Determination of CYP2D6*3 and *4 allele frequency among Turkish population

Year 2018, , 210 - 214, 01.09.2018

Zehra Okat , Kübra Yaman Kezban Uçar Çiftçi Selina Toplayıcı Elif Kurt Yavuz Taga

https://doi.org/10.28982/josam.416309

Abstract

Aim: CYP2D6 takes part in the family of cytochrome P450 enzymes, which is account for the detoxification of multifarious xenobiotics and various drug commonly used in medicine. CYP2D6 is a polymorphic gene encompassing more than 80 known polymorphism within the coding and promoter regions. The mutant CYP2D6*3 allele revealed with the deletion of A2637 found in exon 5 region. The other common mutant allele is CYP2D6*4 and this allele stem from a splice site defect of G1934A can be classified as the most typical mutations. The present study primarily aims to determine the CYP2D6*3 and *4 frequency defects among Turkish population. 

Methods: Within the framework of the study, two critical alleles of CYP2D6 wild type allele, and CYP2D6*3 -CYP2D6*4 mutated alleles are genotyped on eighty healthy volunteers, who are unrelated, by the method of polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP).

Results: CYP2D6*4 allele frequency, which was identified as the loss of BstNI site, was determined as 13.16% on the examined reference group. Besides, the CYP2D6*4/CYP2D6*4 genotype ratio for the searched reference group was observed in only 2.63%. The heterozygous CYP2D6*3 allele frequency was determined as 1.32% on the examined reference group. Finally, CYP2D6*3/CYP2D6*3 genotype was not encountered in that searched reference group. 

Conclusion: In the light of those findings, it can be clearly stated that the prevalence of CYP2D6*3 and *4 allelic variants in the Turkish population is the same with the other demographic groups in Turkey. 

Keywords

Xenobiotics, Turkish population, CYP2D6 polymorphism, PCR-RFLP

Türk popülasyonunda CYP2D6*3 ve *4 allel frekansının saptanması

Abstract

Amaç: CYP2D6, çeşitli ksenobiyotiklerin ve ilaçların detoksifikasyonundan sorumlu sitokrom P450 enzim ailesi içerisinde yer almaktadır. CYP2D6, kodlama ve promotör bölgelerinde 80'den fazla bilinen polimorfizm içeren bir polimorfik gendir. En tipik mutasyonlar olarak sınıflandırılan, CYP2D6*3 mutant alleli, ekson 5'de A2637’nin delesyonuyla, CYP2D6*4 mutant alleli ise G1934A'nın splice site defektiyle meydana gelmiştir. Bu çalışmada öncelikle Türk toplumunda CYP2D6*3 ve *4 frekans defektlerinin belirlenmesi amaçlanmıştır.

Yöntemler: Çalışma çerçevesinde; CYP2D6’nın iki kritik alleli olan wild tip ve mutant CYP2D6*3-*4 allelleri, birbirleriyle ilişkisiz 80 sağlıklı kontrol üzerinde, Polimeraz Zincir Reaksiyonu (PZR) ve Restriksiyon Fragment Uzunluk Polimorfizmi yoluyla genotiplendirilmiştir (RFLP). 

Bulgular: BstNI bölgesinin kaybı olarak tanımlanan CYP2D6*4 allel frekansı, incelenen referans grupta %13.16 olarak belirlenmiştir. Ayrıca; referans grupta araştırılan CYP2D6*4/CYP2D6*4 genotip oranının sadece %2.63 olduğu gözlemlenmiştir. Analiz edilen referans grupta; heterozigot CYP2D6*3 allel frekansı % 1.32 olarak tespit edilmiştir. Son olarak, CYP2D6*3/CYP2D6*3 genotipine araştırılan referans grubunda rastlanılmamıştır. 

Sonuç: Bu bulgular ışığında, Türk populasyonunda CYP2D6*3 ve *4 allelik varyant prevalanslarının diğer demografik gruplarla aynı olduğu açıkça belirtilebilir.

Keywords

Zenobiyotik, Türk popülasyonu, CYP2D6 polimorfizmi, PZR-RFLP

References

• 1. Brosen K, Gram LF. Clinical significance of the sparteine/debrisoquine oxidation polymorphism. Eur J Clin Pharmacol. 1989;36(6):537-47. PMID: 2570698.
• 2. Dahl ML, Bertisson L. Genetically variable metabolism of antidepressants and neuroleptic drugs in man. Pharmacogenetics. 1993;3(2):61-70. PMID: 8100166.
• 3. Cascorbi I. Pharmacogeneticist’s of cytochrome P4502D6: genetic back-ground and clinical implication. Eur J Cln Invest. 2003; 33(2):17-22. PMID: 14641552.
• 4. Gough AC, Miles JS, Spurr NK, Moss JE, Gaedigk A, Eichelbaum M, et al.. Identification of the primary gene defect at the cytochrome P450 CYP2D locus. Nature. 1990;347(6295):773-6. DOI: 10.1038/347773a0.
• 5. Van Der Weide J, Steinjns L. Cytochrome P450 enzyme system: genetic polymorphisms and impact o clinical pharmacology. Ann Clin Biochem. 1999;36(6):722-9. DOI: 10.1177/000456329903600604.
• 6. Lavandera JV, Parera VE, Batlle A, Buzaleh AM. CYP2D6 polymorphisms in patients with porphyrias. Mol Med. 2006;12(9-10):259-63. DOI: 10.2119/2005-00047.Lavandera.
• 7. Stamer UM, Bayerer B, Wolf S, Hoeft A, Stüber F. Rapid and reliable method for cytochrome P450 2D6 genotyping. Clin Chem. 2002;48(9):1412-7. PMID: 12194916.
• 8. Sistonen J, Sajantila A, Lao O, Corander J, Barbujani G, et al. CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure. Pharmacogenet Genomics. 2007;17(2):93-101. DOI: 10.1097/01.fpc.0000239974.69464.f2 .
• 9. Fernandez-Santander A, del Saz M, Tejerina A, Bandres F. CYP2D6*4 allele and breast cancer risk: is there any association? Clin Transl Oncol. 2012;14(2):157-9. DOI: 10.1007/s12094-012-0776-4.
• 10. Schur BC, Bjerke J, Nuwayhid N, Wong SH. Genotyping of cytochrome P450 2D6*3 and *4 mutations using conventional PCR*. Clinica Chimica Acta. 2001;308(1-2):25-31. PMID: 11412814.
• 11. Lennard MS. Genetic polymorphism of sparteine/debrisoquine oxidation: a reappraisal. Pharmacology and Toxicology. 1990;67(4):273-83. PMID: 2077517.
• 12. Mayer UA. Pharmacogenetics- five decades of therapeutic lessons from genetic diversity. Nat Rev Genet. 2004;5(9):669-76. DOI: 10.1038/nrg1428.
• 13. Taninghera M, Malacarnea D, Ugolinia A, Parodia S. Drug metabolism polymorphisms as modulators of cancer susceptibility. Mutat Res. 1999 May;436(3):227-61. PMID: 10354524.
• 14. Preston-Martin S, Pike MC, Ross RK, Jones PA, Henderson BE. Increased cell division as a cause of human cancer. Cancer Res. 1990;50(23):7415-21. PMID: 2174724.
• 15. Zanger UM, Raimundo S, Eichelbaum M. Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemisry. Naunyn Schmiedebergs Arch Pharmacol. 2004;369(1):23-37. DOI: 10.1007/s00210-003-0832-2.
• 16. Alvan G, Bechtel P, Iselius L, Gundert-Remy U. Hydroxylation polymorphisms of debrisoquine and mephenytoin in European populations. Eur J Clin Pharmacol. 1990;39(6):533-7. PMID: 2151318.
• 17. Bradford LD. CYP2D6 allele frequency in European Caucasions, Asians, Africans and their descendants.Pharmacogenomics. 2002;3(2):229-43. DOI: 10.1517/14622416.3.2.229.
• 18. Bertilsson L, Dahl ML, Dalen P, Al-Shurbajı A. Molecular genetics of CYP2D6: clinical relevance with focus om psychotropic drugs. Br J Clin Pharmacol. 2002;3(2):111-22. DOI: 10.1046/j.0306-5251.2001.01548.x.
• 19. Aydin M, Hatirnaz O, Erensoy N and Ozbek U. CYP2D6 and CYP1A1 mutations in the Turkish population. Cell Biochem Funct. 2005;23(2):133-5. DOI: 10.1002/cbf.1222.
• 20. Koseler A, Ilcol YO and Ulus IH. Frequency of mutated allele CYP2D6*4 in the Turkish population. Pharmacology. 2007;79:203-6. DOI: 10.1159/000100959.
• 21. Aynacıoğlu, AS, Sachse C, Bozkurt A. Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther. 1999;66:185-92. DOI: 10.1053/cp.1999.v66.100072001.
• 22. Sahin S, Aydogan L, Benli I, Ozyurt H. Distribution of HLA-B27 and CYP2D6*4 mutations in the middle Black Sea area (Tokat) of Turkey. Genetics and Molecular Research 2011;10(4):3987-91. DOI: 10.4238/2011.December.2.3.
• 23. Antunes MV, Linden R, Santos TV, Wallemacq P, Haufrois V, Classen JF, et al. Endoxifen levels and its association with CYP2D6 genotype and phenotype: evaluation of a southern Brazilian population under tamoxifen pharmacotheraphy. Ther Drug Monit. 2012;34:422-31. DOI: 10.1097/FTD.0b013e318260b46e.
• 24. Jardim DLF, Katz A. Determination of the frequency of CYP2D6 polymorphisms in Brazilian women and literature review. Rev Bras Mastol. 2014;20:55.
• 25. Jonrit H, Petersen S, Dankier P, Flemming N, Grandjean P, Weihe P, et al. Polymorphism of CYP2D6, CYP2C19, CYP2C9 and CYP2C8 in the Faroese population. Eur J Clin Pharmacol. 2005 Aug;61(7):491-7. DOI: 10.1007/s00228-005-0938-1.
• 26. Adithan C, Gerard N, Naveen AT, Koumaravelou K, Shashindran CH, Krishnamoorthy R. Genotype and allele frequency of CYP2D6 in Tamilian population. Eur J Clin Pharmacol. 2003 Oct;59(7):517-20. DOI: 10.1007/s00228-003-0657-4.
• 27. Ling J, Shixiu P, Jacqueline M, Edgar H, Katharina R, Matin H. Single-Step Assays to Analyze CYP2D6 Gene Polymorphisms in Asians: Allele Frequencies and a Novel*I 4B Allele in Mainland Chinese. Clinical Chemistry. 2002;48:983-88.
• 28. Yamada H, Dahl ML, Lannfelt L, Viitanene M, Winbland B, S joqvist F. CYP2D6 and CYP2C19 genotypes in an elderly Swedish population. Eur J Clin Pharmacol. 1998;54(6):479-81. PMID: 9776439.