2020; 40(5): 351-360
Ann Lab Med 2021; 41(2): 129-138
Published online March 1, 2021 https://doi.org/10.3343/alm.2021.41.2.129
Copyright © Korean Society for Laboratory Medicine.
Role of Genetic Variants and Gene Expression in the Susceptibility and Severity of COVID-19
Departments of 1Biochemistry and 2Surgical Oncology, All India Institute of Medical Sciences, Jodhpur, India
Correspondence to: Prasenjit Mitra, M.D., MRSB, FACSc
Department of Biochemistry, All India Institute of Medical Sciences, Basni Industrial Area Phase-2, Jodhpur 342005, Rajasthan, India
*These authors contributed equally to this study.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Since its first report in December 2019, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly emerged as a pandemic affecting nearly all countries worldwide. As the COVID-19 pandemic progresses, the need to identify genetic risk factors for susceptibility to this serious illness has emerged. Host genetic factors, along with other risk factors may help determine susceptibility to respiratory tract infections. It is hypothesized that the ACE2 gene, encoding angiotensin-converting enzyme 2 (ACE2), is a genetic risk factor for SARS-CoV-2 infection and is required by the virus to enter cells. Together with ACE2, transmembrane protease serine 2 (TMPRSS2) and dipeptidyl peptidase-4 (DPP4) also play an important role in disease severity. Evaluating the role of genetic variants in determining the direction of respiratory infections will help identify potential drug target candidates for further study in COVID-19 patients. We have summarized the latest reports demonstrating that ACE2 variants, their expression, and epigenetic factors may influence an individual’s susceptibility to SARS-CoV-2 infection and disease outcome.
Keywords: Angiotensin-converting enzyme 2 (ACE2) variants, Transmembrane protease, Serine 2 (TMPRSS2), Epigenetics, COVID-19, SARS-CoV-2 infection
Coronavirus disease 2019 (COVID-19) emerged in Wuhan city, China, in December 2019. On January 12, 2020, the World Health Organization (WHO) named the causative virus as novel coronavirus (nCov); the virus was renamed on February 11, 2020, as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by the international virus classification commission . During the initial days of the epidemic, various countries followed and implemented different testing strategies, based on the accessibility of diagnostic methods [2, 3]. COVID-19 causes respiratory illness that may range from a mild viral pneumonia to acute respiratory distress syndrome (ARDS) leading to multi-organ failure. The elderly population and individuals suffering from chronic illness have to be extra cautious, as the mortality rate is considerably high among these groups . The massive spread of the virus across countries within a few months of onset led the WHO to declare COVID-19 a pandemic. As of July 19, 2020, the total number of cases and deaths worldwide stood at 14,043,176 and 597,583, respectively .
SARS-CoV-2 is transmitted to lung epithelial cells through aerosols. Various immune cells in the body may also augment the infection; peripheral neutrophilia and lymphocytopenia significantly induce the immune response and cause deleterious ARDS, multi-organ dysfunction, and finally the death in some patients. Additionally, a sudden surge of pro-inflammatory cytokines may lead to fatal outcomes, indicating that cytokines are crucial in the pathophysiology of COVID-19 .
These findings have raised the question of whether genetic or epigenetic variation can be used to identify symptom susceptibility or severity in this disease. A review of a number of studies has suggested that genetic factors along with other risk factors can determine an individual’s susceptibility to respiratory tract infections . As angiotensin-converting enzyme 2 (ACE2) receptor on host cells acts as an entry point for SARS-CoV-2, it is hypothesized that the
Coronaviruses are members of the enveloped single-stranded RNA viruses that cause respiratory, enteric, and cardiovascular diseases in humans and animals. Various coronaviruses, such as NL63,
During earlier SARS outbreaks, studies demonstrated, in an autopsy series using culture techniques, viral isolation, and
ACE2 structure and function
ACE2 is an ACE homologue discovered in 2000. The
ACE2 has multiple roles including catalytic activities with specific substrates; it acts as a negative regulator of the renin-aldosterone system, B0 AT1 amino acid transporter, and receptor for coronaviruses (SARS-CoV) . ACE2 restricts the adverse effects of Ang II on profibrotic and vasoconstrictors. The hydrolysis of Ang II into Ang 1-7 decreases oxidative stress, and Ang 1-7 has counter regulatory mechanisms including antifibrotic and vasodilatory actions. Consequently, ACE2 disturbance leads to elevated Ang II levels and reduced heart function . ACE2 is active in several tissues and is widespread in the lungs, kidneys, heart, and testis. Low levels of
ACE2 as SARS-CoV-2 primary receptor
ACE2 variation and SARS-CoV-2 receptor binding domain
ACE2 utilization by SARS-CoV-2 can be explored to gain insights into the mechanism of restricting SARS-CoV-2 entry into host cells. Although ACE2 is expressed in most vertebrates, SARSCoV-2 cannot always utilize it as a receptor. The ability of SARSCoV-2 to utilize ACE2 was predicted by observing few essential single amino acid (AA) variant sites, which were found to be important for SARS-CoV-2 . Recent reports showed that SARSCoV-2 can utilize ACE2 expressed in humans, Chinese horseshoe bats, swine, and civets, but not that expressed in mouse . In another study, Qiu,
Structural basis for SARS-CoV-2 recognition
In SARS-CoV, receptor recognition and membrane fusion occur through the viral S glycoprotein, which is present on the surface. As soon as the virus enters the host, the trimeric S protein is split into two subunits, S1 and S2, followed by viral release of the S1 subunit for post-fusion confirmation. Subsequently, the S1 subunit binds with the peptidase domain of ACE2 via its RBD, whereas membrane fusion takes place via the S2 subunit. Once the S1 subunit binds to the ACE2 peptidase domain, a single cleavage site is exposed on S2, which is subsequently sliced by various host proteases. This mechanism is crucial for viral infection. The SARS-CoV-2 S protein can also take advantage of ACE2 for host infection in a similar manner.
ACE2 also serves as a chaperone for membrane trafficking of the AA transporter B0 AT1(SLC6A19). B0 AT1 is involved in sodium-dependent uptake of neutral AA in intestinal cells. With the stabilization of B0 AT1, the comprehensive structure of ACE2 in a dimeric assembly has been reported by high-resolution studies . Docking of the S protein trimer onto the structure of the ACE2 dimer together with the RBD of the S protein revealed that two S protein trimers bind to an ACE2 dimer simultaneously. Using a structure-based rational strategy, neutralizing antibodies or decoy ligands with greater affinities for either coronavirus S protein or ACE2 could be produced for viral infection treatment modalities .
ACE2 variants and their association with SARS-CoV-2
Recently, it was suggested that
ACE2 expression in individuals across different ethnicities
In East Asia, the viral infection has spread exponentially; older males, in particular, are more affected by SARS-CoV and the recent SARS-CoV-2 infection.
Consistently, the prevalence of expression quantitative trait loci (eQTL) that show higher
ACE2 expression associated with age and SARS-CoV infection
A different trend of
Transmembrane protease serine 2
In humans, the
TMPRSS2 can also cleave and activate the SARS-CoV-2 S protein during membrane fusion. This protease cleaves the SARS-CoV-2 receptor, the ACE2 carboxypeptidase, and ACE2 cleavage has been shown to augment viral entry into the various host cells . TMPRSS2 also serves as an activator of SARSCoV entry into the host cells via the same mechanism. It is mostly expressed in the epithelial cells of human lungs, absorptive enterocytes, and upper endothelial cells of the esophagus, and it activates influenza A virus and meta-pneumo virus in culture cells . The virus replication stage at which proteases cleave the viral glycoproteins in the plasma membrane varies between SARS-CoV and other viruses such as meta-pneumo virus and influenza A virus . In the influenza A virus and meta-pneumo virus, entry is enabled by TMPRSS2 making a simple cut in the cell membrane glycoprotein, whereas in SARSCoV-2, the S protein is cleaved after the receptor induces a few conformational changes in protease structure . Initially, the protease cleavage site in the S protein was predicted to be exposed after receptor binding; however, it was found to be located very near the C-terminal region of S protein . Further studies have reported that the S protein of mouse hepatitis virus type 2 (MHV-2) usually undergoes conformational changes in two phases, which are facilitated by progressive receptor binding and proteolysis, to be activated for fusion . The MHV-2 S protein was found to be similar to the SARS-CoV S protein. Fusion and effective cleavage, while the receptor binds to the target cells, is very tightly controlled. Premature proteolysis of the activating cleavage site is also prevented efficiently in this way .
Cellular factors required for SARS-CoV-2 entry might provide information regarding viral transmission. Thus, protease dependence of SARS-CoV-2 entry has been studied .
Endosome cysteine proteases cathepsin B/L (CatB/L) are employed for SARS-CoV-2 S protein priming in cells along with TMPRSS2 protease activity. Priming by TMPRSS2 is essential for viral entry and for further spread in the affected host, whereas CatB/L activity is non-essential. Various studies have indicated that SARS-CoV-2 infection rate is also affected by TMPRSS2 proteolytic activity, which raises questions regarding the residual S protein priming conducted by CatB/L. It is hypothesized that furin-mediated pre-cleavage at the S1/S2 site in virally infected cells allows protease dependent entry into these cells, similar to MERS-CoV . In addition, TMPRSS2 is required for homeostasis maintenance and various developmental changes and thus constitutes a drug target for future use. Importantly, TMPRSS2 protease activity is blocked by the serine protease inhibitor camostat mesylate.
Human trials have been recently approved in Japan for testing potential anti-pancreatitis agents; however, the condition is not associated with viral infection. These compounds and various others have been found to significantly increase antiviral activity and thus might be considered as an effective off-label treatment option for SARS-CoV-2-induced respiratory distress . A recent study has reported that using a purified soluble form of TMPRSS11a, receptor binding to the pseudo-typed SARS-CoV S protein significantly enhanced virus multiplication rate. In addition, proteolytic cleavage was shown to be similar to trypsin . A specific spatial orientation of the TMPRSS2 protease with respect to the SARS-CoV-2 S protein is a major factor underlying receptor binding. Additionally, receptor-bound S protein interaction with TMPRSS2 occurs in a specific spatial orientation at the cell surface resulting in inefficient cleavage of SARS-CoV-2 S protein and subsequent membrane fusion. Arginine and lysine residues within ACE2 AAs 697–716 have been predicted to be of prime importance for TMPRSS2-mediated cleavage and histone acetyltransferase activity. In addition, ACE2 needs to be processed for SARS-S-driven entry mediated by these proteases. TMPRSS2 increases SARS-S-entry, because it competes with metalloprotease A disintegrin and metalloprotease 17 for ACE2 processing .
In particular, two different haplotypes can be inferred from the GTEx frequency data :
the haplotype that is more regularly seen is the “European” haplotype that comprises SNVs rs463727, rs34624090, rs55964536, rs734056, rs4290734, rs34783969, rs11702475, rs35899679, and rs35041537. This haplotype was found to be co-expressed and co-regulated with an eQTL (rs8134378). The eQTL (rs8134378) for TMPRSS2 is located 13 kb upstream of an androgen responsive enhancer, possibly upregulating the gene in an androgen-specific manner . However, this haplotype was missing in the Asian population.
Three SNVs, rs2070788, rs9974589, and rs7364083, comprise another haplotype, which was found to have increased
Dipeptidyl peptidase-4 (DPP4)
DPP4 is a transmembrane glycoprotein. It is an ecto-peptidase that cleaves amino-terminal dipeptides causing T cell activation and hence functions in host cell immune-regulation against viral infections. It also functions as a binding protein and ligand of extracellular factors like collagen and fibronectin. DPP4 is expressed by the epithelial and endothelial cells of vessels, as well as by the kidneys, intestines, lungs, and smooth muscle cells of the vasculature. DPP4 accelerates lung inflammation and causes fatal respiratory distress in MERS-CoV infection. Both SARS-CoV-2 and MERS-CoV affect the lower respiratory tract and cause ARDS, thus suggesting a link between SARS-CoV-2 and DPP4.
Molecular interactions between SARS-CoV-2 and DPP4 have been studied via computational model-based docking and 3D structures of the SARS-CoV-2 S glycoprotein and human DPP4 . This model suggests a tight interaction between the S glycoprotein domains and DPP4 receptor. DPP4 binding residues K267, T288, A289, A291, L294, I295, R317, Y322, and D542 interact with the MERS-CoV S protein. The SARS-CoV-2 S1 domain has shown a similar -interaction with DPP4 suggesting that MERS-CoV and SARS-CoV-2 share similar pathways while interacting with host cells. Thus, DPP4 inhibitors, such as gliptins, could be used in COVID-19 patients to significantly reduce viral infection and multiplication rate, as well as reduce cytokine storm and inflammation in the lower airways .
Epigenetic aspects of immune response in SARS-CoV-2 infection
Macrophages and dendritic cells constitute key “hazard” signals among various cells of the innate immune system. These signals are stimulus-specific and cell-specific to ensure the onset of spatial and temporal responses. Such cell-specific signals are facilitated by cytokine, interleukin, and chemokine secretion or direct cell-cell communication. Consequently, their epigenetic ability to alter within minutes of a stimulus is not only important for rapid antiviral host response activation, but also necessary to maintain a sustained and specific defense response. It has been suggested that epigenetic regulation is accountable for virus entry priming and retention of this highly regulated host immune response over the initial activation wave .
Previous studies have focused on epigenetic aspects of the activation and formation of the innate and adaptive immune responses. The primary responsibility of the innate system is manifested via interferon and tumor necrosis factor genes. Interferons are effective mediators in preventing viruses from entering and activating the pathogenic immune response [61, 62]. Consequently, many viruses have possibly developed virulent mechanisms to counteract specific interferon-stimulated gene effectors . Interferons and immune responses are sensitive to epigenetic modifications through different epigenetic pathways . In contrast, interferon-stimulated genes generally show lower amounts of inducing histones, such as H3K4me3 and H4Ac, and lower RNA polymerase II occupancy . Further chromatin remodelers and transcription factors are needed for the initiation of transcription at these genes including ATP-dependent chromatin remodeling complex SWItch / sucrose non-fermentable (SWI / SNF) [66, 67].
Viruses have also developed various pathways to antagonize and disrupt epigenetic regulatory mechanisms, such as viral protein interference with host histone modification enzymes , chromatin remodeling machinery, and modified histones . Current epigenetic studies have focused on the effects of genetic processes on DNA, rather than emphasizing the role of the genetic code itself. Major areas of focus include chromatin remodeling, histone methylation, and many other processes that affect how transcription is initiated, as well as how DNA is packaged in cells. Recently, Pinto
Approximately 60% of mammalian genes are thought to be influenced by miRNAs, especially cancer, metabolism, development, and apoptosis regulatory pathways. Since the first viral miRNAs were discovered in the human Epstein-Barr virus (EBV) , nearly 320 viral miRNA precursors have been identified. Most of the characteristics of miRNA-regulated gene expression appear to be particularly beneficial for viruses. For example, viruses targeting specific human genes via viral miRNAs create a suitable environment for virus replication and survival. In addition, viral miRNAs constitute a potential escape from the host immune system, because the host itself produces the miRNAs in the same way. Recently, Sacar Demirci,
CONCLUSIONS AND FUTURE PERSPECTIVES
The rapid surge in COVID-19 cases and the lack of specific management guidelines to date highlight the urgency and importance of identifying genetic factors that may influence disease susceptibility and severity. At present, information regarding genetic variants of
SC and KS: Literature review and manuscript drafting and revision; PM: conceptualization and design, proofreading and editing, and critical revision; SM and PS: proofreading and supervision. All authors have read the manuscript and provided final approval.
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