Farmakogenomski profil odgovora na terapiju za COVID-19 u populaciji Srbije i poređenje sa populacijama širom sveta
Farmakogenomika potencijalnih lekova za COVID-19 u Srbiji
Ključne reči:
azitromicin, COVID-19, farmakogenomski markeri, hlorokin/hidroksihlorokin, lopinavir, populaciona farmakogenomika, ritonavir
Sažetak
Uvod: Kako ne postoje odobreni terapeutici za lečenje pacijenata COVID-19, mogućnost upotrebe postojećih lekova je postala važna. U nedostatku vremena za testiranje farmakogenomskih markera kod pojedinaca, populaciona farmakogenomika bi mogla biti od koristi u predviđanju povećanog rizika za pojavu neželjenih reakcija i neuspeha lečenja kod pacijenata sa COVID-19. Cilj naše studije bio je identifikovanje farmakogena i farmakogenomskih markera povezanih sa lekovima koji se preporučuju za lečenje COVID-19, hlorokin/hidroksihlorokin, azitromicin, lopinavir i ritonavir, u populaciji Srbije i drugim svetskim populacijama.
Metode: Podaci o genotipu 143 osobe srpskog porekla dobijeni su iz baze podataka prethodno formirane analizama genoma korišćenjem TruSight One Gene Panel (Illumina). Podaci o genotipu pojedinaca iz različitih svetskih populacija dobijeni su iz Projekta 1000 genoma. Fišerov egzaktni test korišćen je za poređenje učestalosti alela.
Rezultati: Identifikovali smo 11 potencijalnih farmakogenomskih markera u 7 farmakogena značajnih za lečenje COVID-19. Na osnovu visoke alterativne učestalosti alela u populaciji Srbije i funkcionalnog efekta varijanti, ABCB1 rs1045642 i rs2032582 mogu biti značajne za smanjeni klirens lekova azitromicina, lopinavira i ritonavira, a varijanta UGT1A7 rs17868323 za hiperbilirubinemiju kod bolesnika sa COVID-19 koji se leče ritonavirom. SLCO1B1 rs4149056 je potencijalni marker odgovora na lopinavir, posebno u populaciji Italije. Naši rezultati potvrdili su da se farmakogenomski profil afričke populacije razlikuje od ostatka sveta.
Zaključci: Uzimajući u obzir farmakogenomski profil specifičan za populaciju, preventivno testiranje farmakogena značajnih za lekove koji se koriste u lečenju COVID-19 moglo bi doprineti boljem razumevanju interindividualnih razlika u odgovorima na terapiju i poboljšanju ishoda lečenja pacijenata sa COVID-19.
Reference
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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.
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2020/09/04
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Original paper
Sva prava zadržana (c) 2020 Biljana Stankovic, Nikola Kotur, Vladimir Gasic, Kristel Klaassen, Bojan Ristivojevic, Maja Stojiljkovic, Sonja Pavlovic, Branka Zukić
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