Open access peer-reviewed chapter

Human Genetic Polymorphisms Associated with Susceptibility to COVID-19 Infection and Response to Treatment

Written By

Necla Benlier, Nevhiz Gundogdu and Mehtap Ozkur

Submitted: June 9th, 2021 Reviewed: August 11th, 2021 Published: November 17th, 2021

DOI: 10.5772/intechopen.99877

Chapter metrics overview

84 Chapter Downloads

View Full Metrics

Abstract

Clinicians and researchers observing the natural history of endemic and epidemic infections have always been fascinated by the vagaries of these diseases, in terms of both the changing nature of the disease severity and phenotype over time and the variable susceptibility of hosts within exposed populations. SARS-CoV-2, the virus that causes COVID-19 and is believed to originate from bats, quickly transformed into a global pandemic. The pandemic of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been posing great threats to the global health in many aspects. Currently, there are no proven effective vaccines or therapeutic agents against the virus. Comprehensive understanding of the biology of SARS-CoV-2 and its interaction with hosts is fundamentally important in the fight against SARS-CoV-2. Advanced age, male sex, and comorbidities such as hypertension and cardiovascular disease as well as diabetes and obesity have been identified as risk factors for more severe COVID-19. However, which and to what extent specific genetic factors may account for the predisposition of individuals to develop severe disease or to contract the infection remains elusive. The increasing availability of data from COVID-19 patient populations is allowing for potential associations to be established between specific gene loci and disease severity, susceptibility to infection, and response to current/future drugs.

Keywords

  • Human Genetic Polymorphisms
  • SARS-COV-2
  • COVID-19
  • Genetic Susceptibility

1. Introduction

Variability in response to drugs, both in terms of efficacy and tolerability, and ways to customize treatments according to their characteristics have become important topics of medical research. It was determined that genetic variations in some ethnic groups may affect the response to drug and the outcomes of treatment [1]. Various enzymes are often involved in drug absorption/distribution/metabolism/excretion (ADME) processes and show multiple interactions [2].

Gene polymorphisms are sequence variations at specific locations within the genome and are observed in more than 1% of the population. Genetic polymorphisms can alter the coding of proteins or their expression, and affect natural or acquired immunity [3]. Single nucleotide polymorphisms (SNPs) have been studied in relation to various diseases, which are associated with variations of DNA sequence with phenotypic changes [4]. Variations in the genes control competence in the cellular and humoral immune systems, which define the individual risk level for diseases [5, 6].

Advertisement

2. SARS-CoV-2

After the investigation that started with the World Health Organization (WHO) China Country Office reporting a cluster of pneumonia cases of unknown cause in Wuhan city of Hubei province of China on 31 December 2019, it was identified on January 7, 2020 that the agent was a new coronavirus that causes infection in humans. The causative virus was designated as 2019-nCoV (2019-novel coronavirus) by the WHO and SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) by the International Virus Taxonomy Committee, and the disease caused by the virus was named as COVID-19 (coronavirus disease- 2019) [7, 8].

The disease is highly contagious and its main clinical symptoms are fever, dry cough, fatigue, muscle pain and shortness of breath. Since the first reported case of COVID-19 in the city of Wuhan, China, at the end of 2019, COVID-19 has rapidly spread all over China and then to all countries of the world [9]. It was confirmed that the virus spreads from person to person, through close contact and via respiratory particles that are generated by coughing or sneezing [10]. Most of the studies conducted in Wuhan at the beginning of the epidemic showed that the first patients worked in or visited a seafood market in Wuhan. Initially, it was thought to be caused by snakes, but later studies have shown it to be related to bats. As the pandemic progressed, it was shown that this viral infection is transmitted from one person to another through droplets and by touching the face with hands exposed to contaminated surfaces [11]. The virus can be found in respiratory secretions of patients 1–2 days before the onset of clinical symptoms and two weeks after disease symptoms [12].

Coronaviruses belong to the subfamily Coronavirinaeof the family Coronaviridaeand include four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus and Deltacoronavirus. The genome of CoVs (27–32 kb) is a single-stranded positive-sense RNA (+ ssRNA) that is larger than other RNA viruses [13]. The genome size of SARS-CoV-2 is approximately 29.9 kb [14].

Coronaviruses contain four structural proteins, namely S (Spike) protein, E (Envelope) protein, M (Membrane) protein and N (Nucleocapsid) protein, which are involved in the formation of mature virus particles (virions) and the emergence of infection [15]. The S protein is responsible for the formation of spikes on the surface of the coronavirus, and these protrusions play a key role in the attachment of the virus to host cell receptors and its entry into the cell. The spike protein is also the main antigenic component of the virus [16].

Depending on viral strains and cell types, coronavirus S proteins can be cleaved by one or more host proteases, including cathepsins, furin, neutrophil elastase (ELANE), transmembrane protease serine protease-2 (TMPRSS-2), and possibly TMPRSS11A [17, 18, 19]. The presence of these proteases on target cells largely determines whether coronavirus particles enter cells via the plasma membrane or endocytosis. Hoffmann et al. showed that SARS-CoV-2 uses transmembrane protease 2 (TMPRSS2) for S protein priming and the SARS-CoV receptor angiotensin-converting enzyme 2 (ACE2) for entry into target cells [20]. Likewise, Ou et al. found that cathepsin L (CTSL) is essential to the virus entry in the host cell [21]. Moreover, it was reported that the S protein of the A2a subtype possesses an additional elastase-specific proteolytic cleavage site that enhances the virus’s ability to penetrate host cells [19]. This virus subtype has been reported in China and has spread rapidly in North America and Europe [22, 23].

Coronaviruses contain sixteen nonstructural proteins (Nsp1–16). Nsp1 mediates RNA processing and replication and Nsp2 modulates the host cell’s survival signaling pathway. Nsp3 separates the translated polyprotein into its distinct proteins. Nsp4 contains transmembrane domain 2 (TM2) and modifies ER membranes. Nsp5 participates in the polyprotein processing during replication. Nsp6 is a putative transmembrane domain. A heterodimer of Nsp7 and Nsp8 significantly increases nsp12 and template-primary RNA combination. Nsp9 participates in viral replication by acting as an ssRNA-binding protein. Nsp10 is crucial for cap methylation of viral mRNAs. Nsp11 is identical to the first segment of Nsp12 and its function is unknown. Nsp12 contains RNA-dependent RNA polymerase (RdRp), a critical component of coronavirus replication/transcription. Nsp13 binds to ATP and the zinc-binding domain of Nsp13 is involved in replication and transcription. Nsp14 is an exoribonuclease domain. Nsp15 has Mn (2+)-dependent endoribonuclease activity. Nsp16 is a 2’-O-ribose methyltransferase [24]. Entry of coronaviruses into host cells is mediated by an increase in glycoprotein (S protein) [16, 25, 26]. Transmembrane spike glycoproteins form homotrimers that protrude from the viral surface. The spike glycoprotein is critical for the entry of coronaviruses, thus making it an attractive antiviral target. A six-helical bundle (6-HB) is formed by HR1 and HR2 which are vital for spike protein-dominated membrane fusion of SARS-CoV or SARS-CoV-2, making HR1 and HR2 a promising drug target [27, 28]. The spike protein of SARS-CoV-2 contains a receptor binding domain that specifically recognizes the ACE2 receptor. The receptor-binding domain is a critical target for antiviral compounds and antibodies [29].

Most patients with COVID-19 develop symptoms such as dyspnea, fever, dry cough, muscle pain, fatigue and diarrhea. However, the rate of complications such as sepsis, septic shock and multiple organ dysfunction syndrome (MODS) has been found to range between 2 and 20% in line with the data collected to date [30, 31, 32]. Pathophysiological findings in the lungs, which are the entry route of the virus, show embolisms caused by thrombus formation at the micro and macro level associated with extensive endothelial involvement, as well as intra-alveolar hyaline membranes and alveolar edema [33]. Widespread pulmonary damage is attributed to a cytokine storm that shows local and then systemic effects, together with the damage that starts directly with the virus-ACE2 receptor relationship [34].

Advertisement

3. ACE2

ACE2 cleaves Ang II to angiotensin [1, 2, 3, 4, 5, 6, 7], which produces vasodilating, anti-inflammatory and anti-fibrotic effects via binding to the Mas receptor [35, 36, 37]. Tissue-bound or membrane-bound ACE2 is a type of transmembrane protein with a single metalloprotease active site and a transmembrane domain [38, 39]. ACE2 is expressed in virtually all human organs in varying degrees. ACE2 expression is present in type II alveolar cells (AT2), respiratory epithelial cells, bronchial transient epithelial secretory cells, myocardial cells, endothelial cells and artery smooth muscle cells, esophagus epithelial cells, tongue epithelial cells, neurons and glia, stomach, cholangiocytes, adipose tissue, pancreatic exocrine glands and islets, bladder urothelial cells, renal proximal tubule cells, podocytes, testis (Leydig and Sertoli cells and spermatogonia), uterus epithelial cells, ovary and breast, maternal–fetal interface, enterocytes from ileum and colon and rectum cells [40, 41]. In the lung, ACE2 is abundantly expressed by Clara cells, type I and II alveolar epithelial cells, macrophages, bronchial epithelium, endothelium, and vascular smooth muscle cells [42].

ACE2 is encoded on chromosome Xp22 and spans 39.98 kb genomic DNA. This gene generates two transcripts originating from the same 805 amino acid residue protein: one transcript consisting of 18 exons and 17 introns (transcript length: 3339 bps), and the other consisting of 19 exons and 18 introns (transcript length: 3507 bps). The ACE2 gene displays high levels of polymorphism; in fact, some single nucleotide polymorphisms (SNPs) of this gene have been reported to be associated with susceptibility to diseases such as hypertension and type 2 diabetes [43, 44].

Single-cell RNA sequencing analysis has shown that ACE2 mRNA is expressed at a higher level in the Asian population than in the Caucasian and African-American populations, and also Asian men have a higher ACE2 mRNA expression compared to Asian women [45, 46].

There is a negative correlation between ACE2 expression and COVID-19 severity. ACE2 is secreted from membranes at different levels. Two cell membrane proteases are important for this secretion: transmembrane protease serine 2 (TMPRSS2) and protein 17 (ADAM17) containing disintegrin and metalloproteinase domain [47].

More specifically, ADAM17 acts directly on ACE2 and leads to the shedding of ACE2 into the extracellular cellular space, whereas TMPRSS2 affects not only ACE2, but also the S protein of SARS-CoV-2, resulting in membrane fusion and cellular uptake of the virus. As a result of an extensive database analysis, Cao et al. identified 1700 variants in the ACE2 gene region on the X chromosome. They identified 15 (14 SNPs and 1 insertion/deletion (INDEL)) uniquely expressed variants with higher minor allele frequencies (MAF) in the Asian population than in the European population [48].

It is still debated whether these differences should be taken into account in epidemiological studies on COVID-19, which includes ethnic associations with disease development [49]. Importantly, diseases correlated with high levels of SARS-Cov-2 infection, such as hypertension and diabetes, have been found to have a lower expression of ACE2 in relation to the SNPs in the ACE2 genes.

Individuals with rs383510/T and rs2070788/G genotypes of TMPSSRSS2 located on chromosome 21q22.3 were found to be more prone to develop a severe form of influenza A (H1N1) and acute respiratory distress syndrome (ARDS) [50]. Remarkably, males have been shown to be more likely to develop severe H1N1 influenza [51].

The ADAM17 gene region on chromosome 2p25.1 has been determined to differ in allele profiles between Asian and European populations and these SNPs are associated with hypertension [52] and/or sepsis [53].

When the S1 protein, located at the spikes of SARS-CoV and SARS-CoV2, attaches to the enzymatic domain of ACE2 on the cell membrane, both the virus and the enzyme are taken up into the host cell by endocytosis [54, 55]. This led to the idea that lowering the amount of ACE2 in cells could help fight against coronavirus infection. As an antithesis to this, ACE2 has also been shown to have a protective effect against viral lung injury by increasing the production of the vasodilator angiotensin 1–7. Also, some studies in mice have demonstrated that the interaction of the coronavirus terminal protein with ACE2 causes a reduction in ACE2 levels in the cell membrane, with the protein being pulled into and degraded, and therefore may increase lung damage [56].

Studies in rodents have shown that both ACE inhibitors and angiotensin receptor blockers (ARBs) used to treat high blood pressure increase the amount of ACE2 and therefore may increase the severity of coronavirus infections [57]. However, scientific societies have recommended continuing standard ACE inhibitor and ARB treatment [58]. A systematic review and meta-analysis published on July 11, 2012 found that the use of ACE inhibitors resulted in a 34% reduction in pneumonia risk compared to controls. Besides, it was observed that the risk of pneumonia is reduced by treatment with ACE inhibitors in patients with a high risk of pneumonia, especially those with stroke and heart failure [59].

ACE2 limits the adverse vasoconstrictor and profibrotic effects of AngII. Hydrolysis of AngII to Ang (1e7) reduces the oxidative stress of AngII on endothelial cerebral arteries. Disruption of ACE2 results in increased AngII levels and impaired cardiac function. Decreased cardiac ACE2 levels have been reported in hypertension (HT) and diabetic heart disease, and low ACE2 mRNA expression has been associated with HT, dyslipidemia, and/or heart failure [60, 61].

It was reported that ACE2 gene polymorphisms can influence both susceptibility to SARS-CoV-2 and the prognosis of COVID-19 disease. The S1 domain of the SARS-CoV2 spike protein mediates its binding to the ACE2 receptor site, while the S2 domain mediates membrane fusion at the membrane-associated portion undergoing postbinding transconformational modifications. In a study conducted by Li et al. in rats, they produced a conformational change in the ACE2 α-helix 1 structure by changing the His353 amino acid of the ACE2’receptor and modifying a glycosylation site (Asp 90), and as a result, they determined that this receptor became more suitable for the binding of SARS-CoV [62]. They also found that Leu584Ala, a point mutation in ACE2, significantly increased the binding of the enzyme, thus facilitating the entry of SARS-CoV into target cells [63]. In some studies, ACE2 expression was found to be low in cells infected with SARS-CoV, and recombinant SARS-CoV spike protein decreased ACE2 expression and thus increased lung damage [64, 65]. In a study by Cao et al. in different populations, seven of the 32 ACE2 variants (Lys26Arg, Ile486Val, Ala627Val, Asn638Ser, Ser692Pro, Asn720Asp and Leu731Ile/Phe) were found to be effective for SARS-CoV2 [48].

In one study, Stawiski et al. reported that while human ACE2 variants K26R, T27A, N64K, S19P, I21V, E23K, T92I, Q102P and H378R are predicted to increase host susceptibility, other ACE2 variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y are putative protective variants predicted to show decreased binding to SARS-CoV-2 S-protein. Among these, T92I variant, part of a consensus NxS/T N-glycosylation motif, exhibited increased affinity for S-protein [66].

Advertisement

4. Transmembrane serine protease

Transmembrane protease serine type 2 (TMPRSS2) belongs to the type II transmembrane serine protease family. It facilitates the entry and activation of the virus by making proteolytic cleavage in the spike protein. After SARS-CoV binds to ACE2, proteolytic cleavage of the S protein via the cysteine protease cathepsin B/L or TMPRSS2 is required for the virus to enter the cell. Although both activate the SARS CoV Spike protein, TMPRSS2 activity has been shown to be required for the spread of the virus in the host. While rodents given TMPRSS2 serine protease inhibitor were protected from SARS-CoV, the same effect was not observed in those given cathepsin B/L cysteine prosthetic inhibitor [67]. The transmembrane serine protease TMPRSS2 is an essential enzyme capable of degrading the hemagglutinin of many influenza virus subtypes and coronavirus S protein [68, 69]. Studies have shown that mice with TMPRSS2 deficiency are more resistant to infections with H1N1 and H7N9 influenza A virus [68, 70]. TMPRSS2 has been demonstrated to help SARS-CoV-2 enter host cells by cleaving the S protein [20]. Matsuyama et al. showed that cell lines expressing TMPRSS2 are highly susceptible to MERS-CoV, SARS-CoV and SARS-CoV-2 [71]. The gene encoding TMPRSS2 is polymorphic and is regarded as a susceptibility gene for H1N1 and H7N9 influenza [50]. TMPRSS2 is expressed in numerous tissues that are targets of COVID-19, such as the lung, heart, kidney, and digestive tract. It is also expressed in microvascular endothelial cells, suggesting that it may play a role in endothelial dysfunction, thrombosis and related complications. TMPRSS2 variants are also thought to contribute to the clinical diversity of COVID-19. In the study of Asselta et al., it was reported that TMPRSS2 exonic variant p.Val160Met and two haplotypes were detected more frequently in the Italian population than in East Asians [72]. Besides, in another study, the presence of TMPRSS2-ERG fusion in prostate cancer and the strong regulation of TMPRSS2 by androgens led to the hypothesis that TMPRSS2 could partly explain the greater involvement of males in the COVID-19 pandemic [73].

Advertisement

5. Elastase

SARS-Cov-2 enters the cell by binding its S protein with cellular receptors [20]. Some proteases, such as TMPRSS2, cathepsin L, neutrophil elastase, and probably TMPRSS11A are involved in this process. As a matter of fact, polymorphisms in their encoding genes could not only have an impact in the expression and/or structure of these proteases but also be associated with susceptibility to SARS-CoV-2 infection. Elastase is secreted by neutrophils as part of an inflammatory response to a viral infection and is also produced by opportunistic bacteria that can colonize virally infected respiratory tissue [74]. Increased elastase activity as a result of the aberrant inflammatory process produces considerable pulmonary damage that contributes significantly to the pathogenesis of chronic obstructive pulmonary disease, cystic fibrosis, ARDS and pulmonary fibrosis [75, 76]. Moreever, the dramatic increase in neutrophil elastase (NE) in severe COVID-19 may be related to neutrophil activation by the IL-8/CXCR2 pathways [77]. The ELANE gene encoding neutrophil elastase is located on chromosome 19p13.3. Two transcripts have been reported for this gene, which produce consensus coding sequence. The first transcript contains 5 exons and 4 introns and 5 exons encode this 267 amino acid protein (transcript length, 909 bps). The second transcript consists of 6 exons and 5 introns, and 5 exons encode this 267 amino acid protein (transcript length, 1028) [78]. In the ELANE gene, 12 polymorphisms with potential functional effects were identified: ten in the promoter region, two in the 5′ region near the gene and two in the 3′ region near the gene. These 12 polymorphisms produce binding sites for various transcription factors and microRNAs [78].

The levels of NE expression are known to be affected by the polymorphisms in the promoter region of the neutrophil elastase (ELANE) gene. Several polymorphisms were identified to date in the six repetitive tandem motifs of the ELANE gene promoter region: -903 T/G, −741G/A, −832G/T, -789C/T, and extra 52 bp between the fourth and fifth repeats. Polymorphisms -903 T/G and -741G/A have been associated with risk of lung cancer [79]. Luciferase activity assays have shown higher activity for ELANE gene promoter constructs carrying -903 T/−741G compared to the constructs carrying -903G/−741A. Based on these findings, predicted activity of ELANE genotypes was classified as low (−903TG), intermediate (−903TT/−741AG and -903TT/−741AA), or high (−903TT/−741GG) [80].

Advertisement

6. Cathepsin L

Cathepsin L is a peptidase that cleaves peptide bonds, preferably with aromatic residues at the P2 position and hydrophobic residues at the P3 position [81]. It was reported previously that cathepsin L participates in the viral glycoprotein processing of Ebola virus and SARS-CoV, and this viral process has been found to be critical for cell membrane fusion and host cell entry [82]. Using cathepsin B and L inhibitors in HEK 293/hACE2 cells, Ou et al. showed that treatment with cathepsin L inhibitor reduced the entry of SARS-CoV-2 into cells [21]. This finding suggests that cathepsin L may be crucial for S protein priming in the lysosome for viral entry.

Six polymorphisms with possible functional implications were identified in the cathepsin L gene. These polymorphisms have been found in various regions of the gene and form binding sites for transcription factors [78]. Among these polymorphisms, rs41307457 has a high frequency only in the African population and rs41312184 is present with a high frequency especially in the European population. The authors suggested that the relationship of these polymorphisms with SARS-CoV-2 infection should be analyzed in these populations [78].

Advertisement

7. Human alpha-1 antitrypsin (A1AT)

Human alpha-1 antitrypsin (A1AT) is a 52 kDa glycoprotein synthesized in the liver and circulates in the blood, and is a natural inhibitor of several proteases. Adequate A1AT activity is crucial for the prevention of proteolytic tissue damage [83]. In people with one of many inherited mutations in A1AT, low circulating A1AT levels increase the risk of devastating diseases, particularly emphysema [84]. Infusion of plasma-purified A1AT protein has proven therapeutic benefits in patients with A1AT deficiency [85]. The pharmacokinetics and safety of A1AT have been well studied. It was accepted as safe with its rare and generally well tolerated side effects [86]. Studies have shown that human A1AT has both anti-inflammatory and anti-SARS-CoV-2 viral effects [87]. This dual role makes it a unique and excellent candidate for the treatment of COVID-19. Alpha-1-antitrypsin (AAT) is a serine protease inhibitor (SERPIN) and the third most abundant circulating protein. AAT plasma level may increase 3 to 5-fold in states of systemic inflammation and/or infection, perhaps an indication of the homeostatic role of AAT, but has been found to be insufficient in severe cases of COVID-19 [88, 89]. Alpha-1-antitrypsin (AAT) has been shown to antagonize various pathophysiological mechanisms induced by SARS-CoV-2. It has been demonstrated that these pathophysiological mechanisms inhibit TMPRSS-2, the host serine protease that degrades the spike protein of SARS-CoV-2, SARS-CoV-2 [20]. AAT also has antiviral activity against other RNA viruses, influenza and HIV. It also induces autophagy, a known host effector mechanism against MERS-CoV, a related coronavirus that causes Middle East Respiratory Syndrome [90]. Additionally, AAT has potent anti-inflammatory properties, in part by inhibiting both nuclear factor-kappa B (NFκB) activation and ADAM17 (also known as tumor necrosis factor-alpha converting enzyme) and may therefore reduce the hyperinflammatory response to COVID-19 [91]. Moreover, AAT inhibits neutrophil elastase, a serine protease that helps recruit potentially harmful neutrophils and is implicated in acute lung injury [92]. AAT inhibition of ADAM17 prevents ACE2 from being scavenged, thus preserving ACE2 inhibition of bradykinin and reducing bradykinin’s ability to cause capillary leakage in COVID-19 [93]. AAT also inhibits thrombin and venous thromboembolism, and microthrombi and macrothrombi in situ are increasingly recognized to play a role in COVID-19 [94]. Furthermore, AAT inhibition of elastase results in the formation of neutrophil extracellular traps (NETs), a complex extracellular structure composed of neutrophil-derived DNA, histones, and proteases, and involved in the immunothrombosis of COVID-19 can antagonize. In fact, AAT has been shown to alter the shape and adherence of NETs not associated with COVID-19 [95]. AAT inhibition of endothelial cell apoptosis may also limit endothelial damage associated with severe COVID-19-related acute lung injury, multi-organ dysfunction, and preeclampsia-like syndrome in gravid women [96]. Although it is well known that alpha 1 antitrypsin deficiency is quite common in Europeans, rs17580 is the most common deficiency variant as reported by most of the studies conducted to date [97].

Advertisement

8. HLA

Human leukocyte antigens (HLA) are encoded by major histocompatibility complex (MHC) genes and are highly polymorphic. MHC molecules act as receptors for viral peptides. Studies have shown that polymorphisms in the HLA region are associated with susceptibility to many common infectious diseases [98]. In a study conducted in 28 patients with severe respiratory failure, HLA-DR expression was found to be very low, suggesting that HLA is an important immune regulator in COVID-19 [99]. In addition, several studies have attempted to determine HLA alleles that are associated with increased or reduced susceptibility. HLA genes are important in olfactory perception. Loss of sense of smell differs among individuals who had COVID-19 [100]. The olfactory receptor gene is located at the same locus as the MHC and is co-transmitted [101]. Therefore, variations in HLA genes are known to play a role in differences in immune response against pathogens.

Advertisement

9. Conclusion

Today, many genetic polymorphisms are known to be involved in pathways that play an important role in the attachment of the microbiological agent to the host cell, resulting in variations in the susceptibility to disease and disease severity. Currently, genetic polymorphisms are used in molecular medicine for many purposes. Better understanding of the mechanisms caused by genetic polymorphisms is expected to allow for the development of new treatments and discovery of preventive drugs. The COVID-19 pandemic shows marked geographical differences in its prevalence and mortality. This variability may be due both to the presence of several subtypes of the virus and to genetic differences in human populations. Given this fact and the important roles of ACE2, TMPRSS2, cathepsin L and elastase in the process of virus entry into the host cell, this article aims to suggest possible variants at these loci for genetic association studies in SARS patients. Although there appears to be a multifactorial genetic influence on the risk of SARS-Cov-2 infection and possible disease severity, SNP profiling of the ACE2, ADAM17 and TMPRSS2 genes is recommended to identify potentially vulnerable populations at risk with a relatively simple and easy-to-perform test such as PCR [102] or MASSarray [103]. Thus, a ‘multiSNP risk score’ applicable to large populations can be determined, and therefore it may be possible to identify subjects carrying a combination of fewer suitable alleles for ACE2, ADAM17 and TMPRSS2. Such an analytical strategy has recently been developed based on patient genetics for immunogenetic profiling designed to individualize immunotherapy [104]. It is known that macrophage activation syndrome (MAS) is an important cause of mortality and morbidity in patients with COVID-19. In a study investigating gene polymorphisms in the pentraxin 3 (PTX3), a molecule that is synthesized by a number of inflammatory cells and considered to be associated with mortality, MAS was found to be less common in COVID-19 patients with the AG genotype (rs1840680 (1449A/G) polymorphism) and PTX3 levels were higher in patients carrying the A allele [103]. In a study on interferon-induced membrane protein- 3 (IFITM-3) gene variants, an established risk factor in severe viral infections, the IFITM3-SNP, rs12252-G allele was found to be significantly associated with hospitalization and mortality in COVID-19 patients and lower IFNγ levels were lower patients with the AG/GG genotype [105]. Homocysteine can be used as a potential biomarker to predict the severity of a number of infections in COVID-19. A study in the Latino population suggested that the MTHFR 677 T allele may contribute to the mortality from COVID-19 [106]. Dipeptidylpeptidase-4 (DPP4) is known to be a key protein for the entry of SARS-CoV-2 into the host cell as well as in obesity and hypertension, which are associated with worse prognosis in COVID-19. In light of these data, a study suggested that the DPP4 rs3788979 polymorphism might be a risk factor for COVID-19 disease [107]. Recently, in a south Asian population, the frequency of Human leukocyte antigen (HLA) variants HLA-B*51 and HLA class II, DRB1*13 was found to be high in patients with fatal COVID-19 [108].

In summary, until now, genetic influences on the interindividual susceptibility of COVID-19 have been largely underestimated; therefore, we hope that this review will fill this gap and pave the way for validation in studies at the experimental and clinical levels. Taken together, these data suggest that several gene variants may have an effect on susceptibility to COVID-19 disease, its prognosis and possibly the efficacy of vaccines. As SARS-CoV-2 continues to threaten global health, it is essential to elucidate the molecular mechanisms involved in this infection to develop specific treatment and prevention strategies.

References

  1. 1. Calcagno A, Cusato J, D'Avolio A,rt al. Genetic Polymorphisms Affecting the Pharmacokinetics of Antiretroviral Drugs. Clin Pharmacokinet. 2017 Apr;56(4):355-369.
  2. 2. Ikediobi O, Aouizerat B, Xiao Y, et al. Analysis of pharmacogenetic traits in two distinct South African populations. Hum Genomics. 2011;5(4):265-282.
  3. 3. Kinane DF, Shiba H, Hart TC. The genetic basis of periodontitis. Periodontol 2000 2005;39:91-117.
  4. 4. Mout R, Willemze R, Landegent JE. Repeat polymorphisms in the interleukin-4 gene (IL4). Nucleic Acids Res 1991;19:3763.
  5. 5. Kinane DF, Hodge P, Eskdale J, et al. Ellis R, Gallagher G. Analysis of genetic polymorphisms at the interleukin-10 and tumour necrosis factor loci in early onset periodontitis. J Periodont Res 1999;34:379-386.
  6. 6. Nunn ME. Understanding the etiology of periodontitis: An overview of periodontal risk factors. Periodontol 2000 2003;32:11-23.
  7. 7. https://www.who.int/emergencies/diseases/novel-coronavirus-2019
  8. 8. Coronaviridae Study Group of the International Committee on Taxonomy of Viruses. The species Severe acute respiratory syndrome-related coronavirus: classifying 2019-nCoV and naming it SARS-CoV-2. Nat Microbiol. 2020;5(4):536-544.
  9. 9. Debnath M, Banerjee M, Berk M. Genetic gateways to COVID-19 infection: Implications for risk, severity, and outcomes, The FASEB Journal.2020; 34:8787– 8795.
  10. 10. Du RH, Liang LR, Yang CQ, et al. Predictors of mortality for patients with COVID-19 pneumonia caused by SARS-CoV-2: a prospective cohort study. Eur Respir J. 2020; 55(5).
  11. 11. Imai Y, Kuba K, Rao S, et al. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature 2005 ;436(7047), 112-116.
  12. 12. Yang XH, Deng W, Tong Z, et al. Mice transgenic for human angiotensin-converting enzyme 2 provide a model for SARS coronavirus infection. Comparative Medicine 2007;57(5), 450-459.
  13. 13. Brian DA, Baric RS. Coronavirus genome structure and replication. Curr Top Microbiol Immunol 2005; 287():1-30.
  14. 14. Lu R, Zhao X, Li J, et al. Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding. Lancet (London England) 2020; 395, 565-574.
  15. 15. Fehr AR, S. Perlman S. Coronaviruses: an overview of their replication and pathogenesis Methods Mol. Biol 2015; 1282, pp. 1-23
  16. 16. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus Nature 2003; 426, pp. 450-454
  17. 17. Millet JK, Whittaker GR. Host cell entry of Middle East respiratory syndrome coronavirus after two-step, furin-mediated activation of the spike protein Proc. Natl. Acad. Sci. U. S. A. 2014; 111 , pp. 15214-15219,
  18. 18. Bertram S, Dijkman R, Habjan M, et al. TMPRSS2 activates the human coronavirus 229E for cathepsin-independent host cell entry and is expressed in viral target cells in the respiratory epithelium. J Virol. 2013;87(11):6150-6160.
  19. 19. Bhattacharyya C, Das C, Ghosh A, et al. SARS-CoV-2 mutation 614G creates an elastase cleavage site enhancing its spread in high AAT-deficient regions. Infect Genet Evol. 2021;90:104760.
  20. 20. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271-280.e8.
  21. 21. Ou X, Liu Y, Lei X, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV [published correction appears in Nat Commun. 2021;12(1):2144].
  22. 22. Biswas NK, Majumder PP. Analysis of RNA sequences of 3636 SARS-CoV-2 collected from 55 countries reveals selective sweep of one virus type Indian J. Med. Res 2020; 10.4103/ijmr.IJMR_1125_20
  23. 23. Gudbjartsson DF, Helgason A, Jonsson H, et al. Spread of SARS-CoV-2 in the Icelandic Population. N Engl J Med. 2020;382(24):2302-2315.
  24. 24. Naqvi AAT, Fatima K, Mohammad T, et al. Insights into SARS-CoV-2 genome, structure, evolution, pathogenesis and therapies: Structural genomics approach. Biochim Biophys Acta Mol Basis Dis. 2020;1866(10):165878.
  25. 25. Li F, Li W, Farzan M, et al. Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Sci. (N. Y. N.Y.)2005; 309, 1864-1868.
  26. 26. Li F. Structure, Function, and Evolution of Coronavirus Spike Proteins. Annu. Rev. Virol 2016; 3, 237-261.
  27. 27. Liu S, Xiao G, Chen Y, et al. Interaction between heptad repeat 1 and 2 regions in spike protein of SARS-associated coronavirus: implications for virus fusogenic mechanism and identification of fusion inhibitors. Lancet (London England) 2004; 363, 938-947.
  28. 28. Xia S, Zhu Y, Liu M, et al. Fusion mechanism of 2019-nCoV and fusion inhibitors targeting HR1 domain in spike protein. Cell Mol Immunol. 2020;17(7):765-767.
  29. 29. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol. 2020;5(4):562-569.
  30. 30. Yang X, Yu Y, Xu J, et al. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study [published correction appears in Lancet Respir Med. 2020 ;8(4):e26]. L
  31. 31. Sun P, Qie S, Liu Z, et al. Clinical characteristics of hospitalized patients with SARS-CoV-2 infection: A single arm meta-analysis. J Med Virol 2020;92:612-617.
  32. 32. Rodriguez-Moralesa AJ, CardonaOspinaa JA, Gutiérrez-Ocampoa E, et al. Clinical, laboratory and imaging features of COVID-19: A systematic review and meta-analysis. Travel Med Infect Dis 2020;34:101623.
  33. 33. Al-Ania F, Chehade S, Lazo-Langner A. Thrombosis risk associated with COVID19 infection. A scoping review. Thromb Res 2020;192:152-160.
  34. 34. Han H, Ma Q, Li C, et al. Profiling serum cytokines in COVID-19 patients reveals IL-6 and IL-10 are disease severity predictors. Emerg Microbes Infect 2020;9:1123-1130.
  35. 35. Sanchis-Gomar F, Lavie CJ, Perez-Quilis C, et al. Angiotensin-Converting Enzyme 2 and Antihypertensives (Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors) in Coronavirus Disease 2019. Mayo Clin Proc. 2020;95(6):1222-1230.
  36. 36. Hamming I, Cooper ME, Haagmans BL, et al. The emerging role of ACE2 in physiology and disease. J Pathol 2007; 212: 1-11.
  37. 37. Bernardi S, Toffoli B, Zennaro C, et al. High-salt diet increases glomerular ACE/ACE2 ratio leading to oxidative stress and kidney damage. Nephrol Dial Transplant 2012; 27: 1793- 1800.
  38. 38. Lambert DW, Yarski M, Warner FJ, et al. Tumor necrosis factor-alpha convertase (ADAM17) mediates regulated ectodomain shedding of the severe-acute respiratory syndrome-coronavirus (SARS-CoV) receptor, angiotensin-converting enzyme-2 (ACE2). J Biol Chem. 2005;280(34):30113-30119.
  39. 39. Xia H, Sriramula S, Chhabra KH, et al. Brain angiotensin-converting enzyme type 2 shedding contributes to the development of neurogenic hypertension. Circ Res. 2013;113(9):1087-1096.
  40. 40. Zou X, Chen K, Zou J, et al. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Frontiers of Medicine. 2020;14:185-192.
  41. 41. Beyerstedt S, Casaro EB, Rangel ÉB. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. Eur J Clin Microbiol Infect Dis. 2021;40(5):905-919.
  42. 42. Santos RA, Frezard F, Ferreira AJ. Angiotensin-(1-7): blood, heart, and blood vessels Curr. Med. Chem. Cardiovasc. Hematol. Agent 2005; 3, pp. 383-391.
  43. 43. Zhang Q, Cong M, Wang N, et al. Association of angiotensin-converting enzyme 2 gene polymorphism and enzymatic activity with essential hypertension in different gender: A case-control study. Medicine (Baltimore). 2018;97(42):e12917.
  44. 44. Liu C, Li Y, Guan T, et al. ACE2 polymorphisms associated with cardiovascular risk in Uygurs with type 2 diabetes mellitus. Cardiovasc Diabetol. 2018;17(1):127.
  45. 45. Zhao Y, Zhao Z, Wang Y, et al. Single-Cell RNA Expression Profiling of ACE2, the Receptor of SARS-CoV-2. Am J Respir Crit Care Med. 2021;203(6):782.
  46. 46. Cai G. Tobacco-use disparity in gene expression of ACE2, the receptor of 2019-nCov. 2020.
  47. 47. Heurich A, Hofmann-Winkler H, Gierer S, et al. TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol. 2014;88(2):1293-1307.
  48. 48. Cao Y, Li L, Feng Z, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov. 2020;6:11.
  49. 49. Yi Y, Lagniton PNP, Ye S, et al. COVID-19: what has been learned and to be learned about the novel coronavirus disease. Int J Biol Sci. 2020;16(10):1753-1766.
  50. 50. Cheng Z, Zhou J, To KK, et al. Identification of TMPRSS2 as a Susceptibility Gene for Severe 2009 Pandemic A(H1N1) Influenza and A(H7N9) Influenza. J Infect Dis. 2015;212(8):1214-1221.
  51. 51. Lin B, Ferguson C, White JT, et al. Prostate-localized and androgen-regulated expression of the membrane-bound serine protease TMPRSS2. Cancer Res. 1999;59(17):4180-4184.
  52. 52. Li Y, Cui LL, Li QQ, et al. Association between ADAM17 promoter polymorphisms and ischemic stroke in a Chinese population. J Atheroscler Thromb. 2014;21(8):878-893.
  53. 53. Shao Y, He J, Chen F, et al. Association Study Between Promoter Polymorphisms of ADAM17 and Progression of Sepsis. Cell Physiol Biochem. 2016;39(4):1247-1261.
  54. 54. Wang H, Yang P, Liu K, et al. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res. 2008;18(2):290-301.
  55. 55. Millet JK, Whittaker GR. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology. 2018;517:3-8.
  56. 56. Akhmerov A, Marbán E. COVID-19 and the Heart. Circ Res. 2020 May 8;126(10):1443-1455.
  57. 57. Jia H. Pulmonary Angiotensin-Converting Enzyme 2 (ACE2) and Inflammatory Lung Disease. Shock. 2016;46(3):239-248.
  58. 58. Diaz JH. Hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe COVID-19. J Travel Med. 2020;27(3):taaa041.
  59. 59. Bozkurt B, Kovacs R, Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020;26(5):370.
  60. 60. Chen YY, Liu D, Zhang P, et al. Impact of ACE2 gene polymorphism on antihypertensive efficacy of ACE inhibitors. J Hum Hypertens 2016;30:766e71.
  61. 61. Luo Y, Liu C, Guan T, et al. Association of ACE2 genetic polymorphisms with hypertension-related target organ damages in south Xinjiang. Hypertens Res 2019;42(5):681e9.
  62. 62. Li W, Zhang C, Sui J, et al. Receptor and viral determinants of SARS-coronavirus adaptation to human ACE2. EMBO J 2005;24:1634e43.
  63. 63. Xiao F, Zimpelmann J, Agaybi S, et al. Characterization of angiotensin-converting enzyme 2 ectodomain shedding from mouse proximal tubular cells. PLoS One 2014;9(1):e85958.
  64. 64. Kuba K, Imai Y, Rao S, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005;11(8):875e9.
  65. 65. Glowacka I, Bertram S, Herzog P, et al. Differential downregulation of ACE2 by the spike proteins of severe acute respiratory syndrome coronavirus and human coronavirus NL63. J Virol 2010;84(2):1198e205.
  66. 66. Stawiski EW, Diwanji D, Suryamohan K, et al. Human ACE2 receptor polymorphisms predict SARS-CoV-2 susceptibility. BioRxiv 2020.
  67. 67. Zhou Y, Vedantham P, Lu K, et al. Protease inhibitors targeting coronavirus and filovirus entry. Antiviral Res. 2015;116:76-84.
  68. 68. Sakai K, Ami Y, Tahara M, et al. The host protease TMPRSS2 plays a major role in in vivo replication of emerging H7N9 and seasonal influenza viruses. J Virol. 2014;88(10):5608-5616.
  69. 69. Glowacka I, Bertram S, Müller MA, et al. Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. J Virol. 2011;85(9):4122-4134.
  70. 70. Tarnow C, Engels G, Arendt A, et al. TMPRSS2 is a host factor that is essential for pneumotropism and pathogenicity of H7N9 influenza A virus in mice. J Virol. 2014;88(9):4744-4751.
  71. 71. Matsuyama S, Nao N, Shirato K, et al. Enhanced isolation of SARS-CoV-2 by TMPRSS2-expressing cells. Proc Natl Acad Sci U S A. 2020;117(13):7001-7003.
  72. 72. Asselta R, Paraboschi EM, Mantovani A,et al. ACE2 and TMPRSS2 variants and expression as candidates to sex and country differences in COVID-19 severity in Italy. Aging (Albany NY). 2020;12(11):10087-10098.
  73. 73. Stopsack KH, Mucci LA, Antonarakis ES, et al. TMPRSS2 and COVID-19: Serendipity or Opportunity for Intervention?. Cancer Discov. 2020;10(6):779-782.
  74. 74. Barrett AJ, Rawlings ND, Woessner JF. Handbook of Proteolytic Enzymes Elsevier Academic Press, London 2004.
  75. 75. Kawabata K, Hagio T, Matsuoka S. The role of neutrophil elastase in acute lung injury. Eur J Pharmacol. 2002;451(1):1-10.
  76. 76. Hashimoto S, Okayama Y, Shime N, et al. Neutrophil elastase activity in acute lung injury and respiratory distress syndrome. Respirology. 2008;13(4):581-584.
  77. 77. Didangelos A. COVID-19 Hyperinflammation: What about Neutrophils?.mSphere. 2020;5(3):e00367-20.
  78. 78. Vargas-Alarcón G, Posadas-Sánchez R, Ramírez-Bello J. Variability in genes related to SARS-CoV-2 entry into host cells (ACE2, TMPRSS2, TMPRSS11A, ELANE, and CTSL) and its potential use in association studies. Life Sci. 2020;260:118313.
  79. 79. Taniguchi K, Yang P, Jett J, et al. Polymorphisms in the promoter region of the neutrophil elastase gene are associated with lung cancer development. Clin Cancer Res.2002; 8:1115-1120
  80. 80. Park JY, Chen L, Lee J, Sellers T, et al. Polymorphisms in the promoter region of neutrophil elastase gene and lung cancer risk. Lung Cancer.2005; 48:315-321
  81. 81. Kirschke H. L. Cathepsin Handb. Proteolytic Enzym. 2013; pp. 1808-1817,
  82. 82. Elshabrawy HA, Fan J, Haddad CS, et al. Identification of a broad-spectrum antiviral small molecule against severe acute respiratory syndrome coronavirus and Ebola, Hendra, and Nipah viruses by using a novel high-throughput screening assay. J Virol. 2014;88(8):4353-4365.
  83. 83. Bristow CL, Di Meo F, Arnold RR. Specific activity of alpha1proteinase inhibitor and alpha2macroglobulin in human serum: application to insulin-dependent diabetes mellitus. Clin Immunol Immunopathol. 1998;89(3):247-259.
  84. 84. Chapman KR, Burdon JG, Piitulainen E, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;386(9991):360-368.
  85. 85. Stoller JK, Aboussouan LS. Alpha1-antitrypsin deficiency. Lancet. 2005; 365 (9478), 2225-2236
  86. 86. Petrache I, Hajjar J, Campos M. Safety and efficacy of alpha-1-antitrypsin augmentation therapy in the treatment of patients with alpha-1-antitrypsin deficiency. Biologics. 2009;3:193-204.
  87. 87. Gao W, Zhao J, Kim H, et al. α1-Antitrypsin inhibits ischemia reperfusion-induced lung injury by reducing inflammatory response and cell death. J Heart Lung Transplant. 2014;33(3):309-315.
  88. 88. de Serres FJ, Blanco I, Fernández-Bustillo E. Genetic epidemiology of alpha-1 antitrypsin deficiency in North America and Australia/New Zealand: Australia, Canada, New Zealand and the United States of America. Clin Genet. 2003;64(5):382-397.
  89. 89. Hazari YM, Bashir A, Habib M, et al. Alpha-1-antitrypsin deficiency: Genetic variations, clinical manifestations and therapeutic interventions. Mutat Res. 2017;773:14-25.
  90. 90. Harbig A, Mernberger M, Bittel L, et al. Transcriptome profiling and protease inhibition experiments identify proteases that activate H3N2 influenza A and influenza B viruses in murine airways. J Biol Chem. 2020;295(33):11388-11407.
  91. 91. Bergin DA, Reeves EP, Meleady P, et al. α-1 Antitrypsin regulates human neutrophil chemotaxis induced by soluble immune complexes and IL-8. J Clin Invest. 2010;120(12):4236-4250.
  92. 92. Ishii T, Doi K, Okamoto K, et al. Neutrophil elastase contributes to acute lung injury induced by bilateral nephrectomy. Am J Pathol. 2010;177(4):1665-1673.
  93. 93. Sodhi CP, Wohlford-Lenane C, Yamaguchi Y, et al. Attenuation of pulmonary ACE2 activity impairs inactivation of des-Arg9 bradykinin/BKB1R axis and facilitates LPS-induced neutrophil infiltration. Am J Physiol Lung Cell Mol Physiol. 2018;314(1):L17-L31.
  94. 94. Gans H, Tan BH. Alpha-1-antitrypsin, an inhibitor for thrombin and plasmin. Clin Chim Acta. 1967;17(1):111-117.
  95. 95. Frenzel E, Korenbaum E, Hegermann J, et al. Does augmentation with alpha1-antitrypsin affect neutrophil extracellular traps formation?. Int J Biol Sci. 2012;8(7):1023-1025.
  96. 96. Petrache I, Fijalkowska I, Zhen L, et al. A novel antiapoptotic role for alpha1-antitrypsin in the prevention of pulmonary emphysema. Am J Respir Crit Care Med. 2006;173(11):1222-1228.
  97. 97. Dutta AK, Goswami K. Host genomics of COVID-19: Evidence point towards Alpha 1 antitrypsin deficiency as a putative risk factor for higher mortality rate. Med Hypotheses. 2021;147:110485.
  98. 98. Tian C, Hromatka BS, Kiefer AK, et al. Genome-wide association and HLA region fine-mapping studies identify susceptibility loci for multiple common infections. Nat Commun. 2017;8(1):599.
  99. 99. Giamarellos-Bourboulis EJ, Netea MG, Rovina N, et al. Complex Immune Dysregulation in COVID-19 Patients with Severe Respiratory Failure. Cell Host Microbe. 2020;27(6):992-1000.e3.
  100. 100. Kanjanaumporn J, Aeumjaturapat S, Snidvongs K, et al. Smell and taste dysfunction in patients with SARS-CoV-2 infection: A review of epidemiology, pathogenesis, prognosis, and treatment options. Asian Pac J Allergy Immunol. 2020;38(2):69-77.
  101. 101. Ehlers A, Beck S, Forbes SA, et al. MHC-linked olfactory receptor loci exhibit polymorphism and contribute to extended HLA/OR-haplotypes. Genome Res. 2000;10(12):1968-1978.
  102. 102. Katsanis SH, Katsanis N. Molecular genetic testing and the future of clinical genomics. Nat Rev Genet. 2013;14(6):415-426.
  103. 103. Kerget F, Kerget B, Kahraman ÇY, et al. Evaluation of the relationship between pentraxin 3 (PTX3) rs2305619 (281A/G) and rs1840680 (1449A/G) polymorphisms and the clinical course of COVID-19 [published online ahead of print, 2021 Jul 27]. J Med Virol.
  104. 104. Refae S, Gal J, Ebran N, et al. Germinal Immunogenetics predict treatment outcome for PD-1/PD-L1 checkpoint inhibitors [published correction appears in Invest New Drugs. 2021 Feb;39(1):287-292].
  105. 105. Alghamdi J, Alaamery M, Barhoumi T, et al. Interferon-induced transmembrane protein-3 genetic variant rs12252 is associated with COVID-19 mortality. Genomics. 2021;113(4):1733-1741.
  106. 106. Ponti G, Pastorino L, Manfredini M, et al. COVID-19 spreading across world correlates with C677T allele of the methylenetetrahydrofolate reductase (MTHFR) gene prevalence. J Clin Lab Anal. 2021;35(7):e23798.
  107. 107. Posadas-Sánchez R, Sánchez-Muñoz F, Guzmán-Martín CA, et al. Dipeptidylpeptidase-4 levels and DPP4 gene polymorphisms in patients with COVID-19. Association with disease and with severity. Life Sci. 2021;276:119410.
  108. 108. Naemi FMA, Al-Adwani S, Al-Khatabi H, et al. Association between the HLA genotype and the severity of COVID-19 infection among South Asians. J Med Virol. 2021;93(7):4430-4437.

Written By

Necla Benlier, Nevhiz Gundogdu and Mehtap Ozkur

Submitted: June 9th, 2021 Reviewed: August 11th, 2021 Published: November 17th, 2021