Pharmacogenomics landscape of COVID-19 therapy response in Serbian population and comparison with worldwide populations
Pharmacogenomics of potential drugs for COVID-19 therapy in Serbia
Keywords:
azithromycin, chloroquine/hydroxychloroquine, COVID-19, lopinavir, pharmacogenomics markers, population pharmacogenomics, ritonavir
Abstract
Background: Since there are no certified therapeutics to treat COVID-19 patients, drug repurposing became important. With lack of time to test individual pharmacogenomics markers, population pharmacogenomics could be helpful in predicting a higher risk of developing adverse reactions and treatment failure in COVID-19 patients. Aim of our study was to identify pharmacogenes and pharmacogenomics markers associated with drugs recommended for COVID-19 treatment, chloroquine/hydroxychloroquine, azithromycin, lopinavir and ritonavir, in population of Serbia and other world populations.
Methods: Genotype information of 143 individuals of Serbian origin was extracted from database previously obtained using TruSight One Gene Panel (Illumina). Genotype data of individuals from different world populations were extracted from the 1000 Genome Project. Fisher’s exact test was used for comparison of allele frequencies.
Results: We have identified 11 potential pharmacogenomics markers in 7 pharmacogenes relevant for COVID-19 treatment. Based on high alterative allele frequencies in population and the functional effect of the variants, ABCB1 rs1045642 and rs2032582 could be relevant for reduced clearance of azithromycin, lopinavir and ritonavir drugs and UGT1A7 rs17868323 for hyperbilirubinemia in ritonavir treated COVID-19 patients in Serbian population. SLCO1B1 rs4149056 is a potential marker of lopinavir response, especially in Italian population. Our results confirmed that pharmacogenomics profile of African population is different from the rest of the world.
Conclusions: Considering population specific pharmacogenomics landscape, preemptive testing for pharmacogenes relevant for drugs used in COVID-19 treatment could contribute to better understanding of the inconsistency in therapy response and could be applied to improve the outcome of the COVID-19 patients.
References
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36. Graffelman J, Weir B S. Multi-allelic exact tests for hardy-weinberg equilibrium that account for gender. Mol Ecol Resour 2018; 18: 461-73.
37. Milosevic G, Kotur N, Krstovski N, Lazic J, Zukic B, Stankovic B, et al. Variants in tpmt, itpa, abcc4 and abcb1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia. Journal of Medical Biochemistry 2018; 37:
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50. Elfiky A A. Anti-hcv, nucleotide inhibitors, repurposing against covid-19. Life Sci 2020; 248: 117477.
51. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate M L, et al. Il28b is associated with response to chronic hepatitis c interferon-α and ribavirin therapy. Nature Genetics 2009; 41: 1100-04.
52. Omrani A S, Saad M M, Baig K, Bahloul A, Abdul-Matin M, Alaidaroos A Y, et al. Ribavirin and interferon alfa-2a for severe middle east respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect Dis 2014; 14: 1090-95.
53. Thomas D, Thio C, Martin M, Qi Y, Ge D, O'Huigin C, et al. Genetic variation in il28b and spontaneous clearance of hepatitis c virus. Nature 2009; 461: 798-801.
54. Jordovic j, Simonovic-Babic J, Gasic V, Kotur N, Zukic B, Pavlovic S, et al. Il-28b genotypes as predictors of long-term outcome in patients with hepatitis c-related severe liver injury. The Journal of Infection in Developing Countries 2019; 13: 526-35.
55. Borivoje S, Svetlana S, Hadži-Milić M, Djonovic N, Milosevic-Djordjevic O, Filip M, et al. Il28b genetic variations in patients with recurrent herpes simplex keratitis. Medicina 2019; 55: 642.
56. Jovanovic-Cupic S, Petrović N, Krajnovic M, Bundalo M, Kokanov N, Bozovic A, et al. Role of host and viral factors and genetic variation of il28b on therapy outcome in patients with chronic hepatitis c genotype 1b from serbia. Genetics & Applications 2019; 3: 36.
57. Lazarevic I, Djordjevic J, Cupic M, Karalic D, Delic D, Svirtlih N, et al. The influence of single and combined il28b polymorphisms on response to treatment of chronic hepatitis c. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 2013; 58:
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64. Patrinos G P. Population pharmacogenomics: Impact on public health and drug development. Pharmacogenomics 2018; 19: 3-6.
2. Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al. A novel coronavirus from patients with pneumonia in china, 2019. N Engl J Med 2020; 382: 727-33.
3. Sanders J M, Monogue M L, Jodlowski T Z, Cutrell J B. Pharmacologic treatments for coronavirus disease 2019 (covid-19): A review. JAMA 2020; 323: 1824-36. Accessed: 5/19/2020
4. Clinicaltrials.Gov. https://clinicaltrials.gov Access Date: 17.05.2020.
5. Colson P, Rolain J-M, Lagier J-C, Brouqui P, Raoult D. Chloroquine and hydroxychloroquine as available weapons to fight covid-19. Int J Antimicrob Agents 2020; 55: 105932-32.
6. Plantone D, Koudriavtseva T. Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neurological diseases: A mini-review. Clinical Drug Investigation 2018; 38:
7. Liu J, Cao R, Xu M, Wang X, Zhang H, Hu H, et al. Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting sars-cov-2 infection in vitro. Cell Discov 2020; 6: 16-16.
8. Bacharier L B, Guilbert T W, Mauger D T, Boehmer S, Beigelman A, Fitzpatrick A M, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: A randomized clinical trial. JAMA 2015; 314: 2034-44.
9. Li G, Clercq E. Therapeutic options for the 2019 novel coronavirus (2019-ncov). Nature Reviews Drug Discovery 2020; 19:
10. de Wilde A H, Jochmans D, Posthuma C C, Zevenhoven-Dobbe J C, van Nieuwkoop S, Bestebroer T M, et al. Screening of an fda-approved compound library identifies four small-molecule inhibitors of middle east respiratory syndrome coronavirus replication in cell culture. Antimicrobial Agents and Chemotherapy 2014; 58: 4875.
11. Chan J F-W, Yao Y, Yeung M-L, Deng W, Bao L, Jia L, et al. Treatment with lopinavir/ritonavir or interferon-β1b improves outcome of mers-cov infection in a nonhuman primate model of common marmoset. The Journal of Infectious Diseases 2015; 212: 1904-13. Accessed: 5/19/2020
12. Rock B, Hengel S, Rock D, Wienkers L, Kunze K. Characterization of ritonavir-mediated inactivation of cytochrome p450 3a4. Molecular pharmacology 2014; 86:
13. Eagling V A, Back D J, Barry M G. Differential inhibition of cytochrome p450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir. Br J Clin Pharmacol 1997; 44: 190-94.
14. Yao T-T, Qian J-D, Zhu W-Y, Wang Y, Wang G-Q. A systematic review of lopinavir therapy for sars coronavirus and mers coronavirus-a possible reference for coronavirus disease-19 treatment option. J Med Virol 2020; 10.1002/jmv.25729.
15. Yao X, Ye F, Zhang M, Cui C, Huang B, Niu P, et al. In vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (sars-cov-2). Clin Infect Dis 2020; ciaa237.
16. Sahraei Z, Shabani M, Shokouhi S, Saffaei A. Aminoquinolines against coronavirus disease 2019 (covid-19): Chloroquine or hydroxychloroquine. Int J Antimicrob Agents 2020; 55: 105945.
17. Kalil A C. Treating covid-19—off-label drug use, compassionate use, and randomized clinical trials during pandemics. JAMA 2020; Accessed: 5/19/2020
18. Beutler E, Kuhl W. Linkage between a pvuii restriction fragment length polymorphism and g6pd a-202a/376g: Evidence for a single origin of the common g6pd a — mutation. Human Genetics 1990; 85: 9-11.
19. Brewer G J, Zarafonetis C J. The haemolytic effect of various regimens of primaquine with chloroquine in american negroes with g6pd deficiency and the lack of an effect of various antimalarial suppressive agents on erythrocyte metabolism. Bull World Health Organ 1967; 36: 303-08.
20. Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir–ritonavir in adults hospitalized with severe covid-19. New England Journal of Medicine 2020; 382: 1787-99. 2020/05/07 Accessed: 2020/05/19
21. Wu J, Li W, Shi X, Chen Z, Jiang B, Liu J, et al. Early antiviral treatment contributes to alleviate the severity and improve the prognosis of patients with novel coronavirus disease (covid-19). Journal of Internal Medicine 2020; n/a: 2020/03/27 Accessed: 2020/05/19
22. Feeney E R, Mallon P W G. Hiv and haart-associated dyslipidemia. Open Cardiovasc Med J 2011; 5: 49-63.
23. Montessori V, Press N, Harris M, Akagi L, Montaner J S G. Adverse effects of antiretroviral therapy for hiv infection. CMAJ 2004; 170: 229-38.
24. Basco L K, Ringwald P. In vitro activities of piperaquine and other 4-aminoquinolines against clinical isolates of plasmodium falciparum in cameroon. Antimicrobial agents and chemotherapy 2003; 47: 1391-94.
25. He X-J, Zhao L-M, Qiu F, Sun Y-X, Li-Ling J. Influence of abcb1 gene polymorphisms on the pharmacokinetics of azithromycin among healthy chinese han ethnic subjects. Pharmacological reports : PR 2009; 61: 843-50.
26. Davidson A, Dassa E, Orelle C, Chen J. Structure, function, and evolution of bacterial atp-binding cassette systems. Microbiology and molecular biology reviews : MMBR 2008; 72: 317-64, table of contents.
27. Abe T, Kakyo M, Tokui T, Nakagomi R, Nishio T, Nakai D, et al. Identification of a novel gene family encoding human liver-specific organic anion transporter lst-1. J Biol Chem 1999; 274: 17159-63.
28. King C, Rios G, Green M, Tephly T. Udp-glucuronosyltransferases. Current Drug Metabolism 2000; 1: 143-61.
29. Danielson P. The cytochrome p450 superfamily: Biochemistry, evolution and drug metabolism in humans. Current drug metabolism 2003; 3: 561-97.
30. Khetarpal S, Zeng X, Millar J, Vitali C, Somasundara A, Zanoni P, et al. A human apoc3 missense variant and monoclonal antibody accelerate apoc-iii clearance and lower triglyceride-rich lipoprotein levels. Nature medicine 2017; 23:
31. Phillips M C. Apolipoprotein e isoforms and lipoprotein metabolism. IUBMB Life 2014; 66: 616-23. 2014/09/01 Accessed: 2020/05/19
32. Pharmgkb. www.pharmgkb.org Access Date: 17.05.2020.
33. Genomes Project C, Auton A, Brooks L D, Durbin R M, Garrison E P, Kang H M, et al. A global reference for human genetic variation. Nature 2015; 526: 68-74.
34. Yates A D, Achuthan P, Akanni W, Allen J, Allen J, Alvarez-Jarreta J, et al. Ensembl 2020. Nucleic Acids Res 2020; 48: D682-D88.
35. Graffelman J, Weir B S. Testing for hardy-weinberg equilibrium at biallelic genetic markers on the x chromosome. Heredity (Edinb) 2016; 116: 558-68.
36. Graffelman J, Weir B S. Multi-allelic exact tests for hardy-weinberg equilibrium that account for gender. Mol Ecol Resour 2018; 18: 461-73.
37. Milosevic G, Kotur N, Krstovski N, Lazic J, Zukic B, Stankovic B, et al. Variants in tpmt, itpa, abcc4 and abcb1 genes as predictors of 6-mercaptopurine induced toxicity in children with acute lymphoblastic leukemia. Journal of Medical Biochemistry 2018; 37:
38. Mette L, Mitropoulos K, Vozikis A, Patrinos G. Pharmacogenomics and public health: Implementing 'populationalized medicine. Pharmacogenomics 2012; 13: 803-13.
39. Philippidis A. Vanquishing the virus: 160+ covid-19 drug and vaccine candidates in development. Journal 2020; Available at https://www.genengnews.com/a-lists/vanquishing-the-virus-160-covid-19-drug-and-vaccine-candidates-in-development/ Accessed on 17.05.2020.
40. Clinicaltrials.Gov covid 19 search results. https://clinicaltrials.gov/ct2/results?cond=COVID-19 Access Date: 17.05.2020.
41. Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of covid-19 associated pneumonia in clinical studies. BioScience Trends 2020; 14: 72-73.
42. Chen Z, Hu J, Zhang Z, Jiang S, Han S, Yan D, et al. Efficacy of hydroxychloroquine in patients with covid-19: Results of a randomized clinical trial. medRxiv 2020; 2020.03.22.20040758. Accessed: 17.05.2020.
43. Chary M A, Barbuto A F, Izadmehr S, Hayes B D, Burns M M. Covid-19: Therapeutics and their toxicities. J Med Toxicol 2020;
44. Tehrani R, Ostrowski R, Hariman R, Jay W. Ocular toxicity of hydroxychloroquine. Seminars in ophthalmology 2009; 23: 201-9.
45. Kassi E N, Papavassiliou K A, Papavassiliou A G. G6pd and chloroquine: Selecting the treatment against sars-cov-2? J Cell Mol Med 2020; 24: 4913-14.
46. Health N I o. Covid19 treatment guidelines. Journal 2020; Available at https://covid19treatmentguidelines.nih.gov/ Accessed on 17.05.2020.
47. Gautret P, Lagier J-C, Parola P, Hoang V T, Meddeb L, Sevestre J, et al. Clinical and microbiological effect of a combination of hydroxychloroquine and azithromycin in 80 covid-19 patients with at least a six-day follow up: A pilot observational study. Travel Med Infect Dis 2020; 34: 101663-63.
48. Gautret P, Lagier J C, Parola P, Hoang V T, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of covid-19: Results of an open-label non-randomized clinical trial. Int J Antimicrob Agents 2020; 105949.
49. Molina J M, Delaugerre C, Le Goff J, Mela-Lima B, Ponscarme D, Goldwirt L, et al. No evidence of rapid antiviral clearance or clinical benefit with the combination of hydroxychloroquine and azithromycin in patients with severe covid-19 infection. Med Mal Infect 2020; 50: 384-84.
50. Elfiky A A. Anti-hcv, nucleotide inhibitors, repurposing against covid-19. Life Sci 2020; 248: 117477.
51. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate M L, et al. Il28b is associated with response to chronic hepatitis c interferon-α and ribavirin therapy. Nature Genetics 2009; 41: 1100-04.
52. Omrani A S, Saad M M, Baig K, Bahloul A, Abdul-Matin M, Alaidaroos A Y, et al. Ribavirin and interferon alfa-2a for severe middle east respiratory syndrome coronavirus infection: A retrospective cohort study. Lancet Infect Dis 2014; 14: 1090-95.
53. Thomas D, Thio C, Martin M, Qi Y, Ge D, O'Huigin C, et al. Genetic variation in il28b and spontaneous clearance of hepatitis c virus. Nature 2009; 461: 798-801.
54. Jordovic j, Simonovic-Babic J, Gasic V, Kotur N, Zukic B, Pavlovic S, et al. Il-28b genotypes as predictors of long-term outcome in patients with hepatitis c-related severe liver injury. The Journal of Infection in Developing Countries 2019; 13: 526-35.
55. Borivoje S, Svetlana S, Hadži-Milić M, Djonovic N, Milosevic-Djordjevic O, Filip M, et al. Il28b genetic variations in patients with recurrent herpes simplex keratitis. Medicina 2019; 55: 642.
56. Jovanovic-Cupic S, Petrović N, Krajnovic M, Bundalo M, Kokanov N, Bozovic A, et al. Role of host and viral factors and genetic variation of il28b on therapy outcome in patients with chronic hepatitis c genotype 1b from serbia. Genetics & Applications 2019; 3: 36.
57. Lazarevic I, Djordjevic J, Cupic M, Karalic D, Delic D, Svirtlih N, et al. The influence of single and combined il28b polymorphisms on response to treatment of chronic hepatitis c. Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology 2013; 58:
58. Wang L-Y, Cui J-J, OuYang Q-Y, Zhan Y, Wang Y-M, Xu X-Y, et al. Genetic profiles in pharmacogenes indicate personalized drug therapy for covid-19. medRxiv 2020; 2020.03.23.20041350. Accessed: 17.05.2020.
59. Wang M, Cao R, Zhang L, Yang X, Liu J, Xu M, et al. Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro. Cell Res 2020; 30: 269-71.
60. Ahsan T, Urmi N J, Sajib A A. Heterogeneity in the distribution of 159 drug-response related snps in world populations and their genetic relatedness. PLoS One 2020; 15: e0228000.
61. Lakiotaki K, Kanterakis A, Kartsaki E, Katsila T, Patrinos G P, Potamias G. Exploring public genomics data for population pharmacogenomics. PLoS One 2017; 12: e0182138.
62. Mizzi C, Dalabira E, Kumuthini J, Dzimiri N, Balogh I, Basak A N, et al. A european spectrum of pharmacogenomic biomarkers: Implications for clinical pharmacogenomics. PloS one 2016; 11: e0162866.
63. Zhou Y, Ingelman-Sundberg M, Lauschke V M. Worldwide distribution of cytochrome p450 alleles: A meta-analysis of population-scale sequencing projects. Clin Pharmacol Ther 2017; 102: 688-700.
64. Patrinos G P. Population pharmacogenomics: Impact on public health and drug development. Pharmacogenomics 2018; 19: 3-6.
Published
2020/09/04
Section
Original paper
Copyright (c) 2020 Biljana Stankovic, Nikola Kotur, Vladimir Gasic, Kristel Klaassen, Bojan Ristivojevic, Maja Stojiljkovic, Sonja Pavlovic, Branka Zukić
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