Genetic polymorphisms of CYP2C9, CYP2C19, and CYP3A5 in Kosovar population

Open access

Abstract

Cytochrome P450 genetic polymorphisms are responsible for individual variations in drug metabolism and drug-drug interactions. They are very important for pharmacogenetics, and their frequency varies across different populations. There is a big gap in the knowledge about the CYP gene family polymorphisms in the population of Kosovo, and the aim of our study was to fill that gap by determining the frequency of the most important variant alleles of CYP2C9, CYP2C19, and CYP3A5 in 234 nonrelated Kosovars. The allele frequencies of CYP2C9*2 and 2C9*3 were 17.52 %, and 10.89 %, respectively. Sixteen participants (6.81 %) were CYP2C9 poor metabolisers. The CYP2C19*2 and *17 variant frequencies were 13.03 % and 19.01 %, respectively. There were 2.13 % CYP2C19 poor and 4.27 % ultra-rapid metabolisers (homozygous carriers of the *17 allele). With regard to CYP3A5, the frequency of the *3 variant allele was 98.29 % (non-expressors), while the remaining participants (1.70 %) were expressors of CYP3A5. These findings are comparable with other European ethnicities, specifically those of Southeast Europe.

1. Lam TN, Hunt CA. Mechanistic insight from in silico pharmacokinetic experiments: roles of P-glycoprotein, Cyp3A4 enzymes, and microenvironments. J Pharmacol Exp Ther 2010;332:398-412. doi:

2. Preissner SC, Hoffmann MF, Preissner R, Dunkel M, Gewiess A, Preissner S. Polymorphic cytochrome P450 enzymes (CYPs) and their role in personalized therapy. PloS One 2013;8(12):e82562. doi:

3. Kantae V, Krekels EH, Esdonk MJ, Lindenburg P, Harms AC, Knibbe CA, Van der Graaf PH, Hankemeier T. Integration of pharmacometabolomics with pharmacokinetics and pharmacodynamics: towards personalized drug therapy. Metabolomics 2017;13:9. doi:

4. Phillips KA, Veenstra DL, Oren E, Lee JK, Sadee W. Potential role of pharmacogenomics in reducing adverse drug reactions: a systematic review. JAMA. 2001;286:2270-9. doi:

5. Hiratsuka M. In vitro assessment of the allelic variants of cytochrome P450. Drug Metab Pharmacokinet 2012;27:68-84. doi:

6. Krasniqi V, Dimovski A, Domjanović IK, Bilic I, Božina N. How polymorphisms of the cytochrome P450 genes affect ibuprofen and diclofenac metabolism and toxicity. Arh Hig Rada Toksikol. 2016;67:1-8. doi:

7. Beitelshees AL, Voora D, Lewis JP. Personalized antiplatelet and anticoagulation therapy: applications and significance of pharmacogenomics. Pharmgenomics Pers Med 2015;8:43-61. doi:

8. Schuck RN, Grillo JA. Pharmacogenomic biomarkers: an FDA perspective on utilization in biological product labeling. AAPS J 2016;18:573-7. doi:

9. Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, Brockmoller J, Frotschl R, Kopke K, Gerloff T, Chernov JN, Roots I. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol 2003;59:303-12.doi:

10. Scordo MG, Caputi AP, D’Arrigo C, Fava G, Spina E. Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population. Pharmacol Res 2004;50:195-200. doi:

11. Scott SA, Sangkuhl K, Shuldiner AR, Hulot JS, Thorn CF, Altman RB, Klein TE. PharmGKB summary: very important pharmacogene information for cytochrome P450, family 2, subfamily C, polypeptide 19. Pharmacogenet Genomics 2012;22:159-65. doi:

12. Lamba J, Hebert JM, Schuetz EG, Klein TE, Altman RB. PharmGKB summary: very important pharmacogene information for CYP3A5. Pharmacogenet Genomics 2012;22:555-8. doi:

13. Arici M, Özhan G. CYP2C9, CYPC19 and CYP2D6 gene profiles and gene susceptibility to drug response and toxicity in Turkish population. Saudi Pharm J 2017;25:376-80. doi:

14. Božina N, Granić P, Lalić Z, Tramišak I, Lovrić M, Stavljenić- Rukavina A. Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population. Croat Med J 2003;44:425-8. PMID: 12950145

15. Yang JQ, Morin S, Verstuyft C, Fan LA, Zhang Y, Xu CD, Barbu V, Funck-Brentano C, Jaillon P, Becquemont L. Frequency of cytochrome P450 2C9 allelic variants in the Chinese and French populations. Fundam Clin Pharmacol 2003;17:373-6. doi:

16. IGSR: The International Genome Sample Resource. Providing ongoing support for the 1000 Genomes Project data [displayed 30 August 2017]. Available at http://www.internationalgenome.org

17. Jakovski K, Nestorovska AK, Labacevski N, Dimovski AJ. Characterization of the most common CYP2C9 and CYP2C19 allelic variants in the population from the Republic of Macedonia. Pharmazie 2013;68:893-8. doi:

18. Daly AK. Pharmacogenetics of drug metabolizing enzymes in the United Kingdom population: review of current knowledge and comparison with selected European populations. Drug Metab Pers Ther 2015;30:165-74. doi:

19. Buzoianu AD, Trifa AP, Muresanu DF, Crisan S. Analysis of CYP2C9*2, CYP2C9*3 and VKORC1 -1639 G>A polymorphisms in a population from South-Eastern Europe. J CellMolMed2 0 1 2 ; 1 6 : 2 9 1 9 - 2 4 . d o i : 10.1111/j.1582-4934.2012.01606.x

20. Yasar U, Eliasson E, Dahl ML, Johansson I, Ingelman- Sundberg M, Sjöqvist F. Validation of methods for CYP2C9 genotyping: frequencies of mutant alleles in a Swedish population. Biochem Biophys Res Commun 1999;254:628-31. doi:

21. Burian M, Grösch S, Tegeder I, Geisslinger G. Validation of a new fluorogenic real-time PCR assay for detection of CYP2C9 allelic variants and CYP2C9 allelic distribution in a German population. Br J Clin Pharmacol 2002;54:518-21. doi:

22. Dorado P, Berecz R, Norberto MJ, Yasar U, Dahl ML, A LL. CYP2C9 genotypes and diclofenac metabolism in Spanish healthy volunteers. Eur J Clin Pharmacol 2003;59:221-5. doi:

23. Arvanitidis K, Ragia G, Iordanidou M, Kyriaki S, Xanthi A, Tavridou A, Manolopoulos VG. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Fundam Clin Pharmacol 2007;21:419-26. doi:

24. Ganoci L, Božina T, Mirošević Skvrce N, Lovrić M, Mas P, Božina N. Genetic polymorphisms of cytochrome P450 enzymes: CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 in the Croatian population. Drug Metab Pers Ther 2017;32:11-21. doi:

25. Chaudhary N, Kabra M, Gulati S, Gupta YK, Pandey RM, Bhatia BD. Frequencies of CYP2C9 polymorphisms in North Indian population and their association with drug levels in children on phenytoin monotherapy. BMC Pediatr 2016;16:66. doi:

26. Allabi AC, Gala JL, Desager JP, Heusterspreute M, Horsmans Y. Genetic polymorphisms of CYP2C9 and CYP2C19 in the Beninese and Belgian populations. Br J Clin Pharmacol 2003;56:653-7. doi:

27. Sipeky C, Lakner L, Szabo M, Takacs I, Tamasi V, Polgar N, Falus A, Melegh B. Interethnic differences of CYP2C9 alleles in healthy Hungarian and Roma population samples: relationship to worldwide allelic frequencies. Blood Cells Mol Dis 2009;43:239-42. doi:

28. Kapedanovska Nestorovska A, Jakovski K, Naumovska Z, Hiljadnikova Bajro M, Sterjev Z, Eftimov A, Matevska Geskovska N, Suturkova L, Dimitrovski K, Labacevski N, Dimovski AJ. Distribution of the most common genetic variants associated with a variable drug response in the population of the Republic of Macedonia. Balkan J Med Genet 2015;17:5-14. doi:

29. Payan M, Tajik N, Rouini MR, Ghahremani MH. Genotype and allele frequency of CYP2C19*17 in a healthy Iranian population. Med J Islam Repub Iran 2015;29:269. PMCID: PMC4715407

30. Scott SA, Sangkuhl K, Gardner EE, Stein CM, Hulot JS, Johnson JA, Roden DM, Klein TE, Shuldiner AR; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450-2C19 (CYP2C19) genotype and clopidogrel therapy. Clin Pharmacol Ther 2011;90:328-32. doi:

31. Ragia G, Arvanitidis KI, Tavridou A, Manolopoulos VG. Need for reassessment of reported CYP2C19 allele frequencies in various populations in view of CYP2C19*17 discovery: the case of Greece. Pharmacogenomics 2009;10:43-9. doi:

32. Fricke-Galindo I, Cespedes-Garro C, Rodrigues-Soares F, Naranjo ME, Delgado A, de Andres F, López-López M, Peñas- Lledó E, LLerena A1 Interethnic variation of CYP2C19 alleles, ‘predicted’ phenotypes and ‘measured’ metabolic phenotypes across world populations. Pharmacogenomics J 2016;16:113-23. doi:

33. Baldwin RM, Ohlsson S, Pedersen RS, Mwinyi J, Ingelman- Sundberg M, Eliasson E, Bertilsson L. Increased omeprazole metabolism in carriers of the CYP2C19*17 allele; a pharmacokinetic study in healthy volunteers. Br J Clin Pharmacol2 0 0 8 ; 6 5 : 7 6 7 - 7 4 . d o i : 10.1111/j.1365-2125.2008.03104.x

34. Frere C, Cuisset T, Gaborit B, Alessi MC, Hulot JS. The CYP2C19*17 allele is associated with better platelet response to clopidogrel in patients admitted for non-ST acute coronary syndrome. J Thromb Haemost 2009;7:1409-11. doi:

35. Sibbing D, Gebhard D, Koch W, Braun S, Stegherr J, Morath T, Von Beckerath N, Mehilli J, Schömig A, Schuster T, Kastrati A. Isolated and interactive impact of common CYP2C19 genetic variants on the antiplatelet effect of chronic clopidogrel therapy. J Thromb Haemost 2010;8:1685-93. doi:

36. Hicks JK, Sangkuhl K, Swen JJ, Ellingrod VL, Muller DJ, Shimoda K, Bishop JR, Kharasch ED, Skaar TC, Gaedigk A, Dunnenberger HM, Klein TE, Caudle KE, Sting JC. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther 2017;102:37-44. doi:

37. Sychev DA, Denisenko NP, Sizova ZM, Grachev AV, Velikolug KA. The frequency of CYP2C19 genetic polymorphisms in Russian patients with peptic ulcers treated with proton pump inhibitors. Pharmgenomics Pers Med 2015;8:111-4. doi:

38. Barrera-Pulido L, Aguilera-Garcia I, Docobo-Perez F, Alamo- Martinez JM, Pareja-Ciuro F, Nunez-Roldan A, Gómez-Bravo MA, Bernardos-Rodríguez A. Clinical relevance and prevalence of polymorphisms in CYP3A5 and MDR1 genes that encode tacrolimus biotransformation enzymes in liver transplant recipients. Transplant Proc 2008;40:2949-51. doi:

39. Ma LM, Liu HC, Ruan LH, Feng YM. CYP3A5 * 3 genetic polymorphism is associated with childhood acute lymphoblastic leukemia risk: A meta-analysis. Biomed J 2015;38:428-32. doi:

40. Adler G, Loniewska B, Parczewski M, Kordek A, Ciechanowicz A. Frequency of common CYP3A5 gene variants in healthy Polish newborn infants. Pharmacol Rep 2009;61:947-51. doi:

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