Predisposición y susceptibilidad genética al COVID-19
Autor principal: Héctor Aram Arellano Fernández
Vol. XIX; nº 13; 404
Predisposition and Genetic Susceptibility to COVID-19
Fecha de recepción: 09/06/2024
Fecha de aceptación: 04/07/2024
Incluido en Revista Electrónica de PortalesMedicos.com Volumen XIX. Número 13 Primera quincena de Julio de 2024 – Página inicial: Vol. XIX; nº 13; 404
Autores:
Héctor Aram Arellano Fernández, Ana Karen Amaro Escobedo, Lessly Barrientos Guerrero, Jarely Vianney Navarrete Muñoz
Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Dgo., México.
Departamento de Genética, Facultad de Medicina y Nutrición, Universidad Juárez del Estado de Durango, Dgo., México
Resumen.
La pandemia de enfermedad Coronavirus 19 (COVID 19) causada por el síndrome respiratorio agudo severo coronavirus 2 (SARS- CoV 2) es un problema que afectó en gran medida globalmente, causando graves efectos sobre la salud de la población mundial, ocasionando complicaciones graves en algunos pacientes particularmente con enfermedades crónico degenerativas como lo son la diabetes, obesidad, hipertensión, entre otras. Esta revisión se centra en la investigación sobre la predisposición genética en las complicaciones de pacientes con COVID 19. Hemos resumido algunos de los principales genes que predisponen en las complicaciones o una forma más grave de enfermedad causada por el COVID 19, así como el mecanismo por el cual las mutaciones de estos genes se traducen en una infección más grave.
Palabras clave: covid-19, receptor de quimioquinas 5 (ccr5), mers-cov, sars-cov-1 y sars-cov-2, sistema renina-angiotensina, enzima convertidora de angiotensina 2 (ace2), enzima tmprss2.
Abstract.
The Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), significantly impacted the global population, causing severe health effects worldwide and leading to serious complications in some patients, particularly those with chronic degenerative diseases such as diabetes, obesity, and hypertension, among others. This review focuses on research into the genetic predisposition to complications in patients with the disease. We have summarized some of the major genes that predispose individuals to complications or more severe forms of disease caused by the infection, as well as the mechanism by which mutations in these genes translate into more severe infections.[1]
Keywords.
covid-19, chemokine receptor 5 (ccr5), mers-cov, sars-cov-1 and sars-cov-2, renin-angiotensin system, angiotensin-converting enzyme 2 (ace2), tmprss2 enzyme.
Introduction.
COVID-19 represented a major challenge to the global population, and comorbidities resulted in a higher risk of hospitalization. However, genetics also influenced the severity, symptoms expressed, and hospitalization or recovery of each patient.[1]. The SARS-CoV-2 virus generates a cascade of systemic reactions, affecting different organs and tissues. It is important to understand these reactions to rule out complications and provide better treatment. It has been found that most of the population has a protein receptor called chemokine receptor 5 or CCR5, which is mainly found on the surface of certain immune system cells. Some people have a mutation resulting in a defective receptor, giving them immunity to COVID-19. However, just as there are factors that decrease susceptibility, there are also some that increase it. [1]
Genetic polymorphisms in genes such as ACE2 and TMPRSS2 can influence the susceptibility and severity of COVID-19.[3]
Pathophysiology and Structure of COVID-19
Viruses from the Coronaviridae family belong to the Nidovirales order. These viruses have a large, positive-sense, non-segmented RNA. They are observed to infect the respiratory tract, gastrointestinal tract, and nervous system. In humans, they are commonly associated with respiratory tract diseases. [5] In the early stages of infection, the SARS-CoV-2 virus targets cells such as nasal and bronchial epithelial cells and pneumocytes. It does this through the viral structural spike (S) protein, which binds to the angiotensin-converting enzyme 2 (ACE2) receptor. The TMPRSS2 enzyme (expressed in type II alveolar epithelial cells) found in host cells facilitates the virus entry by cleaving ACE2 and activating the SARS-CoV-2 spike protein, which is responsible for coronavirus entry into host cells. [6] In the later stages of infection, as viral replication speeds up, the integrity of the epithelial-endothelial barrier becomes compromised.[6]
This virus affects each system in a different and complex way, starting with the renin-angiotensin system, which is mainly composed of angiotensinogen, angiotensin 1, angiotensin 2, and angiotensin-converting enzymes (ACE1 and ACE2). [2] ACE2, an extracellular protease that breaks down angiotensin 2 to produce angiotensin, interacts with specific receptors, such as MAS1, and generally has an opposite effect to angiotensin 2. Receptors such as MAS1 are found in various cell types, including alveolar cells such as type II pneumocytes. The function of angiotensin 2 is inhibited by ACE2, so SARS-CoV-2 infection affects its functioning and, consequently, alters the overall physiology of the RAS. It has been reported that SARS-CoV-2 can directly affect the kidney and that chronic kidney disease increases the risk of a fatal outcome due to the infection. [7] In the respiratory system, SARS-CoV-2 is airborne and has an affinity for tissues with high ACE2 expression, causing pulmonary inflammation following alveolar infection, especially type II pneumocytes, altering surfactant production, and triggering a strong immune response. This induces a change in the genetic expression of type II pneumocytes, increasing antiviral genes and decreasing surfactant production genes. [8] In the cardiovascular system, the main complications and leading cause of death in COVID-19 patients are thrombotic events, venous thromboembolism, or disseminated intravascular coagulation. The pathophysiological basis of this is due to feedback loops between pre-existing disease and the clinical condition produced by the infection. The effect on the endocrine system is widely related to type 2 diabetes (T2DM), with a very high prevalence in Mexico and worldwide, increasing the risk of hospitalization and can be considered a significant risk factor. COVID-19 infection and diabetes mellitus can affect blood glucose regulation, cause inflammation, alter the immune system, and activate the renin-angiotensin system. Additionally, infection can lead to ketoacidosis and increased blood glucose levels due to immune deregulation or the use of steroids in hospitalized patients (e.g., glucocorticoids). Therefore, managing diabetic patients during infection requires special attention, as regular medication to control diabetes may not be compatible with the treatment needed for COVID-19. Regarding the function of other endocrine system organs, reports indicate that SARS-CoV-2 infection produces both hypothyroidism and thyrotoxicosis, as well as deficiencies in parathyroid and adrenal gland function. [10]
In the digestive system, alterations such as nausea, vomiting, and diarrhea were present, even in patients who were asymptomatic. [11]
In the central nervous system, some patients presented headaches to cerebrovascular events (CVE). Loss of taste and smell have been classified as CNS problems. [2] Post-chronic COVID has observed a variety of neurological and especially respiratory complications in patients who suffered from this infection, measuring a period from two weeks to months afterward. [12]
Implication of ACE2 Receptor in COVID-19 Infection
The implication of the ACE2 receptor in COVID-19 infection is fundamental because it is the primary receptor that SARS-CoV-2 uses to enter human cells. The viral spike protein, specifically its receptor-binding domain, effectively attaches to ACE2, present in various organs, including the lungs, heart, and gastrointestinal tract. This interaction facilitates the fusion of the virus membrane with the cell membrane, allowing viral genetic material to enter the cell and begin replication. The wide range of ACE2 expression in different tissues also explains the variety of symptoms and complications associated with COVID-19, including respiratory, cardiovascular, and gastrointestinal problems. [13]
COVID-19 symptoms, such as fever, dry cough, and dyspnea, can be related to ACE2 receptor expression in various tissues. For example, ACE2 is expressed in type II alveolar cells in the lungs, which can explain respiratory symptoms such as dyspnea. Gastrointestinal symptoms like nausea and diarrhea may be related to the presence of ACE2 in the gastrointestinal tract. Additionally, anosmia and dysgeusia could be due to ACE2 expression in epithelial cells in the tongue and nasal cavity, affecting taste and smell senses.
Pre-existing comorbidities significantly increase the risk of severe forms of COVID-19 and mortality. Approximately half of hospitalized patients have pre-existing conditions such as hypertension, diabetes, and cardiovascular diseases. Additionally, advanced age and male gender are associated with higher mortality. Imbalances in the ACE/ACE2 ratio, especially noticeable in patients on chronic hemodialysis, exacerbate these risks, worsening vascular conditions and preventing recovery from vascular injuries. [14]
ACE1/ACE2 Variants
Genetic variability in the ACE1 and ACE2 genes could influence the clinical evolution of COVID-19 among different ethnic populations, although studies are not yet conclusive. Mutations in ACE2 have been identified that could affect the binding of the SARS-CoV-2 virus to the receptor. Additionally, a strong association has been demonstrated between the ACE1 insertion/deletion variant and the severity of COVID-19, including higher ACE levels in deletion variant carriers, correlating with higher mortality rates and severe complications such as Acute Respiratory Distress Syndrome (ARDS). Differences in the distribution of these genetic variants among populations suggest variations in susceptibility and response to the virus between ethnic groups.
Mutations in the ACE2 gene that could affect interaction with the SARS-CoV-2 spike protein include K26R and I468W. Additionally, the ACE1 I/D variant, where the insertion (I) and deletion (D) variants have distinct associations with the disease: the DD variant is associated with higher ACE levels, greater risk of hypertension, ARDS, and hospital mortality, while the II variant negatively correlates with infection and mortality rates. [14]
Genetic variants involved in the phenotypic expression of COVID-19 symptoms include the ACE1 insertion/deletion (I/D) polymorphism. This polymorphism can present in three forms:
Genotype II (insertion/insertion): Associated with lower ACE levels.
Genotype ID (insertion/deletion): Intermediate ACE level.
Genotype DD (deletion/deletion): Associated with higher ACE levels.
Individuals with the DD genotype have higher ACE expression, which has been linked to worse clinical outcomes in COVID-19, including increased risk of hypertension, ARDS, and mortality. These differences in ACE levels can influence the inflammatory response and susceptibility to severe SARS-CoV-2 infections. [16]
TMPRSS2 and the Direct Impact of variants in this Protein on Infection
TMPRSS2 (transmembrane protease, serine 2) is an essential protein for SARS-CoV-2 entry into host cells. This protease facilitates viral entry by cleaving the spike protein, enabling its fusion with the host cell membrane. Genetic polymorphisms in the TMPRSS2 gene may influence susceptibility to SARS-CoV-2 infection and the severity of COVID-19. Variants in TMPRSS2 have been linked to differences in infection rates and clinical outcomes in various populations. These polymorphisms could affect the protease’s expression levels or activity, altering the efficiency of viral entry and, consequently, the disease’s severity. [18]
Mutations in TMPRSS2 that affect its function could potentially influence the severity of SARS-CoV-2 infection. Variants that increase TMPRSS2 expression or activity could enhance viral entry into host cells, leading to more severe disease, while variants that decrease its expression or activity could confer some degree of protection against severe infection. Studies have identified several TMPRSS2 polymorphisms associated with COVID-19 outcomes. For instance, the rs12329760 variant, which leads to a missense mutation (V160M), has been associated with reduced TMPRSS2 expression and a lower risk of severe COVID-19. Understanding these genetic variations can help identify individuals at higher risk for severe disease and develop targeted therapeutic strategies. [19]
Analysis of the CCR5 Delta-32 Variants and its Effect on COVID-19
CCR5 is a receptor involved in the immune response, primarily expressed on the surface of T cells, macrophages, dendritic cells, and eosinophils. The CCR5 Delta-32 mutation results in a truncated receptor, which is non-functional and prevents certain pathogens, including HIV and potentially SARS-CoV-2, from entering cells. Individuals homozygous for the CCR5 Delta-32 mutation are highly resistant to HIV infection and may have some degree of protection against severe COVID-19. [21]
The mechanism by which the CCR5 Delta-32 mutation could confer protection against severe COVID-19 is not fully understood, but it is believed to involve reduced inflammatory responses. The CCR5 receptor plays a role in recruiting immune cells to sites of infection, and its absence could lead to a less aggressive immune response, reducing the risk of cytokine storm and severe complications. Studies have shown that individuals with the CCR5 Delta-32 mutation have a lower risk of severe COVID-19 outcomes, suggesting that this genetic variation may modulate the immune response to SARS-CoV-2 infection. [22]
Conclusion
In summary, genetic factors play a significant role in determining the severity and clinical outcomes of COVID-19. Variations in genes such as ACE1, ACE2, TMPRSS2, and CCR5 can influence susceptibility to SARS-CoV-2 infection and the development of severe disease. Understanding these genetic predispositions can help identify individuals at higher risk and inform the development of targeted therapies and personalized treatment strategies. Future research should continue to explore the genetic basis of COVID-19 severity, with a focus on identifying additional genetic variants and elucidating their mechanisms of action. This knowledge can improve public health responses and contribute to better management of current and future pandemics.
Bibliography
1 .Mar., J. K. (s/f). How sick will the coronavirus make you? The answer may be in your genes. Iitd.ac.in. Recuperado el 1 de junio de 2024,
2 Manta B. Fisiopatología de la enfermedad COVID-19 Pathophysiology of COVID-19 Fisiopatologia da doença COVID-19.
3 Hou Y, Zhao J, Martin W, Kallianpur A, Chung MK, Jehi L, et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine. 2020 Jul 15;18(1).
4 Goldsmith CS, Tatti KM, Ksiazek TG, Rollin PE, Comer JA, Lee WW, et al. Ultrastructural Characterization of SARS Coronavirus. Emerging Infectious Diseases. 2004 Feb;10(2):320–6.
5 Cruz-Durán A, Fernández-Garza NE. Fisiopatología de la COVID-19. Lux Médica [Internet]. [cited 2024 May 18];16(47).
6 Wiersinga WJ, Rhodes A, Cheng AC, Peacock SJ, Prescott HC. Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA [Internet]. 2020 Jul 10;324(8):782–93.
7 Pérez PC, Fernández LM, García-Cosio MD, Delgado JF. Sistema renina-angiotensina-aldosterona y COVID19. Implicaciones clínicas. Revista Española de Cardiología Suplementos. 2020;20:27–32.
8 Pérez PC, Fernández LM, García-Cosio MD, Delgado JF. Sistema renina-angiotensina-aldosterona y COVID19. Implicaciones clínicas. Revista Española de Cardiología Suplementos. 2020;20:27–32. https://journals.physiology.org/doi/full/10.1152/ajplung.00126.2020
10 1.OUP accepted manuscript. Journal of Molecular Cell Biology. 2020; https://academic.oup.com/jmcb/article/12/12/958/5917022
11 Galanopoulos M, Gkeros F, Doukatas A, Karianakis G, Pontas C, Tsoukalas N, et al. COVID-19 pandemic: Pathophysiology and manifestations from the gastrointestinal tract. World Journal of Gastroenterology [Internet]. 2020 Aug 21;26(31):4579–88.
12 Solomon T. Neurological infection with SARS-CoV-2 — the story so far. Nature Reviews Neurology [Internet]. 2021 Jan 7;1–2.
13 Umakanthan S. Origin, transmission, diagnosis and management of coronavirus disease 2019 (COVID-19). 2020 Jun 20;
14 Beyerstedt S, Casaro EB, Rangel ÉB. COVID-19: angiotensin-converting enzyme 2 (ACE2) expression and tissue susceptibility to SARS-CoV-2 infection. European Journal of Clinical Microbiology & Infectious Diseases. 2021 Jan 3;40(5).
15 Hou Y, Zhao J, Martin W, Kallianpur A, Chung MK, Jehi L, et al. New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis. BMC Medicine. 2020 Jul 15;18(1).
16 Yamamoto N, Nishida N, Yamamoto R, Takashi Gojobori, Kunitada Shimotohno, Mizokami M, et al. Angiotensin–Converting Enzyme (ACE) 1 Gene Polymorphism and Phenotypic Expression of COVID-19 Symptoms. 2021 Oct 1;12(10):1572–2. TMPRSS2 [Internet]. Wikipedia. 2020
17 Cuesta-Llavona E, Gómez J, Albaiceta GM, Amado-Rodríguez L, García-Clemente M, Gutiérrez-Rodríguez J, et al. Variant-genetic and transcript-expression analysis showed a role for the chemokine-receptor CCR5 in COVID-19 severity. International Immunopharmacology [Internet]. 2021 Sep 1 [cited 2022 Oct 24];98:107825.
18 Law H.K., Cheung C.Y., Sia S.F., Chan Y.O., Peiris J.S., Lau Y.L. Toll-like receptors, chemokine receptors and death receptor ligands responses in SARS coronavirus infected human monocyte derived dendritic cells. BMC Immunol. 2009;10:35. – PMC – PubMed
19 Chen J., Lau Y.F., Lamirande E.W., Paddock C.D., Bartlett J.H., Zaki S.R., Subbarao K. Cellular immune responses to severe acute respiratory syndrome coronavirus (SARS-CoV) infection in senescent BALB/c mice: CD4+ T cells are important in control of SARS-CoV infection. J. Virol. 2010;84(3):1289-1301. – PMC – PubMed
20 Glass W.G., Liu M.T., Kuziel W.A., Lane T.E. Reduced macrophage infiltration and demyelination in mice lacking the chemokine receptor CCR5 following infection with a neurotropic coronavirus. Virology. 2001;288:8-17. – PMC – PubMed Chua R.L., Lukassen S., Trump S., Hennig B.P., Wendisch D., Pott F., et al. COVID-19 severity correlates with airway epithelium-immune cell interactions identified by single-cell analysis. Nat. Biotechnol. 2020;38 (8):970-979. – PubMed