COVID‑19 and pharmacogenomics: an association that warrants comprehensive assessment
by Adrijana Kekic, PharmD, BCACP and Deepak Asudani, M.D., MPH.
Introduction to drug treatment consideration for COVID-19
Coronavirus disease (COVID-19), caused by a novel coronavirus (SARS-CoV-2), is arguably the most impactful pandemic that humans have experienced since the so-called 1918 “Spanish” flu caused by the H1N1 virus. The rapidity with which COVID-19 has spread is due to the significant infectivity, wider access to travel routes, latency in symptoms (several days at least), symptoms that resemble seasonal flus, and lack of symptoms in many infected people.
The spread has now assumed a proportion that most nations’ health agencies did not have epidemiological models that could appropriately extrapolate the extent and breadth of those who would be infected. Many countries, regions and states have established lock-down guidelines, enhanced social distancing, and developed hygiene regimens to slow the virus spread to allow hospitals to handle the most serious cases; enable epidemiologists to collect data for predictive disease models; and allow many stakeholders to join the accelerated and unprecedented global project to develop rapid diagnostics, effective vaccines, and life-saving therapeutics.
While hundreds of clinical trials for vaccines have been initiated globally, none have yet been approved for COVID-19 use, even via Emergency Use Authorization (note: approval distinct from Phase 1 and 2 trials, which have been started). On the other hand, certain therapeutics (e.g., remdesivir) have received emergency use approval under medical supervision; other treatment strategies are also being used with a great reliance placed on repurposing existing agents. The uncertainty to select safe and effective drugs is compounded by patient-specific factors and complexities of COVID-19 clinical presentations since few of these proposed drugs and molecules have biomarkers to inform their prescribing.
Patients over 65 years of age, especially those on polypharmacy regimens to manage chronic medical conditions, are a subset with some of the highest risk of morbidity and mortality from COVID-19.1 Younger people even without identified risk factors have also been reported to experience severe disease.2 While many in the scientific community have been overwhelmingly engaged in unraveling the pathogenesis of COVID-19, much more needs to be done and understood. The variability of presentation and susceptibility has stirred a strong interest in an individual’s genetic constitution as being one of the key elements contributing to this variation. The COVID-19 Host Genetics Initiative is a global initiative to analyze data to learn about genetic determinant of COVID-19 susceptibility, generate hypotheses for drug repurposing, and identify those who may benefit most from vaccines.3
Drug-body interactions mediated by genes
Genes also influence the way we metabolize and respond to medications, a critical contribution that has been highlighted by those in the pharmacogenomics (PGx) community. As has been established by the FDA (see Table of Pharmacogenomic Biomarkers in Drug Labeling, https://www.fda. gov/drugs/science-and-research-drugs/table- pharmacogenomic-biomarkers-drug-labeling), PGx accounts for drug-drug-gene interactions to improve drug safety, predict responders vs non-responders and those at risk of developing serious or life-threatening adverse drug events with certain medications.4 In practice, PGx testing has been shown to reduce the number of re-hospitalizations, emergency department visits, and mortality.5 Results from PGx testing should be ideally available at the point of care to minimize trial and error in prescribing. In reality, not all patients have been tested and physicians may not have pharmacogenomics data available to prescribe “the right drug at the right time.”6 We discuss opportunities and challenges in applying PGx information with drugs trialed in COVID-19 management, including supportive care medications.
The eventual effect of a drug and its impact on the human body is described by pharmacokinetics (what the body does to a drug) and pharmacodynamics (what a drug does to the body). Enzymes, such as the cytochrome P450 (CYP450) family, play a crucial role in metabolism of most drugs (antivirals, anti-hypertensives, antidepressants, pain medications, etc). Some CYPs are encoded by highly polymorphic genes, such as the CYP2D6 which can result in a significant variability of a person’s ability to metabolize a drug.
Unfortunately, what is a healing potion for some, may be a poison to others. For example, the pain medication codeine is not recommended in poor CYP2D6 metabolizer phenotype due to lack of efficacy (not converted to its active metabolite, morphine) nor in ultra-rapid CYP2D6 metabolizer phenotype, due to toxicity (high levels of morphine). Presence of other medications, as seen in polypharmacy, can affect a drug’s metabolism (in the sense of a drug-drug interaction). If a drug affects drug metabolizing phenotypes, a drug-drug-gene interaction or phenoconversion may occur (phenoconversion is a phenomenon that converts genotypic good metabolizers into phenotypic poor metabolizers of drugs, thereby modifying their clinical response to that of genotypic poor metabolizers). For example, bupropion, a potent CYP2D6 inhibitor, converts normal CYP2D6 metabolizer to a poor metabolizer. This can have a significant impact on drug and dose selection of CYP2D6 substrates (codeine, metoprolol, paroxetine, venlafaxine, tramadol, etc).
Chloroquine (CQ) and hydroxychloroquine (HCQ) were granted emergency use authorization by the FDA to treat hospitalized patients with COVID-19 not enrolled in a clinical trial.6 Before initiating, patients are evaluated for QTc prolongation risk. Genetic variants in CYP2C19 and CYP2D6 genes have been associated with drug-induced arrhythmias – of particular importance for poor CYP2C19 metabolizers who have a greater risk for QTc prolongation with citalopram than normal or rapid metabolizers.7 Therefore, physicians treating patients with these variants should consider additive arrhythmogenic effects before prescribing drugs like citalopram with hydroxychloroquine. More recent initiatives are helping clinicians account for these interactions, such as drug-drug interactions summaries for CQ and HCQ, Pharmazam’s genetics-based medication management system and others.8,9
Scientific considerations whether genetic factors make a person more susceptible to SARS-CoV-2 infection and correlate to the severity of COVID-19 disease remain to be answered. SARS-CoV-2 uses ACE2 receptors expressed on host epithelial cells along with cofactor TMPRSS2 to get inside the cell.
After the virus binds to the ACE2 receptors, endocytosis facilitates movement of these extracellular entities from the cell surface into the cell cytoplasm. ACE2 plays an additional role as an enzyme that converts pro-inflammatory angiotensin II to anti-inflammatory angiotensin- (1-7).10 Genetic variants of genes that encode for these proteins are suggested to play a role in the specificity of viral attachment, degree of ACE2 endocytosis, and disease severity.11,12For example, Ackerman and his team at the Mayo Clinic observed increased risk for COVID-19 manifestations and outcomes with increased ACE2 transcript expression and protein levels in the heart for patients with obstructive hypertrophic cardiomyopathy.13 The next step would be to analyze lung tissue from COVID-19 patients to see if ACE2 levels are higher than in normal lung tissue. Although promising, more evidence is needed, as currently there are no specific PGx recommendations regarding ACE2 receptors that guide therapy selection. Such findings, ongoing losartan clinical trials, and case studies with angiotensin enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) support recommendations by leading cardiology societies to continue ACEI and ARBs when indicated.14
Human leukocyte antigens (HLA) genes are one of the most polymorphic of human genes.15 They encode for proteins that recognize “self” vs “non-self” and prevent self-attacks. Numerous variants are assessed by PGx testing, e.g., Thompson et al found an association between some HLA genes and COVID-19 severity; for example, those with HLA-B*46:01 showed susceptibility with SARS-CoV-2.16
Another aspect that has garnered significant interest is whether blood type can influence SARS-CoV-2 infectivity. Variations in the gene (A, B, AB or no allele) correlate to a blood type, named based on the presence of two types of sugar molecules.17 ABO gene encodes glycosyltransferases which determine addition of N-acetylgalactosamine or galactose to H antigen and subsequently determine A and B antigens. Furthermore, genetic polymorphisms in the ABO and ACE genes are associated with hypertension (a risk factor in COVID-19). Cidl et al found that different glycosylation of the ACE molecule in different ABO blood groups may alter the regulation of blood pressure, depending on the genetic variants of glycosylated genes.18 Vasku et al identified an association of blood pressure with ACE I/D polymorphism and ABO blood group.19 There may be an association between the differences in the distribution of these ABO groups among ethnicities and how that influences the incidence of hypertension.
But could they explain COVID-19 disease severity? In a recent meta-analysis of data from the US and pre-print data from China, there was a higher proportion of blood group A and lower portion of blood group O in COVID-19 positive patients. Such associations are still poorly understood20,21 and need the rigor of peer review and well controlled studies to advise greater scientific interpretation.
Glucose 6-PD genetic deficiently (G6PD) disorder is the most common genetic enzyme deficiency affecting 400 million people worldwide.22While the FDA drug label indicates that CQ and HCQ carry risk of hemolysis associated with G6PD genetic deficiency disorder, the FDA does not explicitly recommend PGx testing. Additionally, polymorphisms of CYP2D6 have been associated with wide variations in blood HCQ concentration, further implicating the role of CYP2D6 enzyme in prescribing considerations.23Limited data from in vitro and preliminary studies point to CYP2D6 and CYP3A4 enzymes as being involved in chloroquine metabolism. What is unclear is how the combination of genetic variants of those genes may affect medication safety with hydroxychloroquine and chloroquine.
A mandate for additional research and validation
In response to the current and foreseeable impact of the COVID-19 outbreak, an unprecedented global effort using tools previously unavailable for prior pathogenic outbreaks have been brought to bear on the COVID-19 pandemic. 
Governments and industries have allocated major funding to power basic science tools (gene sequencing, informatics), purchase hospital equipment (ventilators, pop-up clinics), distribute diagnostics, and develop antiviral drugs and vaccines. Drug approval may happen in an expedited manner and most likely will be launched via emergency use authorization via a drastically different approach than traditional therapeutics approval processes – e.g., safety and outcomes may be reviewed in light of the risks of prolonged isolation.
The rapid shift of focus on developing COVID therapeutics warrants a ramped-up pharmacogenomics analysis intended to identify COVID-19 patients who could tolerate and benefit from novel therapies. Knowing the PGx association has the potential not only to expedite emergency use authorization and approvals but also to afford an additional level of safety and efficacy to patients. PharmGKB, an online pharmacogenomics knowledge base, recently launched a therapeutic resource for COVID-19 intended to provide PGx considerations for the treatment of COVID-19 and the use of adjuvant therapies (drugs used in intensive care settings, antidepressants, etc). The resource includes a list of drugs in COVID-19 clinical trials, genes implicated in COVID-19 and pathways involving drug gene candidates (losartan, fluvoxamine, etc) .
Currently, over 30 drugs out of 128 registered in COVID-19 clinical trials, are referenced in PharmGKB resource. Close to half of drugs referenced have no actionable drug-gene pairs, or genotype guided recommendations (remdesivir, lopinavir/ritonavor, hydroxychloroquine, losartan, etc).24 On the other hand, many drugs used to treat conditions associated with highest risk of morbidity and mortality in COVID-19 have actionable drug- gene pairs. Examples include metoprolol and CYP2D6, clopidogrel and CYP2C19, simvastatin and SLCO1B1, capecitabine/fluorouracil and DPYD, atazanavir/belinostat/irinotecan and UGT1A1, ondansetron and CYP2D6, abacavir and HLA-A, etc.25
As we examine the actionable drug-gene and drug-drug-gene interactions in a more validated manner, we will be able to establish validated database that will be crucial in guiding our management approaches. In many of these cases it will at least help ascertain no harm is likely in the course of determining efficacy. COVID-19 management landscape is a frontier that will demand greater rigor and close examination of genetic facets leading to prognostic and therapeutic considerations.
Adrijana Kekic, PharmD, BCACP
Dr. Adrijana Kekic is a pharmacogenomics pharmacist and Associate Program Director of Education for Outpatient Pharmacy at Mayo Clinic. As a pharmacogenomics clinician, researcher and educator she led implementation of pharmacogenomics services at Mayo Clinic in Arizona where she sits on Pharmacogenomics (PGx) Task Force. Her research work includes pharmacogenomic studies in anesthesia, transplant, oncology, palliative and other areas. She lectures extensively on pharmacogenomics with niche in psychopharmacology. As an international speaker and a PGx subject expert she frequents precision medicine podcasts, conferences and other platforms.
Dr. Kekic earned the Doctor of Pharmacy degree from Midwestern University College of Pharmacy in Glendale, Arizona. She is a Board Certified Ambulatory Care Pharmacist with Pharmacogenomics Certification from University of Florida College of Pharmacy, Global Leadership Certification from Oxford University, Said School of Business, among others.
With almost two decades of pharmacy leadership and clinical expertise in personalized medication therapy management, Adrijana continues to advance pharmacy practice. She is a founder of a networking platform dedicated to high impact professional women in healthcare.
Deepak Asudani, M.D, MPH.
Dr. Deepak Asudani is an Associate Clinical Professor of Medicine at University of California, San Diego and is engaged in several academic, clinical, and leadership responsibilities. He currently serves as Vice Chief of Division of Hospital Medicine at UCSD and also serves as the Medical Director for Hospital Medicine International Patients’ Program. Besides direct patient care and medical education, he has a strong interest in applied genomics and pharmacogenomics (PGx). An alumnus of Harvard Kennedy School of Government, he holds Master’s in Public Health from University of Massachusetts, Amherst, and is a Certified Physician Executive from the American Academy of Physician Leadership. He also has Certification in Genetics and Genomics, from Stanford University Center for Professional Development, Palo Alto, CA. He has previously published on pharmacogemonics, CRSIPR Cas techniques and has been invited as a speaker both national and international precision medicine fora. He believes that with sophistication in genomic sequencing and advances in applied genomics, precision medicine is not just here to stay, but will define a paradigm shift in being a cornerstone of how we practice medicine. He has served as the editor-in-chief of the Internet Journal of Internal Medicine and is a reviewer for several medical publications. He is on the editorial board for the Journal of Precision Medicine.
References
1. Zheng Z, Peng F, Xu B, et al. J Infect. 2020 Apr 23. pii: S0163-4453(20)30234-6. doi: 10.1016/j.jinf.2020.04.021. [Epub ahead of print]
2. Oxley, T.J., et al. (2020). “Large-Vessel Stroke as a Presenting Feature of Covid-19 in the Young.” New England Journal of Medicine: e60. Doi:10.1056/NEJMc2009787
3. Th e COVID-19 Host Initiative. (2020) New partner portal and gearing up for analysis. [online] [Accessed on 1st May. 2020]. https://www.covid19hg.org/blog/2020-04-09-new-partner-portal-and-gearing-upfor-
analysis/
4. Mayo Clinic. (2020) Centers and Programs. Center for Individualized Medicine. Pharmacogenomics https://www.mayo.edu/research/centers-programs/center-individualized-medicine/patient-care/pharmacogenomics/pgx-profi le-service
5. Elliott LS, et al. Clinical impact of pharmacogenetics profi ling with a clinical decision support tool in polypharmacy home health patients: A prospective pilot randomized control trial. PLoS One. 2017 Feb 2;12(2):e0170905. doi: 10.1371/journal.pone.0170905. eCollection 2017
6. Hydroxychloroquine or Chloroquine for COVID-19: Drug Safety Communication-FDA Cautions Against Use of Outside of the Hospital Setting or a Clinical Trial Due to Risk of Heart Rhythm Problems. U.S. Food and Drug Administration Web site. https://www.fda.gov/safety/medical-product-safety-information/hydroxychloroquine-orchloroquine-covid-19-drug-safety-communication-fda-cautions-againstuse. Published April 24, 2020. Accessed May 1, 2020.
7. Maartje N. et al. Pharmacogenomics of drug-induced QT interval prolongation: an update. Drug Saf. 2015; 38(10): 855–867. doi: 10.1007/s40264-015-0316-6
8. Marcucci C. et al. Summary of Chloroquine and Hydroxychloroquine Drug-Drug Interactions. [online]. Anesthesia Patient Safety Foundation. https://www.apsf.org/news-updates/summary-of-chloroquine-andhydroxychloroquine-drug-drug-interactions/. Published March 27, 2020. Accessed May 1, 2020.
9. Pharmazam. (2020) [Mobile app]. https://pharmazam.com/
10. Bennion, D. et al. Neuroprotective Mechanisms of the ACE2–Angiotensin-(1-7)–Mas Axis in Stroke. Curr Hypertens Rep. 2015 Feb;17(2):3. doi: 10.1007/s11906-014-0512-2
11. Li, M., Li, L., Zhang, Y. et al. Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infect Dis Poverty 9, 45(2020). https://doi.org/10.1186/s40249-020-00662-x
12. Chen, J.; Jiang, Q.; Xia, X.; Liu, K.; Yu, Z.; Tao, W.; Gong, W.; Han, J.J. Individual Variation of the SARS-CoV2 Receptor ACE2 Gene Expression and Regulation. Preprints 2020, 2020030191
13. Martijn Bos J, et al. Marked Up-Regulation of ACE2 in Hearts of Patients with Obstructive Hypertrophic Cardiomyopathy: Implications for SARS-CoV-2-Mediated COVID-19. Mayo Clinic Proceedings, Volume 0, Issue 0
14. HFSA/ACC/AHA Statement Addressing Concerns Re: Using RAAS Antagonists in COVID-19. American College of Cardiology. Published March 27, 2020 http://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concernsre-using-raas-antagonists-in-covid-19 Accessed May 1, 2020.
15. Erlich, H. HLA Polymorphism and Disease Susceptibility.Computational Genetics and Genomics, 2005. ISBN : 978-1-58829-187-5
16. Nguyen A et al. Human leukocyte antigen susceptibility map for SARSCoV-2. 17 April 2020, Journal of Virology.
17. https://www.ncbi.nlm.nih.gov/gene/28 ABO genes ABO,alpha 1-3-N-acetylgalactosaminyltransferase and alpha 1-3-galactosyltransferase [ Homo sapiens (human) ]
18. Cídl K, Strelcov L, Znojil V, Váchi J . Angiotensin I-converting enzyme (ACE) polymorphism and ABO blood groups as factors codetermining plasma ACE activity. Exp Hematol 1996; 24: 790–794.
19. Vasku A, Soucek M, Hajek D, Holla V, Znojil V, Vacha I . Association analysis of 24-h blood pressure records with I/D ACE gene polymorphism and ABO blood group system. Physiol Res 1999; 48: 99–104.
20. Zhao J, Yang Y, Huang HP, et al. Relationship between the ABO blood group and the COVID-19 susceptibility. Med RxIV. Doi: https://doi.org/10.1101/2020.03.11.20031096.
21. Zietz M, Tatonetti NP. Testing the assocation between blood type and COVID-19 infection, intubation, and death. Med RxIV. Doi: https://doi.org/10.1101/2020.04.08.20058073.
22. National Organization of Rare Disorders. Glucose-6-Phosphate Dehydrogenase Defi ciency. (2017). https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-defi ciency/ Accessed May 1, 2020.
23. Lee, J.Y., Vinayagamoorthy, N., Han, K., Kwok, S.K., Ju, J.H., Park, K.S., Jung, S.‐H., Park, S.‐W., Chung, Y.‐J. and Park, S.‐H. (2016), Association of Polymorphisms of Cytochrome P450 2D6 With Blood Hydroxychloroquine Levels in Patients With Systemic Lupus Erythematosus. Arthritis & Rheumatology, 68: 184-190. doi:10.1002/ art.39402
24. PharmGKB. Th erapeutic Resource for COVID-19. Published https://www.pharmgkb.org/page/COVID Updated May 11, 2020. Accessed May 11, 2020
25. Clinical Pharmacogenomics Implementation Consortium.Genes-Drugs. Updated May 7, 2020. https://cpicpgx.org/genes-drugs/Accessed May 11, 2020
