Indian Journal of Clinical Biochemistry

, Volume 33, Issue 2, pp 208–213 | Cite as

Genetic Polymorphism of CYP2C9 Among Sistani Ethnic Group in Gorgan

Original Article
  • 71 Downloads

Abstract

Cytochrome P450 2C9 (CYP2C9) is involved in metabolism of many important drugs and its genotype variations is thought to affect drug efficacy and the treatment process. The aim of this study was to assess the distribution of CYP2C9 allele and genotypic variants in Sistani ethnic group, living in Gorgan, South East of Caspian Sea and North East of Iran. This study included 140 Sistani, referred to the health center of Gorgan. CYP2C9 genotyping was carried out by polymerase chain reaction–restriction fragment length polymorphism technique. The allele frequency of CYP2C9*1, CYP2C9*2 and CYP2C9*3 was 76.1, 16.1 and 7.8%, respectively. The frequency of CYP2C9*1/*1, CYP2C9*1/*2, CYP2C9*1/*3, CYP2C9*2/*2, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes was 53.9, 22.1, 11.4, 2.9, 4.3% and nil, respectively. In this study the genotypic variations of the CYP2C9 allele among the Sistani ethnic group was investigated and great differences were observed in comparison to other populations. Our findings suggest that different genotypes of CYP2C9 may influence the pharmacokinetics of some drugs. More studies on the pharmacokinetic effects of CYP2C9 genotypes may help physicians choose optimal dosage of some drugs for treatment and prevention of their side effects. Since different ethnic groups from all over the world use medications, it suggests to investigate the pharmacokinetic effects of CYP2C9 genotypes in different populations.

Keywords

Polymorphism of CYP2C9 Sistanee ethnic group Polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) 

Notes

Acknowledgements

The authors would like to thank the Research Deputy of Golestan University of Medical Sciences for financial support. This research project was derived from research proposal in Clinical Biochemistry. The corresponding author wishes to thank Mr. Aman Mohammad Gharanjik for his sincere help.

Funding

This work has been supported by the Research Deputy of Golestan University of Medical Science.

Compliance with Ethical Standards

Conflict of interest

The authors declared no conflicts of interest.

References

  1. 1.
    Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in vitro and human data. Pharmacogenetics. 2002;12:251–63.CrossRefPubMedGoogle Scholar
  2. 2.
    Goldstein JA, de Morais SM. Biochemistry and molecular biology of the human CYP2C subfamily. Pharmacogenetics. 1994;4:285–99.CrossRefPubMedGoogle Scholar
  3. 3.
    Goldstein JA. Clinical relevance of genetic polymorphisms in the human CYP2C subfamily. Br J Clin Pharmacol. 2001;52:349–55.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Garcıá-Martıń E, Martıńez C, Ladero JM, Aguńdez JA. Interethnic and intraethnic variability of CYP2C8 and CYP2C9 polymorphisms in healthy individuals. Mol Diagn Ther. 2006;10(1):29–40.CrossRefPubMedGoogle Scholar
  5. 5.
    Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med. 2005;7:97–104.CrossRefPubMedGoogle Scholar
  6. 6.
    Miners J, Birkett D. Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Br J Clin Pharmacol. 1998;45:525–38.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Zanger U, Turpeinen M, Klein K, Schwab M. Functional pharmacogenetics/genomics of human cytochromes P450 involved in drug biotransformation. Anal Bioanal Chem. 2008;392:1093–108.CrossRefPubMedGoogle Scholar
  8. 8.
    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.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Veenstra DL, Blough DK, Higashi MK, Farin FM, Srinouanprachan S, Rieder MJ, et al. CYP2C9 haplotype structure in European American warfarin patients and association with clinical outcomes. Clin Pharmacol Ther. 2005;77:353–64.CrossRefPubMedGoogle Scholar
  10. 10.
    Van Booven D, Marsh S, McLeod H, Carrillo MW, Sangkuhl K, Klein TE, et al. Cytochrome P450 2C9-CYP2C9. Pharmacogenet Genomics. 2010;20:277–81.PubMedPubMedCentralGoogle Scholar
  11. 11.
    Kurose K, Sugiyama E, Saito Y. Population differences in major functional polymorphisms of pharmacokinetics/pharmacodynamics-related genes in Eastern Asians and Europeans: implications in the clinical trials for novel drug development. Drug Metab Pharmacokinet. 2012;27:9–54.CrossRefPubMedGoogle Scholar
  12. 12.
    Ross KA, Bigham AW, Edwards M, Gozdzik A, Suarez-Kurtz G, Parra EJ. World allele frequency distribution of four polymorphisms associated with warfarin dose requirements. J Hum Genet. 2010;55:582–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Obayashi K, Nakamura K, Kawana J, Ogata H, Hanada K, Kurabayashi M, et al. VKORC1 gene variations are the major contributors of variation in warfarin dose in Japanese patients. Clin Pharmacol Ther. 2006;80:169–78.CrossRefPubMedGoogle Scholar
  14. 14.
    Ghiyas Tabari M, Naseri F, Agh Ataby M, Marjani A. Genetic polymorphism of cytochrome p450 (2C9) enzyme in Iranian Baluch Ethnic Group. Open Biochem J. 2015;9:37–41.CrossRefPubMedGoogle Scholar
  15. 15.
    Agh Ataby O, Ghiyas Tabari R, Mansourian AR, Mansour Samai N, Marjani A. Genetic polymorphism of cytochrome P450 2C9 (CYP2C9) in two ethnic groups in Iran. Am J Biomed Sci. 2013;5(3):177–87.CrossRefGoogle Scholar
  16. 16.
    Chang M, Dahl M-L, Tybring G, Gotharson E, Bertilsson L. Use of omeprazole as a probe drug for CYP2C19 phenotype in Swedish Caucasians: comparison with S-mephenytoin hydroxylation phenotype and CYP2C19 genotype. Pharmacogenetics. 1995;5:358–63.CrossRefPubMedGoogle Scholar
  17. 17.
    Brosen K, de Morais SMF, Meyer UA, Goldstein JA. A multifamily study on the relationship between CYP2C19 genotype and S-mephenytoin oxidation phenotype. Pharmacogenetics. 1995;5:312–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet. 1999;353:717–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Azarpira N, Namazi S, Hendijani F, Banan M, Darai M. Investigation of allele and genotype frequencies of CYP2C9, CYP2C19 and VKORC1 in Iran. Pharmacol Rep. 2010;62(4):740–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Mirghani RA, Chowdhary G, Elghazali G. Distribution of the major cytochrome P450 (CYP) 2C9 genetic variants in a Saudi population. Basic Clin Pharmacol Toxicol. 2011;109(2):111–4.CrossRefPubMedGoogle Scholar
  21. 21.
    Yang Z, Cui H, Hasi T, Jia S, Gong M, Su X. Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Mongolian population in China. Genet Mol Res. 2010;9(3):1844–51.CrossRefPubMedGoogle Scholar
  22. 22.
    Ota T, Kamada Y, Hayashida M, Iwao-Koizumi K, Murata S, Kinoshita K. Combination analysis in genetic polymorphisms of drug-metabolizing enzymes CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A5 in the Japanese population. Int J Med Sci. 2015;12(1):78.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Arvanitidis K, Ragia G, Iordanidou M, Kyriaki S, Tavridou A, Manolopoulos VG. Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population. Fundam Clin Pharmacol. 2007;21(4):419–26.CrossRefPubMedGoogle Scholar
  24. 24.
    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(2):195–200.CrossRefPubMedGoogle Scholar
  25. 25.
    Gaikovitch EA, Cascorbi I, Mrozikiewicz PM, Brockmöller J, Frötschl R, Köpke K, et al. Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of P-glycoprotein in a Russian population. Eur J Clin Pharmacol. 2003;59(4):303–12.CrossRefPubMedGoogle Scholar
  26. 26.
    Sipeky C, Lakner L, Szabo M, Takacs I, Tamasi V, Polgar N, et al. Interethnic differences of CYP2C9 alleles in healthy Hungarian and Roma population samples: relationship to worldwide allelic frequencies. Blood Cells Mol Dis. 2009;43(3):239–42.CrossRefPubMedGoogle Scholar
  27. 27.
    Jakjovski K, Labachevski N, Petlichkovski A, Senev A, Trojacanec J, Atanasovska E, et al. Distribution of CYP2C9 and VKORC1 gene polymorphisms in healthy Macedonian male population. Maced J Med Sci. 2013;6(4):339–43.CrossRefGoogle Scholar
  28. 28.
    Buzoianu AD, Trifa AP, Mureşanu DF, Crişan S. Analysis of CYP2C9*2, CYP2C9*3 and VKORC1-1639 G>A polymorphisms in a population from South-Eastern Europe. J Cell Mol Med. 2012;16(12):2919–24.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Castelán-Martínez OD, Hoyo-Vadillo C, Sandoval-García E, Sandoval-Ramírez L, González-Ibarra M, Solano-Solano G, et al. Allele frequency distribution of CYP2C9*2 and CYP2C9*3 polymorphisms in six Mexican populations. Gene. 2013;523(2):167–72.CrossRefPubMedGoogle Scholar
  30. 30.
    Niemi M, Cascorbi I, Timm R, Kroemer HK, Neuvonen PJ, Kivisto KT. Glyburide and glimepiride pharmacokinetics in subjects with different CYP2C9 genotypes. Clin Pharmacol Ther. 2002;72:326–32.CrossRefPubMedGoogle Scholar
  31. 31.
    Kirchheiner J, Brockmoller J, Meineke I, Bauer S, Rohde W, Meisel C, et al. Impact of CYP2C9 amino acid polymorphisms on glyburide kinetics and on the insulin and glucose response in healthy volunteers. Clin Pharmacol Ther. 2002;71:286–96.CrossRefPubMedGoogle Scholar
  32. 32.
    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.CrossRefPubMedGoogle Scholar
  33. 33.
    Herman D, Dolzan V, Breskvar K. Genetic polymorphism of cytochromes P450 2C9 and 2C19 in Slovenian population. ZDRAV VESTN. 2003;72:347–51.Google Scholar
  34. 34.
    Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005;106:2329–33.CrossRefPubMedGoogle Scholar
  35. 35.
    Hamdy SI, Hiratsuka M, Narahara K, El-Enany M, Moursi N, Ahmed MS, et al. Allele and genotype frequencies of polymorphic cytochromes P450 (CYP2C9, CYP2C19, CYP2E1) and dihydropyrimidine dehydrogenase (DPYD) in the Egyptian population. Br J Clin Pharmacol. 2002;53:596–603.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Isaza C, Henao J, Martínez JH, Arias JC, Beltrán L. Phenotype-genotype analysis of CYP2C19 in Colombian mestizo individuals. BMC Clin Pharmacol. 2007;7:6.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Zand N, Tajik N, Moghaddam AS, Milanian I. Genetic polymorphisms of cytochrome P450 enzymes 2C9 and 2C19 in a healthy Iranian population. Clin Exp Pharmacol Physiol. 2007;34:102–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Kidd RS, Straughn AB, Meyer MC, Blaisdell J, Goldstein JA, Dalton JT. Pharmacokinetics of chlorpheniramine, phenytoin, glipizide and nifedipine in an individual homozygous for the CYP2C9*3 allele. Pharmacogenetics. 1999;9(1):71–80.CrossRefPubMedGoogle Scholar

Copyright information

© Association of Clinical Biochemists of India 2017

Authors and Affiliations

  1. 1.Metabolic Disorders Research Center, Department of Biochemistry and Biophysics, Gorgan Faculty of MedicineGolestan University of Medical SciencesGorganIran
  2. 2.Student Research Committee, Gorgan Faculty of MedicineGolestan University of Medical SciencesGorganIran

Personalised recommendations