Genetic Polymorphisms of CYP2D6: Prevalence in Healthy Kurds

Author(s): Muslih Abdulkarim Ibrahim*, Zalina Zahari*, Nurfadhlina Musa, Khoo Boon Yin

Journal Name: Current Pharmacogenomics and Personalized Medicine
Formerly Current Pharmacogenomics

Volume 17 , Issue 1 , 2020

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Graphical Abstract:


Abstract:

Background: Identifying the genetic polymorphisms of drug metabolizing enzyme CYP2D6 is useful in pharmacogenomics. Unfortunately, until today, the prevalence of the CYP2D6 polymorphisms among Kurds is scarce.

Objective: In this study, we explored the CYP2D6 polymorphisms among Kurds.

Methods: Four hundred and fifty-nine unrelated healthy Kurds were recruited for the study. DNA was extracted from whole blood and was then used for genotyping CYP2D6*3, *4, *5, *6, *9, *10, *17, *114 and gene duplication using the nested allelespecific multiplex Polymerase Chain Reaction (PCR).

Results: The most common alleles and genotypes identified were CYP2D6*1 (75.5%), gene duplication (10.0%), *4 (8.6%), *10 (3.4%) and CYP2D6*1/*1 (62.5%), *1/*4 (16.3%), *1/*1xN (8.3%) and *1/*10 (6.3%). Thirty-nine (8.5%) subjects had genotypes that predicted Ultrarapid Metaboliser (UM) phenotypes, whereas two (0.4%) showed genotypes that predicted Intermediate Metabolisers (IMs), and four (0.8%) subjects had genotypes that Predicted Poor Metabolism (PMs).

Conclusion: The data add to our knowledge of CYP2D6 alleles, the genotypes and the distributions of predicted phenotypes in Kurds. Majority of the observed variant alleles confer no function and gene duplication. CYP2D6 polymorphisms were found to be very heterogeneous in relation to genotype frequencies. Further study in relation to the evaluation of drug therapy adjustment based on CYP2D6 genotype may help to understand the clinical consequences of CYP2D6 polymorphisms.

Keywords: CYP2D6, pharmacogenetics, polymorphism, Kurds, debrisoquine-4-hydroxylase, CYP2D6 genotype.

[1]
Zhou SF, Liu JP, Chowbay B. Polymorphism of human cytochrome P450 enzymes and its clinical impact. Drug Metab Rev 2009; 41(2): 89-295.
[http://dx.doi.org/10.1080/03602530902843483] [PMID: 19514967]
[2]
Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part II. Clin Pharmacokinet 2009; 48(12): 761-804.
[http://dx.doi.org/10.2165/11318070-000000000-00000] [PMID: 19902987]
[3]
Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: Part I. Clin Pharmacokinet 2009; 48(11): 689-723.
[http://dx.doi.org/10.2165/11318030-000000000-00000] [PMID: 19817501]
[4]
He ZX, Chen XW, Zhou ZW, Zhou SF. Impact of physiological, pathological and environmental factors on the expression and activity of human cytochrome P450 2D6 and implications in precision medicine. Drug Metab Rev 2015; 47(4): 470-519.
[http://dx.doi.org/10.3109/03602532.2015.1101131] [PMID: 26574146]
[5]
Kimura S, Umeno M, Skoda RC, Meyer UA, Gonzalez FJ. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene. Am J Hum Genet 1989; 45(6): 889-904.
[PMID: 2574001]
[6]
Del Tredici AL, Malhotra A, Dedek M, et al. Frequency of CYP2D6 alleles including structural variants in the United States. Front Pharmacol 2018; 9: 305.
[http://dx.doi.org/10.3389/fphar.2018.00305] [PMID: 29674966]
[7]
Gaedigk A, Sangkuhl K, Whirl-Carrillo M, Klein T, Leeder JS. Prediction of CYP2D6 phenotype from genotype across world populations. Genet Med 2017; 19(1): 69-76.
[http://dx.doi.org/10.1038/gim.2016.80] [PMID: 27388693]
[8]
Teh LK, Bertilsson L. Pharmacogenomics of CYP2D6: molecular genetics, interethnic differences and clinical importance. Drug Metab Pharmacokinet 2012; 27(1): 55-67.
[http://dx.doi.org/10.2133/dmpk.DMPK-11-RV-121] [PMID: 22185816]
[9]
Gaedigk A. Complexities of CYP2D6 gene analysis and interpretation. Int Rev Psychiatry 2013; 25(5): 534-53.
[http://dx.doi.org/10.3109/09540261.2013.825581] [PMID: 24151800]
[10]
Hicks JK, Swen JJ, Gaedigk A. Challenges in CYP2D6 phenotype assignment from genotype data: a critical assessment and call for standardization. Curr Drug Metab 2014; 15(2): 218-32.
[http://dx.doi.org/10.2174/1389200215666140202215316] [PMID: 24524666]
[11]
Gaedigk A, Ingelman-Sundberg M, Miller NA, Leeder JS, Whirl-Carrillo M, Klein TE. PharmVar steering committee. The pharmacogene variation (PharmVar) consortium: Incorporation of the human cytochrome P450 (CYP) allele nomenclature database. Clin Pharmacol Ther 2018; 103(3): 399-401.
[http://dx.doi.org/10.1002/cpt.910] [PMID: 29134625]
[12]
Zahari Z, Lee CS, Ibrahim MA, et al. CYP2D6 gene polymorphisms and cold pressor pain sensitivity among malay males. IMJ 2018; 25(3): 157-62.
[13]
Zahari Z, Salleh MR, Teh LK, Ismail R. Influence of CYP2D6 polymorphisms on symptomatology and side-effects of patients with schizophrenia in Malaysia. Malays J Med Sci 2009; 16(3): 12-20.
[PMID: 22589660]
[14]
Zahari Z, Ismail R. Influence of Cytochrome P450, Family 2, Subfamily D, Polypeptide 6 (CYP2D6) polymorphisms on pain sensitivity and clinical response to weak opioid analgesics. Drug Metab Pharmacokinet 2014; 29(1): 29-43.
[http://dx.doi.org/10.2133/dmpk.DMPK-13-RV-032] [PMID: 23759977]
[15]
Caudle KE, Dunnenberger HM, Freimuth RR, et al. Standardizing terms for clinical pharmacogenetic test results: consensus terms from the Clinical Pharmacogenetics Implementation Consortium (CPIC). Genet Med 2017; 19(2): 215-23.
[http://dx.doi.org/10.1038/gim.2016.87] [PMID: 27441996]
[16]
Gaedigk A, Dinh JC, Jeong H, Prasad B, Leeder JS. Ten years’ experience with the CYP2D6 activity score: A perspective on future investigations to improve clinical predictions for precision therapeutics. J Pers Med 2018; 8(2) E15
[http://dx.doi.org/10.3390/jpm8020015] [PMID: 29673183]
[17]
Gaedigk A, Simon SD, Pearce RE, Bradford LD, Kennedy MJ, Leeder JS. The CYP2D6 activity score: translating genotype information into a qualitative measure of phenotype. Clin Pharmacol Ther 2008; 83(2): 234-42.
[http://dx.doi.org/10.1038/sj.clpt.6100406] [PMID: 17971818]
[18]
Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and CYP2C19 genotypes and dosing of selective serotonin reuptake inhibitors. Clin Pharmacol Ther 2015; 98(2): 127-34.
[http://dx.doi.org/10.1002/cpt.147] [PMID: 25974703]
[19]
Goetz MP, Sangkuhl K, Guchelaar HJ, et al. Clinical pharmacogenetics implementation consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clin Pharmacol Ther 2018; 103(5): 770-7.
[http://dx.doi.org/10.1002/cpt.1007] [PMID: 29385237]
[20]
Bell GC, Caudle KE, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron. Clin Pharmacol Ther 2017; 102(2): 213-8.
[http://dx.doi.org/10.1002/cpt.598] [PMID: 28002639]
[21]
Hicks JK, Swen JJ, Thorn CF, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guideline for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants. Clin Pharmacol Ther 2013; 93(5): 402-8.
[http://dx.doi.org/10.1038/clpt.2013.2] [PMID: 23486447]
[22]
Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther 2014; 95(4): 376-82.
[http://dx.doi.org/10.1038/clpt.2013.254] [PMID: 24458010]
[23]
Gan SH, Ismail R, Wan Adnan WA, Zulmi W. Impact of CYP2D6 genetic polymorphism on tramadol pharmacokinetics and pharmacodynamics. Mol Diagn Ther 2007; 11(3): 171-81.
[http://dx.doi.org/10.1007/BF03256239] [PMID: 17570739]
[24]
Teh LK, Zilfalil BA, Marina I, Rosemi BS, Ismail R. Genetic polymorphism of CYP2D6 in patients with cardiovascular disease -- a cohort study. J Clin Pharm Ther 2004; 29(6): 559-64.
[http://dx.doi.org/10.1111/j.1365-2710.2004.00600.x] [PMID: 15584944]
[25]
Pirmohamed M. Pharmacogenetics and pharmacogenomics. Br J Clin Pharmacol 2001; 52(4): 345-7.
[http://dx.doi.org/10.1046/j.0306-5251.2001.01498.x] [PMID: 11678777]
[26]
Bagheri A, Kamalidehghan B, Haghshenas M, et al. Prevalence of the CYP2D6*10 (C100T), *4 (G1846A), and *14 (G1758A) alleles among Iranians of different ethnicities. Drug Des Devel Ther 2015; 9: 2627-34.
[PMID: 25999696]
[27]
Ibrahim MA, Zahari Z, Derani Z, Musa N, Boon Yin K. Comparison of the prevalence of four coding polymorphisms of KCNH2 in healthy Kurds and Malays. Merit Res J Med Med Sci 2018; 6(6): 219-27.
[28]
Steen VM, Andreassen OA, Daly AK, et al. Detection of the poor metabolizer-associated CYP2D6(D) gene deletion allele by long-PCR technology. Pharmacogenetics 1995; 5(4): 215-23.
[http://dx.doi.org/10.1097/00008571-199508000-00005] [PMID: 8528268]
[29]
Lundqvist E, Johansson I, Ingelman-Sundberg M. Genetic mechanisms for duplication and multiduplication of the human CYP2D6 gene and methods for detection of duplicated CYP2D6 genes. Gene 1999; 226(2): 327-38.
[http://dx.doi.org/10.1016/S0378-1119(98)00567-8] [PMID: 9931507]
[30]
Chamnanphon M, Gaedigk A, Vanwong N, et al. CYP2D6 genotype analysis of a Thai population: platform comparison. Pharmacogenomics 2018; 19(12): 947-60.
[http://dx.doi.org/10.2217/pgs-2018-0075] [PMID: 29992861]
[31]
Qumsieh RY, Ali BR, Abdulrazzaq YM, Osman O, Akawi NA, Bastaki SM. Identification of new alleles and the determination of alleles and genotypes frequencies at the CYP2D6 gene in Emiratis. PLoS One 2011; 6(12) e28943
[http://dx.doi.org/10.1371/journal.pone.0028943] [PMID: 22216145]
[32]
Aynacioglu AS, Sachse C, Bozkurt A, et al. Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population. Clin Pharmacol Ther 1999; 66(2): 185-92.
[http://dx.doi.org/10.1053/cp.1999.v66.100072001] [PMID: 10460072]
[33]
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.
[http://dx.doi.org/10.1016/j.phrs.2004.01.004] [PMID: 15177309]


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Article Details

VOLUME: 17
ISSUE: 1
Year: 2020
Page: [40 - 47]
Pages: 8
DOI: 10.2174/1875692117666190416145331

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