CoV-2 through interaction with the spike (S) protein [35] . The ACE-2 gene is located on chromosome Xp22.2 and contains 18 exons [36] . This enzyme is anchored in the cell membranes as a type 1 integral membrane glycoprotein with a high expression level in lung, heart, artery, intestinal, and kidney tissues [37] . The primary role of ACE-2 is converting angiotensin II to angiotensin 1-7, but it also converts angiotensin I to angiotensin 1-9 [34] . Aberrant expression of ACE-2 has been associated with atherosclerosis, hypertension, heart failure, chronic kidney disease, and increased vascular permeability, facilitating respiratory system edema [38] [39] [40] [41] [42] [43] .

Entry of SARS-CoV-2 into target cells is facilitated by the S protein, which consists of two subunits, S1 and S2. The S1 subunit contains the receptor-binding domain (RBD), which interacts with the peptidase domain (PD) of the ACE-2 protein, and this is a critical step for entry of the virus into the host cell [44] . Therefore, genetic variations in the ACE-2 sequence might alter the molecular interaction of the RBD and PD domains, which not only changes the host susceptibility to the virus but also influences the severity of the disease and the outcome of infection.

A recent investigation indicated that genetic variations and expression patterns of ACE-2 might reduce susceptibility to SARS-CoV-2 infection. Given that ACE-2 is located on sex chromosome X, it could be related to the observed gender discrepancies in disease outcome. Srivastava et al. reported a significant positive correlation between ACE2 rs2285666 polymorphism and a lower frequency of infection and case-fatality rate in SARS-CoV-2 infection in the Indian population [45] . Moreover, it has been reported that three SNPs -K26R (rs4646116), M82I (rs267606406) and E329G (rs143936283) -are associated with higher binding affinity for the RBD domain of the S protein compared to wild-type ACE-2. This might result in increased susceptibility to SARS-CoV-2 infection [46] . In contrast, the I21T (rs1244687367), E37K (rs146676783) and D355N (rs961360700) SNPs cause a significantly lower binding affinity and could decrease the susceptibility to infection [46] . Moreover, the hotspot N720D variant in the C-terminal collectrin-like domain of ACE-2 affects the ACE-2-TM-PRSS2 complex and creates a favorable site for TMPRSS2 binding and cleavage, thus facilitating binding to the S protein and potentially promoting virus entry into the cell [47] . Molecular docking simulations have revealed that six ACE2 missense variants -I21T, A25T, K26R, E75G, T55A and  E37K -increase binding affinity, while 11 variants -I21V,  E35K, K26E, T27A, S43R, Y50F, N51D, N58H, K68E, E23K and M82I -decrease the affinity of ACE-2 for the RBD of the S protein [48] . Hashizume et al. reported that ACE-2 SNPs have a limited impact on the ACE-2-dependent cell entry of SARS-CoV-2 [49] . Furthermore, a large cohort study on an Italian population demonstrated no significant relationship between ACE-2 polymorphisms and the severity of COVID-19 [15] (Table 2) .

Both SARS-CoV and human coronavirus NL-63 replication cause a reduction in the expression of the ACE-2 protein, which has been demonstrated to induce more-severe complications in SARS-CoV infection [50] . This reduction is caused by the inhibitory effect of the S protein on ACE-2 expression in infected cells and might result in severe acute lung failure [50] . Hence, considering the protective function of ACE-2 in the tissues, SARS-CoV-2 infections might induce an imbalance in Ang II/Ang1-7 and consequently result in inflammation and hypoxia [51] . Another report has indicated that an increase in the concentration and/or expression of ACE-2 receptors in pediatric lung pneumocytes probably provides protection against severe clinical manifestations of SARS-CoV-2 infection [52] . It has been shown that the injection of the SARS-CoV S protein into mice leads to pulmonary failure. This effect was diminished by blocking the renin-angiotensin pathway [53] . Angiotensin II type I receptor (AT1R) is an important receptor that mediates vascular permeability, and its activation promotes severe acute pulmonary damage [54] . A study performed in mice demonstrated that the inhibition of AT1R reduces severe lung damage as well as pulmonary edema [53] .

In addition to its involvement in coronavirus infection, ACE-2 has also been associated with other viral respiratory infections. For instance, Gu et al. reported that ACE-2 plays a considerable role in pulmonary damage related to respiratory syncytial virus (RSV) infection, which might be related to the high level of angiotensin II in the plasma [55] . Increased levels of angiotensin II could be the result of decreased ACE-2 expression and could lead to severe lung damage by mediating AT1R during RSV infection [55] . Moreover, an association was observed between influenza virus infection and ACE-2 expression levels, which was different with various strains of influenza virus [56, 57] . Although some studies have focused on studying pulmonary pathology to evaluate the impact of these viruses, the molecular mechanisms by which one is predisposed to pulmonary damage are not completely explained by the effects of infection on the renin-angiotensin system (RAS) and ACE-2.

The transmembrane protease serine 2 (TMPRSS2) gene, with a length of 43.59 kbp, is located on chromosome 21q22.3 and consists of 14 exons [58] . It encodes a transcript that is processed by alternative splicing to provide two mRNA variants of 3.25 and 3.21 kb. The TMPRSS2 protein (492 amino acids) is a type II transmembrane serine protease that is expressed on the surface of different tissues/cells, including the small intestine, prostate, colon, salivary gland, and stomach [58] . TMPRSS2 upregulation has been demonstrated in some cancerous cells, and it promotes metastasis by proteolytic activation of hepatocyte growth factor (HGF), a pathway that is targeted by specific drugs [59] . Some polymorphisms in TMPRSS2 have been reported to be genetic risk factors for specific types of cancers and viral infections [15, 60] . For instance, the TMPRSS2 M160V polymorphism increases the susceptibility to prostate cancer in Japanese men [60] .

Recently, it was reported that polymorphisms in the TMPRSS2 gene might be involved in susceptibility to SARS-CoV-2 infection and COVID-19 outcome [15] . Proteolytic cleavage of the S protein by TMPRSS2 at the S1/S2 boundary triggers S2-mediated fusion of the viral envelope and endosome membrane, which is a crucial step for the release of the ribonucleoprotein into the cytoplasm [35] . Expression of the TMPRSS2 gene is Janssen et al. 2020 [217] affected by androgen and estrogen hormones, which might partially explain the observed gender differences in disease severity [53, 57, 61] . A study in Italy demonstrated that some SNPs, including rs2070788, rs9974589, and rs7364083, were associated with a higher expression level of TMPRSS2 and played a considerable role in determining the severity of COVID-19 [15] . Moreover, four other polymorphisms -rs77675406, rs713400, rs112657409, and rs11910678 of TMPRSS2 -affect the expression of the TMPRSS2 gene [62] . Another study showed that four variants of TMPRSS2 -rs2070788, rs383510, rs464397 and rs469390 -which affect the expression of TMPRSS2 in lung tissue, had a higher frequency in European and American populations than in Asian populations. These observations might explain the relatively higher susceptibility of European and American populations to SARS-CoV-2 infection [63] (Table 1) . Furthermore, a recent report by Fuentes et al. demonstrated that synonymous variants of rs61735794 and rs61735792 were significantly associated with SARS-CoV-2 infection outcome [64] . Variations in the TMPRSS2 gene have also been associated with the outcome of other viral infections. For instance, Cheng et al. reported that rs2070788 and rs383510 polymorphisms were associated with higher susceptibility to H1N1 and H7N9 infection. Based on these findings, the authors suggest that people carrying these polymorphisms might have a higher risk of progression to severe disease [65] .

The relationships between polymorphisms of the immune genes and the outcome of viral infections have always been a matter of concern. Considering the pivotal role of these genes in viral clearance and immunopathogenesis, polymorphisms in these regions are likely to affect the outcome of an uncharacterized disease like COVID-19 (Tables 1, 2 ).

Cytokines are small proteins (~5-20 kDa) that are important for cell signaling and include interleukins, chemokines, lymphokines, interferons, and tumour necrosis factors. In severe cases of SARS-CoV-2 infection, high concentrations of innate inflammatory cytokines, including type I interferons (IFNs), tumor necrosis factor α (TNF-α), IL-6, IL-1β, and some chemokines, including CCL-2, CCL-3, CCL-5, and IP-10, are secreted by epithelial and immune cells [66] . This uncontrolled and excessive release of pro-inflammatory cytokines, i.e., cytokine storm, has been observed in patients infected with influenza virus, SARS-CoV, and MERS-CoV [66, 67] . A cytokine storm is characterized by a strong proliferation and hyperactivation of T lymphocytes, overexpression of more than 100 pro-inflammatory genes, and massive endothelial and epithelial cell apoptosis of the lung, which results in alveolar edema, hypoxia and ARDS, and finally, death [66, 68] . The significant role of this aberrant immune response in severe COVID-19 has inspired the search for antibodies that block pro-inflammatory cytokines such as IL-6 and IL-17 as well as monocyte recruitment elements [68] . Additional immune gene variations have been associated with susceptibility to SARS-related pathogenesis. For instance, the IFN-γ +874A allele variant is considered a risk factor for susceptibility to SARS [69] . Interleukin-6 (IL-6, a 21-kDa) glycoprotein polymorphism has been associated with viral infections such as influenza virus, RSV, hepatitis B virus (HBV), and HCV [70] . For example, the IL6-174 C/C genotype (rs1800795) is associated with severe RSV infection [71] . Although IL-6 plays a significant role in the initiation of the cytokine storm in SARS-CoV-2-infected patients, little information is available concerning IL-6 polymorphisms and the pathogenesis of idiopathic pulmonary fibrosis in SARS-CoV-2 infection. A meta-analysis showed that the IL6 174C allele is associated with elevated cytokine production and the outcome of pneumonia [72] . Based on the regulatory function of IL-6 for CD4 T cell fate, it can be hypothesized that studying polymorphisms of the IL-6 genes may provide further insights into COVID-19 pathogenesis [73] . In fact, IL6 polymorphism is considered a valid indicator for the severity or pathology associated with SARS-CoV-2 infection. Moreover, Panda et al. reported that the CCR5 Δ32 polymorphism might influence susceptibility to SARS-CoV-2 infection [74]. Also, IL4 gene polymorphism (SNP: rs2070874; risk allele: T) might influence the outcome of SARS-CoV-1 infection [75] .

The IFNAR2 gene is located on chromosome 21q22.11 and encodes the IFN-α/β receptor beta chain [76] . Data analysis has shown that polymorphism at the rs2236757 locus of the IFNAR2 gene is associated with the outcome of COVID-19 disease [77] .

IFNL4 is another gene that might be involved in SARS-CoV-2 infection. IFNL4 is located on chromosome 19q13.2 and is involved in the defense against viral infections, such as HCV, RSV and influenza virus [78] . Amodio et al. reported that polymorphisms at the rs368234815TT/∆G locus of the IFNL4 gene are associated with a higher SARS-CoV-2 viral load [79] .

Chemokine (C-C motif) ligand 5 (CCL5), also known as regulated on activation, normal T cell expressed and secreted (RANTES), is a protein involved in inflammatory and immunoregulatory processes and encoded by the CCL5 gene located on chromosome 17q12 [80] [81] [82] . CCL5 gene polymorphism (SNP rs2280788, risk allele, C; SNP rs4239252, risk allele, A), is associated with SARS-CoV-1 infection outcome [83, 86] .

The 2′-5′-oligoadenylate synthetase (OAS) family includes IFN-inducible genes that have a prominent role in innate immunity against viral infections such as picornaviruses. This family include four types of IFN-inducible genes: OAS1, OAS2, OAS3, and OAS-like protein [84] . OAS interferes with viral replication through the induction of apoptosis and inhibition of protein synthesis [84] .

The OAS-RNase L axis is rapidly activated following cellular infection with various RNA viruses, e.g., flaviviruses, alphaviruses, picornaviruses, and coronaviruses [85, 87] . Moreover, the variant of rs10735079 in a gene cluster encoding antiviral restriction enzyme activators (OAS1, OAS2, OAS3) is associated with SARS-CoV-2 infection outcome [77] . Human Mx1 is another IFN-type-1-induced gene that is located on chromosome 21q22.3, and the encoded protein targets viral nucleoproteins [88, 89] . Regarding the role of these genes in innate immunity against viral infections, some studies have suggested that SNPs in the OAS1 gene and MxA promoter might be associated with a higher susceptibility to more-severe SARS infection [90] . In this regard, He et al. reported that SNPs in the 3'-UTR region of the OAS1 gene and the MxA promoter were associated with susceptibility to SARS in the Han population of China [90] . The results of their study revealed that the frequency of the AG and GG genotypes of the OAS1 gene was higher in the control group than in SARS patients. Therefore, they suggested that the G allele might have a protective effect against SARS-CoV infection [90] . Also, studies have revealed that polymorphisms at the -123 (C/A) and -88 (G7T) loci of the Mx1 gene affect the levels of protein expression, thereby influencing disease outcomes in patients infected with HBV, HCV, and enterovirus 71, and SARS-CoV [90] [91] [92] [93] [94] [95] [96] [97] [98] .

CD14 is a transmembrane glycoprotein that is located on chromosome 5q31.3 and expressed on cells of the monocytemacrophage lineage and neutrophils [99] . CD14 is involved in a variety of biological activities, including cell differentiation and host-pathogen interactions, and it is a key molecule in the activation of innate immune cells [99] . It has been reported that the frequency of CD14-159CC polymorphism (rs2569190) is significantly higher among patients suffering from severe SARS, indicating its importance in determining the disease outcome [99] . On the other hand, it has also been reported that IL-10 and TNF-α polymorphisms are not associated with SARS sensitivity [69] . In a study carried out by Tu et al., it was found that the CCL2G-2518A (rs1024611) polymorphism and variations in codon 54 in MBL (rs1800450) are significantly associated with the risk of SARS-CoV infection [100] .

The CD209 gene is located on chromosome 19p13.2 and encodes a critical dendritic-cell surface receptor named dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN) [101, 102] . In innate immunity and antiviral defense, DC-SIGN has key functions, including DC migration, antigen uptake, and T-cell priming [103] . DC-SIGN was first discovered as an attachment factor for HIV that binds to the viral envelope glycoprotein and increases the efficiency of infection [104] . Subsequently, DC-SIGN and DC-SIGNR (or L-SIGN) were shown to enhance Ebola virus and SARS-CoV infection [105] . Studies have suggested that polymorphisms in the DC-SIGN gene might be involved in susceptibility/resistance to dengue virus, tick-borne encephalitis virus, cytomegalovirus, and SARS-CoV-2 infection [106, 107, 110] . Supporting this hypothesis, Iyer et al. recently reported that polymorphisms at rs2287886 and rs8105483 are correlated with protection, and those at rs11881682, rs8105572, rs7252229, rs11465384, rs7248637, and rs1146541 are correlated with risk of/susceptibility to symptomatic COVID-19 disease [106] (Table 2 ). In addition, they revealed that the G allele in rs10518270 and rs2335525 SNPs is a risk allele in SARS-CoV-1 infection [106] .

The mucin 5B (MUC5B) gene is located on chromosome 11p15.5 and encodes MUC5B, which plays a role in the viscoelastic and lubricating properties of the mucosa [108] . The MUC5B gene is upregulated in some human diseases related to pulmonary fibrosis and end-stage lung disease [109] . Many symptoms related to MUC5B upregulation in lung disease resemble COVID-19 disease [106] . It has been suggested that the SNPs in the MUC5B gene might be associated with human diseases such as pulmonary fibrosis and COVID-19 disease [106, [110] [111] [112] . Iyer et al. reported that polymorphisms at rs2672794, rs56235854, rs7115457, rs2735727, rs12417955, and rs56367042 might be associated with susceptibility to COVID-19 disease and that those at rs2735733, rs2249073, rs2857476 might be associated with comorbidities [106] .

Another IFN-inducible gene is the IFN-induced transmembrane protein 3 (IFITM3) gene, which is located on chromosome 11p15.5 [113] . This gene encodes a membrane protein that inhibits viral fusion with cholesterol-depleted endosomes [113] . It has been shown that IFITM3 is active against viral infections, including influenza virus, SARS-CoV, dengue virus, Ebola virus, and HIV-1 [114, 115] . Functional polymorphisms in this gene have been studied in several infections. Iyer et al. reported that polymorphisms at rs34481144 might have a protective role, whereas those at rs7948108, rs12252, rs4804800, rs4804803, rs6598045, and rs3888188 might increase susceptibility to SARS-CoV-2 infection [106] . Furthermore, Gómez et al. revealed that the rs12252 C variant of the IFITM3 gene might be associated with COVID-19 disease outcome [116] .

The IFN induced with helicase C domain 1 (IFIH1) gene is located on chromosome 2q24.2, is induced by IFN type I, and encodes MDA5, an intracellular sensor of viral RNA [117] . It has been reported that the lower frequency of the T allele at the locus rs1990760 of IFIH1 in the African-American population might be associated with COVID-19 infection outcome due to decreased expression of IFN-β [118] . Formyl peptide receptor 1 (FPR1), a pattern-recognition receptor, is involved in the induction of innate immune responses against bacterial infections [119] . Although it has been reported recently that FPR1 expression is involved in lung inflammation and fibrosis, a genetic investigation showed no association between polymorphisms at the rs867228 and rs5030880 loci of the FPR1 gene and the severity of COVID-19 disease [120] ( Table 2 ).

Dipeptidyl peptidase 9 (DPP9) is a Dipeptidyl peptidase 9 (DPP9) is a member of the S9B family, and its gene is located on chromosome 19p13.3 [77] . DPP9 is a serine protease that plays an important role in antigen presentation, activation of inflammasomes, and cleavage of important elements of the immune system such as chemokines (CXCL10, CXCL11, and CXCL12) [121] [122] [123] . It has been reported that polymorphisms at the locus rs2109069 of the DPP gene might be associated with COVID-19 outcome. For instance, variations at this location were associated with idiopathic pulmonary fibrosis in COVID-19 patients [77, 124] .

Tyrosine kinase 2 (Tyk2), a member of the Janus kinase (JAK) family, is associated with the cytoplasmic domain of type I and II cytokine receptors [77] . The Tyk2 gene is located on chromosome 19p13.2. It has been reported that polymorphisms at rs2109069 near the Tyk2 gene might be associated with COVID-19 outcome [77] .

Human leukocyte antigens (HLAs) are encoded by the major histocompatibility complex (MHC) genes in humans and are responsible for regulation of the immune system. The HLA gene complex is located on chromosome 6p21 [125] . Previous investigations have shown that various polymorphisms of HLA, such as HLA-DR B1*1202, HLA-B*4601, HLA-B*0703, and HLA-Cw*0801 might predispose carriers to more-severe SARS-CoV infection [126, 127] . In contrast, the HLA-A*0201, HLA-Cw1502, and HLA-DR0301 alleles are correlated with protection from SARS-CoV infection [128] , while HLA-DQB1*02:0 and HLA-DRB1*11:01 are associated with a higher risk of MERS-CoV infection [129] . Amoroso et al. reported that HLA-DRB1*08 was more frequent in COVID-19 patients and correlated with an increased mortality rate [130] .

Alpha-2-HS-glycoprotein (AHSG, alpha-2-Heremans-Schmid glycoprotein or fetuin-A) is a protein that is encoded on chromosome 3q27.3 [131] . This protein is synthesized by hepatocytes and adipocytes and has several functions in brain development, endocytosis, and the formation of bone tissue [132] . Like carrier proteins (e.g., albumin) it is present in the serum, and SNPs have been associated with serum fetuin-A levels [133] . Fetuin-A can increase insulin resistance and inflammation, and it is essential for the deactivation of macrophages by modulating endogenous cations [134] . Low serum levels of AHSG have been associated with uncontrolled production of proinflammatory cytokines [135, 136] . Furthermore, polymorphisms in the AHSG (SNP rs2248690; risk allele, T) gene might affect the outcome of SARS-CoV-1 infection [137] . So far, polymorphisms in this gene have not been studied in COVID-19 patients.

The intercellular adhesion molecule 3 (ICAM3) gene is located on chromosome 19p13.2. ICAM3 acts as an adhesion molecule and a signaling molecule, and it also functions in the initiation of the immune response [138] . ICAM3 gene polymorphisms (SNP rs2304237, risk allele, C; SNP rs3181049, risk allele, A; SNP rs3176767, risk allele, G; SNP rs4611572, risk allele, G; SNP rs2304240, risk allele, G) might affect SARS-CoV-1 infection outcome [139] .

The Toll-like receptor 3 (TLR3) gene is located on chromosome 4q35.1. TLR3 is a member of the TLR family of pattern recognition receptors and has an important function in sensing and activation of the innate immune system. An in silico analysis by Teimouri et al. showed that polymorphisms at rs3775290 and rs3775291 enhanced recognition of SARS-CoV-2 dsRNA by TLR3, whereas those at rs73873710 decreased its efficiency [140] .

Vitamin D binding protein (DBP) is a multifunctional protein that is involved in various clinical conditions by regulating vitamin D metabolite levels [141] . The DBP gene is located on chromosome 4q11-q13 and is predominantly expressed in liver tissue [142] . Some factors such as estrogen, glucocorticoid, and inflammatory cytokines modulate DBP expression levels. Consisting of 458 amino acids, DBP has been identified as the most polymorphic protein [142] . Allele variations have a substantial impact on its biological functions (e.g., the alleles Gc1s (rs7041 locus) and Gc2 (rs4588 locus) increase the affinity of DBP for vitamin D and are associated with lower free vitamin D levels [141] . In HCV infection, the G allele at the rs7041 locus has been reported to be associated with the expression of a high-affinity receptor, which increases the risk of infection [143] . People carrying the GG genotype at the rs4588 locus of the Gc2 polymorphic region have lower levels of 25(OH) D compared to individuals carrying the AA genotype following vitamin D supplementation [144] . Batur et al. showed that DBP variations such as the GT genotype at rs7041 are significantly correlated with a higher frequency of COVID-19-related deaths, while the TT genotype showed a significant negative correlation with mortality [141] . In addition, the polymorphism at the rs4588 locus had no significant impact on COVID-19 severity [141] . These findings indicate that variations in mortality rate may be explained by DBP polymorphisms, which affect vitamin D metabolism [141] .

The vitamin D receptor (VDR) gene is located in the region q13.11 of chromosome 12 [145] . VDR is a nuclear receptor that functions as a transcription factor when activated by its ligand [146] . Most of the VDR activity is controlled by the interaction with the ligand 1,25(OH)2D, but some functions are vitamin-D-independent. [147, 148] . VDR belongs to the steroid receptor family, which includes retinoic acid, thyroid hormone, sex hormones, and adrenal steroid receptors, which have a broad distribution among different cells [149, 150] . Vitamin D signaling is involved in calcium and bone homeostasis, skin biology, immune health, oral health, cancers, and cardiovascular diseases [148] . Many cells of the innate and adaptive immune system express VDR. Some of these cells express CYP27B1 for producing the biologically active form of vitamin D [148] . Data from experiments using animal models have demonstrated that vitamin D/VDR signaling modulates autoimmune T cell responses and immuneinflammatory reactions, but the physiological activity in humans is not completely understood [151] . Therefore, its role in the pathogenesis and outcome of immune-inflammatory diseases remains to be elucidated [148, 152] .

Based on a meta-analysis by Laplana et al., a polymorphism at locus rs2228570 was associated with viral infections. The TT genotype and T allele were reported to be risk factors for infections with enveloped viruses, including RSV [153] . There are numerous findings indicating that vitamin D supplementation can reduce the risk of severe infection and death related to influenza and COVID-19. However, none of the studies have reported the importance of vitamin D receptor polymorphisms in COVID-19 disease outcome [154] . When examining the antimicrobial role of vitamin D in different populations, we need to take VDR polymorphisms into account.

Glucose-regulated protein (GRP78), or heat shock protein family A (HSPA) member 5, belongs to the HSP70 family and is found on the membrane of the endoplasmic reticulum (ER). The gene encoding this protein is located on chromosome 9q33.3 [155, 156] . GRP78 plays an accessory role in many stages of the viral life cycle, including viral attachment and entry (facilitating or alternative factor), protein production (proper folding and processing), release (assembly and maturation), and re-infectivity (released together with mature virions and acting as accessory infectivity factor) [157] . Bioinformatic modeling has predicted favorable binding between GRP78 and the III (C391-C525) and IV (C480-C488) regions of the SARS-CoV-2 S protein [158] . In cells harboring the -415A/-180G allele, expression of HSPA5 was significantly increased compared to cells harboring the -415 G/-180 del allele following ER stress [159] . GRP78 expression and its polymorphisms may be associated with SARS-CoV-2 infection and mortality rates, but their role in COVID-19 is still poorly understood.

CD147 is a cell-surface glycoprotein belonging to the immunoglobulin superfamily that plays a role in intercellular recognition [160] . The CD147 gene encompasses a stretch of 7500 bp on chromosome 19p13.3 and encodes a protein from eight exons [161, 162] . CD147 is also known as extracellular matrix metalloproteinase inducer (EMM-PRIN) or basigin and is expressed by a variety of cell types, including endothelial cells, epithelial cells, and lymphocytes [163] [164] [165] [166] . It has been reported that CD147 regulates proliferation, differentiation, migration, metastasis, and apoptosis of tumor cells, particularly in hypoxic situations [167, 168] . Therefore, the role of CDl47 in the progression and metastasis of tumors has been studied [169] .

CD147 has recently been identified as a marker of inflammation [170] . Moreover, some studies have shown that CD147 is an important molecule in proteolysis and inflammation [171] . CD147 has various ligands, e.g., integrins, cyclophilin, and Plasmodium falciparum reticulocyte binding-like homologue 5 [168] . The role of CD147 in infections by viruses such as Kaposi's sarcoma-associated herpesvirus (KSHV), HBV, HCV, and HIV has been studied extensively, and these studies have supported the importance of CD147 in viral pathogenesis and tumorigenesis [168] . Interactions of CD147 with cyclophilin A during HIV infection accelerate its uptake into cells. A similar mechanism has been reported for SARS coronavirus infection [172, 173] . Furthermore, CD147 on epithelial cells acts as a receptor for measles virus [174] . Studies have reported that the CD147 gene contains a number of SNPs in coding and regulatory regions, including rs2283574, rs6757, rs8637, rs4919862, rs6758, rs8259, rs4919859, and rs28915400. These regions might be involved in numerous diseases and disorders [175, 176] . For instance, it has been reported that polymorphisms in the CD147 gene might effectively contribute to the initiation and progression of acute coronary syndrome and skin diseases [171, 177, 178] . Although CD147 has been studied in the context of viral pathogenesis and tumorigenesis, the significance of its polymorphisms in viral infection outcome remains to be determined [168] .

Recent studies have suggested that CD147 can serve as an alternative receptor for SARS-CoV-2 [179] . Although some studies have investigated ACE-2 polymorphisms that enhance or diminish binding of the S protein to ACE-2, polymorphisms that affect S protein binding to CD147 have not been reported in SARS-CoV-2 infection. Meanwhile, Wu et al. have reported that the polymorphism T/A (rs8259) in the 3′-UTR of the CD147 gene, which interacts with miR-492, alters the expression of CD147 [178] . However, no studies have been conducted to investigate the relationship between SNPs of CD147 or miRNA-492 and the risk of SARS-CoV-2 infection. miRNA-492 is encoded on chromosome 12q22 and binds to complementary sequences in the 3΄-UTRs of target mRNAs.

Dipeptidyl peptidase 4 (DPP4), also known as CD26, is encoded by the DPP4 gene, which is located on chromosome 2q24.2 [180] . DPP4 is a serine exopeptidase that is expressed on the surface of most cell types and cleaves X-alanine or X-proline dipeptides from the N-termini of polypeptides. DPP4 has been identified as the cellular entry receptor for MERS-CoV. Current data suggest that CD26 does not act as a receptor for SARS-COV-2 [181] . However, one study has shown that polymorphisms in the rs13015258 locus in the CD26 gene affect the expression of key regulatory genes related to internalization of SARS-CoV-2 into the host cell [62] .

Understanding the mechanisms and pathways involved in the cellular entry of SARS-CoV-2 is essential to delineate virus tropism to develop preventive strategies. In addition to ACE-2 and CD147, receptor for advanced glycation endproducts (RAGE), and olfactory receptors, recent experiments have suggested neuropilin 1 (NRP-1) to be a new mediator of SARS-CoV-2 entry in the nervous system [181, 182] . An in vitro study confirmed the direct binding of the S1 CendR motif of SARS-CoV-2 NRP-1 [181] . Moreover, it has been shown that NRP-1 binds to furin-cleaved substrates and consequently enhances the infectivity of SARS-CoV-2. This mechanism can be targeted by NRP-1 monoclonal antibodies to block entry of the cell by the virus [182] .

NRP-1 is a type I transmembrane protein, and its gene is located on chromosome 10p11.22 [153] . NRP-1 is involved in providing cues for axonal guidance and neuronal development. Furthermore, it has been identified as a co-receptor for multiple ligands, such as vascular endothelial growth factor (VEGF), semaphorins (SEMA), and transforming growth factor beta (TGF-β) [184, 185] . A higher level of expression of NRP-1 has been detected in the upper respiratory tract and olfactory epithelium covering the nasal cavity [186] . Similar polybasic furin-type cleavage sites (RRAR^S) in the S1-S2 junction of the spike glycoproteins have been observed in other human viruses including Ebola virus, HIV-1, and highly virulent strains of avian influenza virus. In contrast, a similar site was found to be lacking in SARS-CoV-1 [187, 188] .

There are a growing number of studies investigating the role of NRP-1 in the immune response. Hwang et al. demonstrated that NRP-1 regulates the secondary CD8 T cell response to viral infections. NRP-1 was also found to be important for the function of regulatory T (Treg) cells [189] . Overexpression of NRP-1 in T-reg cells enhances their interactions with dendritic cells, which attenuated the immune responses in the absence of danger signals. Based on these findings, polymorphisms in the NRP-1 gene might affect the immune response to SARS-CoV-2 infection by inhibiting antigen presentation in the lymph nodes and subsequent viral clearance. In one study, 11 functional SNPs were reported in the NRP-1 gene, which have been associated with various clinical conditions. For instance, a polymorphism at rs2228638 was shown to be associated with an increased risk of cyanotic congenital heart disease [190] . Recently, it was reported that binding of miR-338 to the 3'-UTR of NRP-1 significantly inhibits the expression of NRP-1. Since the rs10080 SNP is located in the 3'-UTR region, it might affect the expression pattern of NRP-1 [190] . For instance, it has been reported that the G allele of rs10080 can downregulate the expression of NRP-1 [191] . Therefore, individuals carrying the G allele might express lower levels of NRP-1 on the target cells, which alters the neuropathogenesis associated with COVID-19 disease. More investigations regarding the effect of SNPs in NRP-1 on the pathogenesis of SARS-CoV-2 infection in other tissues are recommended.

Heme oxygenase 1 (HO-1, HMOX1) is located on chromosome 22q12.3 [191] . The heme oxygenase system is an antiinflammatory cytoprotecting system that includes HO-1 and HO-2. It degrades heme to bilirubin, free iron, and carbon monoxide and plays an important role in the antioxidant and antiapoptotic activity of the cells [192] . The high-affinity binding of the SARS-CoV-2 spike protein to porphyrin [193] upregulates the formation of reactive oxygen species (ROS) and free heme and decreases the level of HO-1 [192, 194, 195] . Therefore, the SARS-CoV-2-porphyrin complex may cause impairment of HO-1 signaling by downregulating HO-1 gene expression, which results in severe oxidative stress induced by free heme and iron [192, 194, 196] . It has been reported that a genetic polymorphism, a di-nucleotide repeat of GT, in the promoter region of the HO-1 affects the transcription of HO-1 and might be associated with the COVID-19-induced cytokine storm [192, [197] [198] [199] [200] [201] [202] . In this regard, Fakhouri et al. concluded that individuals with longer GT repeats in the HO-1 promoter were at higher risk of developing severe COVID-19 disease [192] . Moreover, it has been reported that the T allele at the locus rs2071746 of the HO-1 gene can modulate the expression of HO-1 and influence the severity of COVID-19 disease [203] .

Apolipoprotein L1 (APOL1), a member of APOL gene family, is encoded by a gene located on chromosome 22q12.3 [204] . APOLs play important roles in lipid transport and metabolism, innate immunity, apoptosis, and autophagy [205] [206] [207] [208] [209] [210] [211] . Furthermore, APOL1 is involved in inflammatory and pro-inflammatory responses. For instance, cytokines such as TNF-α and IFN-γ can upregulate APOL1 expression [210] . Recently, the relationship between COVID-19 disease and APOL1 polymorphism in African patients was reported [212] . These researchers emphasized the potential key role of G1 and G2 alleles in the formation of collapsed focal segmental glomerulosclerosis (FSGS) related to SARS-CoV-2 [212] . Moreover, Larsen et al. reported that CG variants of the APOL1 gene were associated with COVID-19-related severity of kidney disease [213] . The CG genotype has not been reported in Chinese and European populations. Therefore, the high-risk APOL1 genotypes might exist only in African populations [213, 214] .

The vitamin K epoxide reductase complex 1 (VKORC1) gene is located on chromosome 16p11.2 [215] . Polymorphism at the regulatory -1639A locus of the VKORC1 gene is common in the East Asian population and is associated with low vitamin K turnover [216] . Based on reported data, it has been proposed that VKORC1-1639A polymorphisms (rs9923231) are associated with protection against thrombotic complications of COVID-19 infection, which might partially explain the differences in the severity of COVID-19 infection between Western and Eastern countries [217] .

The ABO blood group system is based on the presence or absence of A and B glycan antigens on red blood cells. A particular ABO blood type might confer resistance to infectious diseases. Several studies found an association between the ABO blood group and susceptibility to SARS-CoV-2 infection. For instance, individuals with blood group O had a lower risk of infection than those with blood group A [130, 218] . Moreover, SNP rs657152 at the locus 9q34.2, which mapped on the ABO locus, was reported to be a genetic susceptibility locus in COVID-19 patients diagnosed with respiratory failure [219] .

In addition to being a local respiratory disease, COVID-19 is a complex multi-organ disease in which human genetic polymorphisms play a distinctive role in the disease outcome. Currently, there is insufficient and controversial knowledge about the role of gene polymorphisms in the pathogenesis of SARS-CoV-2 infection. In this review, we have provided a comprehensive overview of the relevant research data currently available. The affinity-determining variants in the ACE-2 gene, such as rs2285666, rs4646116, rs267606406, rs143936283, rs961360700, rs146676783, and rs1244687367, are associated with SARS-CoV-2 infection outcome. The expression level of TMPRSS2 plays a considerable role in determining the severity of COVID-19. Polymorphisms in the TMPRSS2 gene, including rs2070788, rs9974589, and rs7364083, are associated with increased expression of this gene. The G allele at rs10080 of the NRP-1 gene might be associated with lower expression of the NRP-1 protein on target cells and might result in decreased COVID-19 pathogenesis. Moreover, polymorphisms in the immune-related genes, including TLR3, IFNL4, IFIH1, and CCR5, are likely to influence the outcome of COVID-19 disease. Finally, genetic polymorphisms in some other genes, including the HO-1, APOL1, VKORC1, DPP4, and DBP genes, might influence the SARS-CoV-2 infection outcome. The present review was an attempt to clarify the importance of human gene polymorphisms in the clinical outcome of SARS-CoV-2 infection. This overview provides insights for disease management and control.

Author contributions All authors contributed to the writing and revision of the manuscript. All authors read and approved the final manuscript.

Funding The present study was financially supported by Shiraz University of Medical Sciences (Grant no. 22169)

Conflict of interest The authors declare no conflict of interest.

The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2

Coronavirus disease 2019 (COVID-19): a literature review

Coronavirus genomics and bioinformatics analysis

Genomic characterization of a novel SARS-CoV-2

Air conditioning system usage and SARS-CoV-2 transmission dynamics in Iran

Real-time tentative assessment of the epidemiological characteristics of novel coronavirus infections in Wuhan, China, as at 22

Lu R (2020) A novel coronavirus from patients with pneumonia in China

Epidemiological evidence of an early wave of the 1918 influenza pandemic in New York City

Severe respiratory disease concurrent with the circulation of H1N1 influenza

Epidemiology of human coronavirus NL63 infection among hospitalized patients with pneumonia in Taiwan

Characteristics of communityacquired respiratory viruses infections except seasonal influenza in transplant recipients and non-transplant critically ill patients

The virus inoculum volume influences outcome of influenza A infection in mice

Risk factors of critical & mortal COVID-19 cases: a systematic literature review and meta-analysis

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy

Genotype and phenotype of COVID-19: their roles in pathogenesis

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study

Ten challenging questions about SARS-CoV-2 and COVID-19

Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Angiotensin-I-converting enzyme and its relatives

ACE1 polymorphism and progression of SARS

Soubrier F (1990) An insertion/deletion polymorphism in the angiotensin I-converting enzyme gene accounting for half the variance of serum enzyme levels

Angiotensin-converting enzyme 2 (ACE2) in disease pathogenesis

Variation in DCP1, encoding ACE, is associated with susceptibility to Alzheimer disease

ACE I/D polymorphism is a risk factor of Alzheimer's disease but not of vascular dementia

Alzheimer disease risk and genetic variation in ACE: a meta-analysis

The DD-ACE genotype and cardiovascular disease

Angiotensin converting enzyme (ACE D/I) polymorphism and its relation to liver fibrosis progression in Egyptian patients with chronic hepatitis C virus infection

Association between ACE A240T polymorphism and cancer risk: a meta-analysis

Angiotensin converting enzyme insertion/deletion polymorphism is associated with susceptibility and outcome in acute respiratory distress syndrome

SARS-CoV-2 infections and COVID-19 mortalities strongly correlate with ACE1 I/D genotype

Absence of association between angiotensin converting enzyme polymorphism and development of adult respiratory distress syndrome in patients with severe acute respiratory syndrome: a case control study

Angiotensin I-converting enzyme (ACE) gene polymorphism and breast cancer risk among Chinese women in Singapore

A human homolog of angiotensin-converting enzyme cloning and functional expression as a captopril-insensitive carboxypeptidase

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

ACE2: the molecular doorway to SARS-CoV-2

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Angiotensin-converting enzyme 2 (ACE2) is a key modulator of the renin angiotensin system in health and disease

Renin-angiotensin system and atherothrombotic disease: from genes to treatment

Angiotensin-(1-7) blockade attenuates captopril-or hydralazine-induced cardiovascular protection in spontaneously hypertensive rats-treated with L-NAME

Expression of reninangiotensin system components in the heart, kidneys, and lungs of rats with experimental heart failure

A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9

Haemodynamic and endocrine effects of type 1 angiotensin II receptor blockade in patients with hypoxaemic cor pulmonale

Structure of SARS coronavirus spike receptor G binding domain complexed with receptor

Genetic association of ACE2 rs2285666 polymorphism with Covid-19 spatial distribution in India

Molecular simulation of SARS-CoV-2 spike protein binding to pangolin ACE2 or human ACE2 natural variants reveals altered susceptibility to infection

Structural analysis of ACE2 variant N720D demonstrates a higher binding affinity to TMPRSS2

Molecular docking simulation reveals ACE2 polymorphisms that may increase the affinity of ACE2 with the SARS-CoV-2 Spike protein

Population-specific ACE2 single-nucleotide polymorphisms have limited impact on SARS-CoV-2 infectivity in vitro

Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63

Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration

Will children reveal their secret? The coronavirus dilemma

A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury

Angiotensin-converting enzyme 2 protects from severe acute lung failure

Angiotensin-converting enzyme 2 inhibits lung injury induced by respiratory syncytial virus

Angiotensin II plasma levels are linked to disease severity and predict fatal outcomes in H7N9-infected patients

Angiotensin II receptor blocker as a novel therapy in acute lung injury induced by avian influenza A H5N1 virus infection in mouse

Molecular characterization of TMPRSS2-ERG gene fusion in the NCI-H660 prostate cancer cell line: a new perspective for an old model

The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis

TMPRSS2 M et160 V al polymorphism: significant association with sporadic prostate cancer, but not with latent prostate cancer in J apanese men

ETV1 directs androgen metabolism and confers aggressive prostate cancer in targeted mice and patients

Assessment of risk conferred by coding and regulatory variations of TMPRSS2 and CD26 in susceptibility to SARS-CoV-2 infection in human

Genetic variants that influence SARS-CoV-2 receptor TMPRSS2 expression among population cohorts from multiple continents

ACE2, TMPRSS2, and Furin variants and SARS-CoV-2 infection in Madrid, Spain

Identification of TMPRSS2 as a susceptibility gene for severe 2009 pandemic A (H1N1) influenza and A (H7N9) influenza

The Cytokine storm in COVID-19: An overview of the involvement of the chemokine/chemokine-receptor system

An enlightening role for cytokine storm in coronavirus infection

Cytokine storm intervention in the early stages of COVID-19 pneumonia

The interferon gamma gene polymorphism+ 874 A/T is associated with severe acute respiratory syndrome

Impact of host genetic polymorphisms on vaccine induced antibody response

The interleukin 6-174 C/C genotype predicts greater rhinovirus illness

Anti-IL-6 receptor antibody treatment for severe COVID-19 and the potential implication of IL-6 gene polymorphisms in novel coronavirus pneumonia

Panda AK, Padhi A, Prusty BAK (2020) CCR5 Δ32 minorallele is associated with susceptibility to SARS-CoV-2 infection and death: an epidemiological investigation

The role of host genetic factors in respiratory tract infectious diseases: systematic review, meta-analyses and field synopsis

The human interferon αβ receptor: characterization and molecular cloning

Genetic mechanisms of critical illness in Covid-19

IFNL4 genotypes predict clearance of RNA viruses in Rwandan children with upper respiratory tract infections

SARS-CoV-2 viral load, IFNλ polymorphisms and the course of COVID-19: an observational study

Transcriptional regulation of RANTES expression in T lymphocytes

CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells

The association of RANTES polymorphism with severe acute respiratory syndrome in Hong Kong and Beijing Chinese

The human 2′, 5′-oligoadenylate synthetase locus is composed of three distinct genes clustered on chromosome 12q24. 2 encoding the 100-, 69-, and 40-kDa forms

Inhibition of the OAS/RNase L pathway by viruses

Activation and ******antagonism of the OAS-RNase L pathway

Viral encounters with 2′,5′-oligoadenylate synthetase and rnase l during the interferon antiviral response

cDNA cloning and assignment to chromosome 21 of IFI-78K gene, the human equivalent of murineMx gene

Interferon-induced Mx proteins in antiviral host defense

Association of SARS susceptibility with single nucleic acid polymorphisms of OAS1 and MxA genes: a case-control study

The haplotype of the MxA gene promoter is associated with hepatitis B virus infection in a Chinese population

Significance of the Myxovirus resistance A (MxA) gene-123C> a singlenucleotide polymorphism in suppressed interferon β induction of severe acute respiratory syndrome coronavirus infection

Polymorphisms of interferon-inducible genes OAS-1 and MxA associated with SARS in the Vietnamese population

Identification of a single nucleotide polymorphism in the MxA gene promoter (G/T at nt-88) correlated with the response of hepatitis C patients to interferon

Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA

MxA induction may predict sustained virologic responses of chronic hepatitis B patients with IFN-α treatment

Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection

Association of functional polymorphisms in the MxA gene with susceptibility to enterovirus 71 infection

High prevalence of the CD14-159CC genotype in patients infected with severe acute respiratory syndrome-associated coronavirus

Functional polymorphisms of the CCL2 and MBL genes cumulatively increase susceptibility to severe acute respiratory syndrome coronavirus infection

Novel member of the CD209 (DC-SIGN) gene family in primates

The evolutionary history of the CD209 (DC-SIGN) family in humans and non-human primates

DC-SIGN and immunoregulation

Sequence and expression of a membrane-associated C-type lectin that exhibits CD4-independent binding of human immunodeficiency virus envelope glycoprotein gp120

C-type lectins DC-SIGN and L-SIGN mediate cellular entry by Ebola virus in cis and in trans

Infectivity and progression of COVID19 based on selected host candidate gene variants

Single nucleotide polymorphism in the promoter region of the CD209 gene is associated with human predisposition to severe forms of tick-borne encephalitis

Characterization of human mucin 5B gene expression in airway epithelium and the genomic clone of the amino-terminal and 5′-flanking region

The possible pathogenesis of idiopathic pulmonary fibrosis considering MUC5B

The N-terminal region of IFITM3 modulates its antiviral activity by regulating IFITM3 cellular localization

Promoter analysis and aberrant expression of the MUC5B gene in diffuse panbronchiolitis

Genetically determined variation of respiratory mucins: disease and demography

IFITM genes, variants, and their roles in the control and pathogenesis of viral infections

Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation

Genetic variants in C-type lectin genes are associated with colorectal cancer susceptibility and clinical outcome

The Interferon-induced transmembrane protein 3 gene (IFITM3) rs12252 C variant is associated with COVID-19

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

The African-American population with a low allele frequency of SNP rs1990760 (T allele) in IFIH1 predicts less IFN-beta expression and potential vulnerability to COVID-19 infection

Recognition of bacterial signal peptides by mammalian formyl peptide receptors

No impact of cancer and plague-relevant FPR1 polymorphisms on COVID-19

Identification of novel dipeptidyl peptidase 9 substrates by two-dimensional differential in-gel electrophoresis

The cytoplasmic peptidase DPP9 is rate-limiting for degradation of proline-containing peptides

DPP9's enzymatic activity and not its binding to CARD8 inhibits inflammasome activation

Genome-wide association study identifies multiple susceptibility loci for pulmonary fibrosis

Introductory chapter: concept of human leukocyte antigen (HLA). human leukocyte antigen (HLA). IntechOpen

Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population

Epidemiological and genetic correlates of severe acute respiratory syndrome coronavirus infection in the hospital with the highest nosocomial infection rate in Taiwan in 2003

Human-leukocyte antigen class I Cw 1502 and class II DR 0301 genotypes are associated with resistance to severe acute respiratory syndrome (SARS) infection

Association of human leukocyte antigen class II alleles with severe Middle East respiratory syndrome-coronavirus infection

HLA and AB0 polymorphisms may influence SARS-CoV-2 infection and COVID-19 severity

A synonymous coding polymorphism in the α2-Heremans-Schmid glycoprotein gene is associated with type 2 diabetes in French Caucasians

Fetuin-A: a multifunctional protein

Haplotype analysis of the human α2-HS glycoprotein (fetuin) gene

Pathophysiological implication of Fetuin-A glycoprotein in the development of metabolic disorders: a concise review

Serum concentration of human alpha 2 HS glycoprotein during the inflammatory process: evidence that alpha 2 HS glycoprotein is a negative acute-phase reactant

Fetuin, a negative acute phase protein, attenuates TNF synthesis and the innate inflammatory response to carrageenan

Genetic variation of the human α-2-Heremans-Schmid glycoprotein (AHSG) gene associated with the risk of SARS-CoV infection

Intercellular adhesion molecules (ICAM)-1 ICAM-2 and ICAM-3 function as counter-receptors for lymphocyte function-associated molecule 1 in human immunodeficiency virusmediated syncytia formation

Association of ICAM3 genetic variant with severe acute respiratory syndrome

Single-Nucleotide polymorphisms in host pattern-recognition receptors show association with antiviral responses against SARS-CoV-2, in-silico trial

The role of DBP gene polymorphisms in the prevalence of new coronavirus disease 2019 infection and mortality rate

Vitamin D binding protein, total and free vitamin D levels in different physiological and pathophysiological conditions

Vitamin D binding protein polymorphisms influence susceptibility to hepatitis C virus infection in a high-risk Chinese population

Associations of vitamin D binding protein variants with the vitamin D-induced increase in serum 25-hydroxyvitamin D

Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease

Vitamin D receptor signaling mechanisms: integrated actions of a well-defined transcription factor

The vitamin D receptor: new paradigms for the regulation of gene expression by 1, 25-dihydroxyvitamin D3

The biological activities of vitamin D and its receptor in relation to calcium and bone homeostasis, cancer, immune and cardiovascular systems, skin biology, and oral health

The nonskeletal effects of vitamin D: an Endocrine Society scientific statement

Vitamin D and 1, 25 (OH) 2D regulation of T cells

Mechanisms underlying the regulation of innate and adaptive immunity by vitamin D

Vitamin D Receptor polymorphisms and risk of enveloped virus infection: a meta-analysis

Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths

hsp70 genes in the human genome: Conservation and differentiation patterns predict a wide array of overlapping and specialized functions

Genetic association of promoter in GRP78 gene with nasopharyngeal carcinoma in a Chinese population

The stressinducible molecular chaperone GRP78 as potential therapeutic target for Coronavirus infection

COVID-19 spike-host cell receptor GRP78 binding site prediction

Association between promoter polymorphisms of the GRP78 gene and risk of type 2 diabetes in a Chinese Han population

Basigin: a multifunctional membrane protein with an emerging role in infections by malaria parasites

Human leukocyte activation antigen M6, a member of the Ig superfamily, is the species homologue of rat OX-47, mouse basigin, and chicken HT7 molecule

CD147 immunoglobulin superfamily receptor function and role in pathology

The MRC OX-47 antigen is a member of the immunoglobulin superfamily with an unusual transmembrane sequence

Human keratinocytes express EMMPRIN, an extracellular matrix metalloproteinase inducer

Distribution of the integral plasma membrane glycoprotein CE9 (MRC OX-47)

among rat tissues and its induction by diverse stimuli of metabolic activation

A novel anti-EMMPRIN function-blocking antibody reduces T cell proliferation and neurotoxicity: relevance to multiple sclerosis

EMMPRIN promotes angiogenesis, proliferation, invasion and resistance to sunitinib in renal cell carcinoma, and its level predicts patient outcome

The biological function and clinical utilization of CD147 in human diseases: a review of the current scientific literature

Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics

CD147 in regulatory T cells

Association study between an SNP in CD147 and its expression with acute coronary syndrome in a Jiangsu Chinese population

CD147 facilitates HIV-1 infection by interacting with virus-associated cyclophilin A

Function of HAb18G/CD147 in invasion of host cells by severe acute respiratory syndrome coronavirus

CD147/EMMPRIN acts as a functional entry receptor for measles virus on epithelial cells

The single nucleotide polymorphisms of chromosome 9p21 and CD147 were relevant with the carotid plaque risk in acute cerebral infarction patients among Chinese Han population

Association of BSG genetic polymorphisms with atherosclerotic cerebral infarction in the Han Chinese population

Repressing CD147 is a novel therapeutic strategy for malignant melanoma

A miRNA-492 binding-site polymorphism in BSG (basigin) confers risk to psoriasis in central south Chinese population

CD147-spike protein is a novel route for SARS-CoV-2 infection to host cells

Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV

Structure of MERS-CoV spike receptorbinding domain complexed with human receptor DPP4

Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity

Neuropilin-1 as a new potential SARS-CoV-2 infection mediator implicated in the neurologic features and central nervous system involvement of COVID-19

Neuropilin is a receptor for the axonal chemorepellent Semaphorin III

Molecular angiogenesis

The role of Neuropilin-1 in COVID-19

The spike glycoprotein of the new coronavirus 2019-nCoV contains a furin-like cleavage site absent in CoV of the same clade

A novel activation mechanism of avian influenza virus H9N2 by furin

Neuropilin-1 regulates the secondary CD8 T cell response to virus infection

Functional polymorphisms of the neuropilin 1 gene are associated with the risk of tetralogy of Fallot in a Chinese Han population

Heme oxygenase-1 and 2 common genetic variants and risk for multiple sclerosis

Genetic polymorphisms complicate COVID-19 therapy: pivotal role of HO-1 in cytokine storm

The Agreed Experts' Position of the Eurasian Association of Therapists on Some new Mechanisms of COVID-19 Pathways: focus on hemostasis, hemotransfusion issues and blood gas exchange

Pharmacological and clinical aspects of heme oxygenase

COVID-19 and heme oxygenase: novel insight into the disease and potential therapies

Heme oxygenase-1 gene promoter microsatellite polymorphism is associated with progressive atherosclerosis and incident cardiovascular disease

Microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with susceptibility to emphysema

A microsatellite polymorphism in the heme oxygenase-1 gene promoter is associated with risk for melanoma

Microsatellite polymorphism in heme oxygenase-1 gene promoter is associated with susceptibility to oxidant-induced apoptosis in lymphoblastoid cell lines

Association of lung function decline with the heme oxygenase-1 gene promoter microsatellite polymorphism in a general population sample. Results from the European Community Respiratory Health Survey (ECRHS), France

Association between heme oxygenase-1 gene promoter polymorphisms and type 2 diabetes mellitus: a HuGE review and meta-analysis

The role of heme oxygenase-1 promoter polymorphisms in human disease

The apolipoprotein L1 (APOL1) gene and nondiabetic nephropathy in African Americans

The trypanolytic factor of human serum: many ways to enter the parasite, a single way to kill

Human high density lipoproteins are platforms for the assembly of multi-component innate immune complexes

The apolipoprotein L family of programmed cell death and immunity genes rapidly evolved in primates at discrete sites of host-pathogen interactions

Apolipoprotein L6, a novel proapoptotic Bcl-2 homology 3-only protein, induces mitochondria-mediated apoptosis in cancer cells

Apolipoprotein L6, induced in atherosclerotic lesions, promotes apoptosis and blocks Beclin 1-dependent autophagy in atherosclerotic cells

Apolipoprotein L1, a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death

ApoL1, a BH3-only lipid-binding protein, induces autophagic cell death

Indirect effects of severe acute respiratory syndrome coronavirus 2 on the kidney in coronavirus disease patients

Collapsing glomerulopathy in a patient with coronavirus disease 2019 (COVID-19)

Acute kidney injury due to collapsing glomerulopathy following COVID-19 infection

Positive selection in the chromosome 16 VKORC1 genomic region has contributed to the variability of anticoagulant response in humans

Worldwide allele frequency distribution of four polymorphisms associated with warfarin dose requirements

Vitamin K epoxide reductase complex subunit 1 (VKORC1) gene polymorphism as determinant of differences in Covid-19-related disease severity

Blood group ABO polymorphism inhibits SARS-CoV-2 infection and affects COVID-19 progression

Genomewide association study of severe Covid-19 with respiratory failure

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