key: cord-0901487-3a8gvsze authors: AL‐Eitan, Laith N.; Alahmad, Saif Z. title: Pharmacogenomics of genetic polymorphism within the genes responsible for SARS‐CoV‐2 susceptibility and the drug‐metabolising genes used in treatment date: 2020-11-17 journal: Rev Med Virol DOI: 10.1002/rmv.2194 sha: d9a66a248a02cccf7191b037c5c716cc5ac5bbcb doc_id: 901487 cord_uid: 3a8gvsze The ongoing outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) represents a significant challenge to international health. Pharmacogenomics aims to identify the different genetic variations that exist between individuals and populations in order to determine appropriate treatment protocols to enhance the efficacy of drugs and reduce their side‐effects. This literature review provides an overview of recent studies of genetic polymorphisms in genes that mediate the SARS‐CoV‐2 infection mechanism (ACE1, ACE2, TMPRSS2 and CD26). In addition, genetic variations in the drug‐metabolising enzyme genes of several selected drugs used in the treatment of COVID‐19 are summarised. This may help construct an effective health protocol based on genetic biomarkers to optimise response to treatment. Potentially, pharmacogenomics could contribute to the development of effective high‐throughput assays to improve patient evaluation, but their use will also create ethical, medical, regulatory, and legal issues, which should now be considered in the era of personalised medicine. In December 2019, many cases of pneumonia stemming from an unknown aetiology were reported in Wuhan, Hubei Province, China. Throat swab samples were taken from patients in January 2020, which led to the identification of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus as the cause of coronavirus disease 2019 . 1 SARS-CoV-2, has since infected and killed millions of people around the world, prompting the World Health Organization (WHO) to declare SARS-CoV-2 to be a global pandemic and a public health emergency of international concern (PHEIC) on March 11. Countries were quick to implement measures and restrictions to reduce the spread of the virus. 2 As of November 13, more than 53,000,000 confirmed cases and 1,302,000 deaths have been reported around the world according to the WHO. 3 Epidemiological studies have demonstrated a large disparity in the infection and mortality rates between men and women. This could be attributed to the difference between copies of the number of X-linked genes that play an important role in the immune response. 4, 5 Furthermore, more than 50% of fatalities were reported among elderly people (more than 60 years old) and those who have underlying medical conditions such as cardiovascular disease, diabetes, chronic respiratory disease and hypertension. 6 In contrast, children and infants have shown low morbidity and mortality rates, and moderate symptoms regardless of gender. 6 The symptoms that result from COVID-19 vary; some patients are asymptomatic, while others show mild or severe symptoms including fever, muscle pain, difficulty breathing and a loss of taste or smell. 7 Pharmacogenomics reveals the influence of genetic polymorphisms in drug response. These genetic variations are generally recognised as one of the major contributors to the individual or ethnic variations in the toxicity and efficacy of drugs. Pharmacogenomics gives new insights into the management, prevention and treatment of COVID-19 by analysing genetic variants and taking effective action for each patient based on these genetic differences. 8 Research should focus on the genes (including receptors, transporters and enzymes) that facilitate entry and infection of SARS-CoV-2. Furthermore, several drugs have been investigated for treating . Studying the genetic variation of genes responsible for drug metabolism (pharmacodynamics and pharmacokinetics) assists in guiding personalised treatment programmes by examining the efficacy and toxicity levels of particular drugs. This review aims to summarise the pharmacogenomic studies available for the genetic biomarkers that could influence susceptibility to SARS-CoV-2 and the drug metabolism of several candidate drugs used in its treatment. At the time of writing, remdesivir and dexamethasone have been licensed based on the results of randomised controlled trials and another RCT of inhaled interferon-beta reports clinical benefit by inhibiting the cytokine storm that underlies severe COVID-19. 9,10 All other drugs mentioned here are in early phase clinical trials. Coronaviruses are a family of viruses enveloped with a positive-sense single-strand RNA and helical symmetry capsid. 11 15 The SARS-CoV-2 genome has also shown a high homology with SARS-CoV-1 (79.5%) and moderate homology with MERS-CoV (50%). 16 Structural proteins in SARS-CoV-2 particles, include spike glycoprotein (S), envelope protein (E), membrane protein (M), nucleocapsid protein (N) and hemagglutinin-esterase protein (HE) (Figures 1(a) and 2). 17 Additionally, there are eight accessory proteins 3a, 3b, p6, 7a, 7, 8, 9b, and orf14, that play a role in the viral replication process ( Figure 1(b) ). 17 The host protease, transmembrane protease/serine subfamily member 2 (TMPRSS2) mediates proteolytic cleavage of the S protein resulting in two subunits, receptor-binding S1 and membrane-fusion S2 that play an essential role in the virus-receptor binding and integration with the host plasma membrane. Within the S1 subunit, there are two functional domains: the receptor-binding domain (RBD) and the receptor-binding motif (RBM) (Figure 1 (c)). 18, 19 The S2 subunit is structured from the cytoplasm domain, a transmembrane domain, the heptad repeat 1 (HR1) and 2 (HR2) regions and the fusion peptide region (Figure 1(c) ). 18, 19 Respiratory droplets generated by coughing and sneezing are the most common route of transmission for SARS-CoV-2. 20 SARS-CoV-2 virions have also been detected in saliva, urine and faeces. 20 Moreover, SARS-CoV-2 has been found in conjunctival secretions, gastrointestinal tissue, and in tear samples from COVID-19 patients. 21, 22 The angiotensin-converting enzyme 2 (ACE2) receptor-which is widely expressed in different organs such as the lungs, heart, intestines and kidneys 23 -acts as the principal entry point for SARS-CoV-2 into cells. The virus entry process to the host cell begins when the RBD binds to a specific enzymatic domain in the ACE2 receptor, known as the peptidase domain (PD). At the same time, three HR1 are combined into a trimer-coiled structure, followed by attachment of three HR2 subunits into the hydrophobic grooves of the trimeric-coiled structure results in the construction of the six-helical bundle (6-HB). 24, 25 This leads to fusion between the host and the viral membrane, allowing SARS-CoV-2 to enter the host cells via endocytosis. 26 Pharmacogenomic studies should be focused on the genetic variation found in the genes that relate to the entry and infection mechanisms of the virus. Moreover, many genes are implicated, both directly and indirectly, in the metabolism of selected drugs to treat COVID-19. The polymorphisms in these genes should therefore be analysed to ensure an effective response rate and a low level of toxicity. has shown twice the ACE1 activity compared with the II genotype. 31 Moreover, patients with the II genotype have a significantly greater chance of survival than patients with other genotypes. 31 The prevalence of the DD genotype is higher in patients with severe lung infections and is significantly correlated with a high death rate. 32 For example, African Americans in the United States are considered to have the highest D allele frequency (89%) compared with white Americans (69%). 33 Additionally, populations in France, Italy and Spain have shown a high D allele frequency of between 82% and 87%. 34 Conversely, populations in East Asian countries such as Japan, China, Taiwan and Korea have a high frequency of the II genotype. 35 Accordingly, the high II genotype frequency and the low DD genotype frequency in the ACE1 gene seem to be correlated with the relatively low mortality rate of COVID-19 among these populations. 36 On the other hand, European populations have shown a higher mortality rate, as in the case of black ethnicity in the United States. 37, 38 It is clear that the ethnic variation of the ACE I/D genotype tends to correlate with the variations in outcomes where populations with a high D genotype frequency tend to experience higher mortality rates. 39, 40 Another study indicates that I/D polymorphism in the teractions between ACE2 and S1, thereby reducing the infection rate (Tables 2 and 3) . 45 These SNPs also found among the populations in different countries around the world. 45 In another study, eight rare variants that have a role in the virus-ACE2 interaction were mapped. However, based on the entropy-enthalpy calculations, none of the variants demonstrated any resistance against the SARS-CoV-2 entry mechanism. 46 Transmembrane serine protease 2 (TMPRSS2) primes S during the entry of SARS-CoV-2 into host cells. 47 A previous study showed a deficiency of TMPRSS2 expression in the airways, which reduced the severity of lung pathology after SARS-CoV infection. 48 Irham et al. reported that TMPRSS2 is highly expressed in the human respiratory system. 49 Dipeptidyl peptidase 4 (DPP4), also identified as CD26, is a serine exopeptidase that is expressed in organs such as the lungs, stomach allele has associated with an overexpression of the CD26 gene, resulting in a high mortality rate in COVID-19 patients who also suffered from type-2 diabetes mellitus. 50 Cytokines are small proteins, synthesize by various immune cells such as T lymphocytes, B lymphocytes and macrophages, as well as fibroblasts and endothelial cells. 51 Cytokines are involved in the immune response against a wide range of viruses by implicating in the control of the inflammatory signals. 52 Cytokine storm is defined as an activation signal of over cytokine releasing due to uncontrolled immune response to various stimuli. 53 patients. Hydroxychloroquine and chloroquine are antiviral drugs used to treat and prevent malaria and are also used in the treatment of autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and chronic discoid lupus erythematosus. 61 Hydroxychloroquine is developed by adding a hydroxyl group to chloroquine to decrease its toxicological effects and to conserve its therapeutic potential. Although it was investigated against SARS-CoV-2 at the beginning of the pandemic, more recent studies suggest that the risks exceed its potential efficacy in treating The pharmacokinetics of hydroxychloroquine and chloroquine are complicated due to their long half-life and their large volume of distribution inside the body. Moreover, their toxicity thresholds and dose-response associations have not been fully investigated. 63 These antimalarial medications have direct impacts on the autophagy process, cellular transduction pathways and lysosomal activity. 64 Hydroxychloroquine accumulates inside cell vesicles such as endosomes and lysosomes, which generate a highly acidic environment leading to the suppression of vesicles that mediate SARS-CoV-2 entry. 65 Moreover, hydroxychloroquine could directly affect the interactions between the SARS-CoV-2 and ACE2 by reducing ACE2 glycosylation. 66 Cytochrome P450 (CYP) isomers, including CYP2D6, CYP2C8, CYP1A1 and CYP3A4, are involved in the metabolism of both hydroxychloroquine and chloroquine. 67 Genetic polymorphisms among these isomers affect metabolism rate, and thus affect the potential response to both drugs. CYP2C8*4, CYP2C8*2 and CYP2C8*3 alleles reduce enzyme activity in vitro when compared with the wild-type allele CYP2C8*1A, thereby leading to a slow response to hydroxychloroquine and chloroquine treatment. 68 Additionally, variants in the CYP2D6 (rs1135840 andrs1065852) gene increased hydroxychloroquine metabolism in a patient with systemic lupus erythematosus. 69 SNPs in the glucose-6-phosphate dehydrogenase (G6PD) gene are associated with a greater risk of haemolysis. Three important SNPs-rs5030868, rs1050828 and rs1050829-reduce G6PD activity and increase the risk of haemolysis after treatment with chloroquine. 7 Ribavirin is a synthetic guanosine nucleoside which is used to treat hepatitis C and a variety of viral haemorrhagic fevers and it used to treat SARS-CoV-2. 70, 71 It may also be used to treat rabies in combination with other drugs such as amantadine and midazolam. 72 One Captopril is an antihypertensive drug that inhibits the ACE receptors and has activity against SARS-CoV-2. 77 α-Interferon is a cytokine synthesised from immune cells during viral infection and is mainly used to treat hepatitis B and C. 80 The number of detectable SARS-CoV-2 virions was significantly reduced in the upper respiratory tract due to the effect of α-interferon. 81 Genetic variations in different genes can affect the response to α-interferon. For example, an SNP (rs303218) found in the interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) can affect the α-interferon response in hepatitis B patients. 82 The genotype rs303218 GG has a greater virological response rate (52%) when compared with the rs303218 GG genotype (27%). 82 Azithromycin is a macrolide commonly used to treat bacterial infections that, when used in conjunction with hydroxychloroquine, inhibited SARS-CoV-2. 85 There are no pharmacogenomics studies that illustrate the impacts of the genetic polymorphisms found in the drug-metabolizing genes of Remdesivir. There is a need to conduct more studies on the genetic biomarkers found in the metabolism-related genes of Remdesivir. Dexamethasone is a corticosteroid drug, a class of steroid hormones, implicated in the metabolizing-related genes such as CYP3A7, CYP3A5 and CYP3A4 could affect the corticosteroids response. 102 Moreover, receptor binding genes including Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1) and Corticotropin-Releasing Hormone Receptor 1 (CRHR1), and transporters such as ABCB1 are also involved in the corticosteroid's response. 102 Several studies are needed to determine the effect of the genetic variation in the genes related to Dexamethasone metabolism in the COVID-19 patients. Genetic variations among individuals and populations should be considered when drug protocols are being developed using healthy subjects. This article summarised some of the polymorphisms found in genes that have a direct role in SARS-CoV-2 infection, such as ACE1, ACE2, TMPRSS2 and DPP4. We also described some selected drugs currently used in the treatment of SARS-CoV-2. Future research should focus on more detailed analyses and studies of polymorphisms among genes that play a role in drug metabolism to help create effective therapy regimens and reduce adverse effects of these drugs. However, the genetic differences that affect the treatment of SARS-CoV-2 are still being studied and will require more research. 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The authors declare that there are no conflicts of interests. Data sharing not applicable-no new data generated. Laith N. AL-Eitan initiated the review. Laith N. AL-Eitan and Saif Z.