The outbreak of coronavirus disease 19 (COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is considered to be the century’s third plague. COVID-19 was declared as the sixth international concerned public health emergency by the World Health Organization (WHO) on January 30, 2020. As of September 27, 2021, the COVID-19 pandemic has claimed the lives of over 4.75 million.
Study: Human genetic basis of coronavirus disease 2019. Image Credit: Naty.M / Shutterstock.com
Being highly heterogeneous, the severity of COVID-19 is related to several factors such as quarantine effectiveness, healthcare factors, societal norms, government policies, cultural practices, economics, viral characteristics, pollution, climate, and host-associated factors. For host-associated factors, apart from age, pre-existing diseases, smoking, initial heath, and previous vaccinations also contribute to the severity and an individual’s susceptibility of COVID-19. Differences at the genetic level can also be a factor that impacts differences in susceptibility and severity of individuals suffering from COVID-19.
A new review article published in Nature Signal Transduction and Targeted Therapy investigated the clinical and viral characteristics, pathogenesis, as well as human genetic basis associated with COVID-19. This study primarily focuses on the protective and risk effects of variants of COVID-19 related genes such as the angiotensin-converting enzyme (ACE) gene, the angiotensin-converting enzyme 2 gene (ACE2), ABO blood groups, the transmembrane protease serine 2 gene (TMPRSS2), and the HLA genotypes.
Clinical characteristics of COVID-19
COVID-19 is heterogeneous and associated with a wide range of clinical characteristics. Those who are infected with SARS-CoV-2 can experience a wide range of effects including asymptomatic, moderate, severe, to critical conditions. The most common symptoms associated with COVID-19 infection are fever, smell and taste dysfunction, dyspnea, fatigue, chest discomfort, myalgia, anorexia, headache, nausea, diarrhea or vomiting, nasal congestion, abdominal discomfort, and hemoptysis.
Patients with severe forms of COVID-19 can develop pneumonia that can further lead to acute respiratory distress syndrome (ARDS) or multiple organ failure. Furthermore, in addition to affecting the respiratory tract, COVID-19 can also cause damage to the heart, kidneys, blood vessels, gastrointestinal (GI) tract, liver, skin, and nervous system.
Common laboratory abnormalities that have been found in COVID-19 patients include increased C-reactive protein, D-dimer, glucose, aspartate aminotransferase, troponin, alanine aminotransferase, procalcitonin, total bilirubin, creatine kinase, and creatinine, along with decreased albumin. Additionally, it has been found that there was an increase or decrease in the level of lactate dehydrogenase, neutrophils, lymphocytes, platelets, and leukocytes in COVID-19 patients.
Chest computed tomography (CT) scans are often performed to determine the onset of pneumonia and to determine the severity of viral pneumonia.
The SARS-CoV-2 pathogen
SARS-CoV-2 is an enveloped, non-segmented, positive-sense single-stranded ribonucleic acid (RNA) virus that consists of 29,903 nucleotides in its genome. SARS-CoV-2 belongs to the genus Betacoronavirus of the Coronaviridae family. It is 5’ capped and 3’ polyadenylated.
The genome of SARS-CoV-2 consists of open reading frames (ORF). ORF1a and ORF1b encode non-structural proteins, while the remaining ORFs encode for structural and accessory proteins.
The structural proteins of SARS-CoV-2 include the spike (S), envelope (E), membrane (M), and nucleocapsid (N) proteins. The S, M, and E proteins make up the viral envelope, while the role of the N protein is to encapsulate the viral genome.
The viral envelope comprises a phospholipid bilayer consisting of phospholipids and cholesterol. The presence of these components in the viral envelope makes it susceptible to detergents, dry heat, and organic solvents.
The transmission of SARS-CoV-2 occurs via various pathways such as droplets, direct contact, aerosol, transplacental, and fecal-oral routes. The small droplets bearing SARS-CoV-2 are able to travel tens of meters and remain both viable and infectious for several days.
Mutated variants of SARS-CoV-2
Reports from May 2021 suggested that the variants of SARS-CoV-2 that were circulating throughout the world included B.1.617.2, B.1.526, B.1.1.7, and P.1. The B.1.1.7 variant was first detected in September 2020 in the United Kingdom and was found to contain 21 different mutations in its genome.
Two of the most prominent S protein mutations involve the N501Y substitution and the del69–70 mutation. The N501Y substitution causes a conformational change in the receptor-binding domain (RBD) and may increase the fatality rate. The del69–70 mutation led to S-gene target failure. Two other S protein substitutions, L452R in B.1.617.2 and E484K in B.1.1.7, can lead to poor antibody effects on target cases.
Pathogenesis of SARS-CoV-2
The entry of SARS-CoV-2 inside the host cell depends on two factors including the recognition of the ACE2 receptor by the viral S protein and priming of the S protein by TMPRSS2. The S1 subunit of the S protein binds to the ACE2 receptor, which is followed by proteolytic cleavage at the S1/S2 site by TMPRSS2. Cleavage can also be brought about by furin and Cathepsin proteins.
The cleavage results in the formation of separate S1 and S2 domains. The cell surface receptor neuropilin-1 (NRP1) binds to the cleavage site of S1 and also helps in the isolation of S2 from S1. The S2 subunit then undergoes a conformational change that subsequently leads to the fusion of the host and viral membranes, thus mediating the entry of the virus into the host.
The renin-angiotensin–aldosterone system (RAAS) is a complex system that is responsible for maintaining the ACE/ACE2 balance in humans. Overactivation of RAAS can also be considered an important pathophysiological alteration that occurs during COVID-19.
Immunopathogenesis of SARS-CoV-2
SARS-CoV-2 is known to activate both the acquired and innate immune responses. Furthermore, it causes cytokine storms, which are uncontrolled inflammatory responses brought about by high levels of circulating cytokines.
SARS-CoV-2 is detected through pathogen-associated molecular patterns (PAMPs) by the pattern recognition receptors (PRRs). Recognition of the virus leads to activation of a signaling pathway that ultimately causes the innate immune cells to release inflammatory mediators.
In the case of acquired immunity, the virus targets the CD147 spike protein of the T lymphocyte. The virus binds with class I and II MHC molecules and is presented to the CD8 and CD4 T-cells.
The generation of proinflammatory cytokines and mediators is brought about by CD4 T-cells that help to activate other immune cells. B-cells are directly activated by SARS-CoV-2 and produce G antibodies that also increase the generation of proinflammatory cytokines.
The cytokine storm causes extensive tissue damage, body dysfunction, and ultimately death. Recent studies have found that out of all the inflammatory cytokines, interleukin 6 (IL-6) played a major role in the development of cytokine storms. Thus, it was concluded by many researchers that SARS-CoV-2 causes a chemokine, rather than a cytokine, storm.
Genes of the autosomal loci that are associated with COVID-19
2q24.2 and the interferon-induced with helicase C domain 1 gene (IFIH1)
The IFIH1 protein is a PRR that is known to trigger innate immunity as well as the mitochondrial antiviral protein. The variant rs1990760 (p.Ala946Thr) of the IFIH1 gene has been found to positively correlate with the increased expression of viral resistance genes IF-induced gene and IFIH1. Thus, the rs1990760 T-allele is capable of providing resistance to COVID-19 to its carriers.
3p21.31
The 3p21.31 gene cluster comprises the leucine zipper transcription factor-like 1 gene (LZTFL1), the solute carrier protein family 6 member 20 gene (SLC6A20), the FYVE and coiled-coil domain autophagy adaptor 1 gene (FYCO1), the X–C motif chemokine receptor 1 gene (XCR1), the C–X–C motif chemokine receptor 6 gene (CXCR6), and the C-C motif chemokine receptor 9 gene (CCR9). This cluster is susceptible to respiratory failure due to COVID-19 and is also responsible for severe COVID-19 infections.
6p21.3 and HLA genotype
The HLA system comprises approximately 27,000 alleles. Genetic differences between subtypes of the HLA gene may alter the process of viral infection.
Certain HLA genes are considered to be strong presenters, whereas others are deemed weak presenters. The genomes of individuals that comprise the weak presenters are susceptible to COVID-19, while strong presenters provide protection against COVID-19. Differences in HLA genes can also help to determine the severity of COVID-19 based on the genes that are present in different individuals.
9q34.2 and the ABO, alpha 1–3-N-acetylgalactosaminyltransferase and alpha 1–3-galactosyltransferase gene (ABO)
The A, B, and O blood groups are known to possess the A, B, and H antigens, respectively. The antigen encoding gene comprises A, B, and O alleles and is expressed in four genetic phenotypes.
Susceptibility and survival to COVID-19 can be related to the ABO blood groups. Individuals with A blood type have a higher risk of infection, while those with O blood are associated with better protection against COVID-19.
11p15.5 and the interferon-induced transmembrane protein 3 gene (IFITM3)
The IFITM3 comprises the rs12252 C-allele that can be related to disease severity in COVID-19 patients. The nearby rs34481144 A-allele causes methylation of the IFITM3 promoter that, in turn, decreases messenger RNA (mRNA) expression in CD8 T-cells and thus increases susceptibility to COVID-19.
12q24.33 and the golgin A3 gene (GOLGA3)
The GOLGA3 gene is known to encode the Golgi complex-associated protein that participates in apoptosis, Golgi positioning, protein transportation, and spermatogenesis. GOLGA3 may contribute to COVID-19 severity by influencing interactions between SARS-CoV-2 and the innate immune pathways.
13q12.3 and the high mobility group box 1 gene (HMGB1)
The HMGB1 gene encodes a DNA binding protein, which may increase COVID-19 susceptibility by inducing the cytokine storm and expression of ACE2 in alveolar epithelial cells.
15q26.1 and the FURIN gene
The FURIN gene encodes a protein convertase that causes cleavage of the SARS-CoV-2 S protein into two subunits, S1 and S2. The S2 subunit then causes fusion to occur between of the viral and host membranes, thus bringing about infection.
17q23.3 and the ACE gene
The insertion of Alu element in the ACE intron 16 leads to protein shortening and a loss of active protein domain in ACE I-allele, while no such effect takes place on the ACE D-allele. The variability of ACE is determined by the ACE I/D variant in general populations. The recovery and prevalence rates of COVID-19 also depend on the ratio of the ACE I/D allele frequency, as well as the geographical variations of the ACE I/D variant.
19q13.32 and the apolipoprotein E gene (APOE)
The APOE gene comprises three common alleles of ε2, ε3, and ε4. Individuals who are homozygous for APOE ε4 were found to have twice the risk of having COVID-19. The APOE ε4ε4 homozygous genotype is associated with a higher risk of having severe COVID-19 due to proinflammatory pathways and lipoprotein function getting affected.
21q22.3 and the TMPRSS2 gene
The gene variants of TMPRSS2 play an important role in determining the gender-related bias of COVID-19 susceptibility and severity. The three most common variants are rs61299115, rs4303794, and rs11088551. These variants have a high frequency in the general population, while their frequency is much lower in East Asia's population.
Genes of the X or Y loci associated with COVID-19
Gender bias of COVID-19
According to Leon’s theory, X-chromosome inactivation (XCI) takes place in females in the late blastocyst stage. The complete inactivation process is controlled by two non-coding RNAs that condense one X chromosome into a compact structure known as the Barr body and maintains another active X chromosome. Few of the X-linked genes are capable of escaping from the XCI.
The escape from XCI can be variable in individuals because some cells express the maternal copy while others express the paternal copy. The presence of any abnormal gene variant is bypassed in females; however, in males, they are expressed phenotypically. This explains the relationship between SARS-CoV-2 and gender bias.
Xp22.2 and the TLR7 gene
The TLR7 gene encodes for Toll-like receptors that are responsible for the recognition and antiviral response against SARS-CoV-2. Studies indicate that the emergence of loss of function (LOF) variants in the TLR7 gene can lead to increased susceptibility to COVID-19.
Xp22.22 and the ACE2 gene
The ACE2 gene encodes a dipeptidyl carboxydipeptidase containing an N-terminal signal peptide and a C-terminal collectrin-like domain. Generation of ACE2 variants leads to alteration in COVID-19 susceptibility, as well as mortality.
The heterogeneous expression of ACE2 in different ethnic groups may also be responsible for differential population reactions to COVID-19. Furthermore, ACE2 expression can be increased in females due to skewed XCI, which could explain the lower severity of COVID-19 in females as compared to males.
Xq12 and the androgen receptor gene (AR)
The AR binding element is an important part of the TMPRSS2 promoter where androgen binding and transcriptional regulation takes place. Length variation of the AR gene is associated with more severe COVID-19 in males.
Conclusion
SARS-CoV-2 continues to infect and cause the deaths of many individuals throughout the world. Therefore, knowledge about the relationship between COVID-19 and host genetic bias can help to indicate biomarkers for individuals who are at a high risk of experiencing the severe effects of COVID-19.
This information may also help to provide potential therapeutic targets. Large-scale screening of potential drugs as well as experimental therapeutic studies will help in the development of a new drug or repurposing of an existing drug for the treatment of COVID-19.
Journal reference:
- Deng, H., Yan, X., & Yuan, L. (2021). Human genetic basis of coronavirus disease 2019. Nature Signal Transduction and Targeted Therapy 6(344). doi:10.1038/s41392-021-00736-8.
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