CYP2D6 ALLELE DISTRIBUTION IN MACEDONIANS, ALBANIANS AND ROMANIES IN THE REPUBLIC OF MACEDONIA
Kuzmanovska M, Dimishkovska M, Maleva Kostovska I, Noveski P, Sukarova Stefanovska E, Plaseska-Karanfilska D*
*Corresponding Author: Dijana Plaseska-Karanfilska, M.D., Ph.D., Research Centre for Genetic Engineering and Biotechnology “Georgi D. Efremov,” Macedonian Academy of Sciences and Arts, Krste Misirkov 2, 1000 Skopje, Republic of Macedonia. Tel: +389-2-3235-410. Fax: +389-2-3115-434. E-mail: dijana@manu.edu.mk
page: 49

INTRODUCTION

Physiological responses to the same drug are known to vary substantially between different individuals. Although this may result from environmental and physiological factors or drug-drug interactions, in many cases the response is inherited and arises from a polymorphism in genes that encode drug transporters, drug receptors, and especially, drugmetabolizing enzymes [1]. Of the genes that encode drug-metabolizing enzymes, CYP2D6, a member of the cytochrome P450 superfamily (CYP450), is well characterized. Approximately 57 CYP genes that encode cytochrome P450 proteins and 58 pseudogenes are present in the human genome and are classified into distinct families and subfamilies according to their sequence similarity [2]. The CYP2D subfamily comprises the CYP2D6 gene and two pseudogenes (CYP2D7 and CYP2D8), located in tandem on chromosome 22q13.1, at the 3’ end of the CYP2D cluster. The CYP2D6 gene contains nine exons comprised of 1461 codons. The evolution of this locus has involved elimination of three genes and inactivation of two neighboring genes (CYP2D7 and CYP2D8), all of which display 92.0-97.0% nucleotide similarity across their sequences [3]. The CYP2D6 gene mediates the metabolism of almost a quarter of drugs in common clinical use, including opiate analgesics, antiarrhythmics, antipsychotics, antidepressants, tamoxifen and β blockers [1]. The CYP2D6 gene is highly polymorphic, with more than 100 variations and numerous subvariants having been identified [4]. These variations include: single-base changes, short insertions and deletions, major deletions [5] and whole gene duplications [6]. There are four major phenotype classes: ultrarapid metabolizers (UMs), extensive metabolizers (EMs), poor metabolizers (PMs) and intermediate metabolizers (IMs) and two subclasses: IMS to EMs and PMs to IMs. The sub-classification of the intermediate metabolizers is ascribed to the wide spectrum of metabolic activity that can range from marginally better than the PM phenotype to activity that is close to that of the EM phenotype (Table 1) [4,7]. The EM phenotype is expressed by the majority of the population and is therefore considered “the norm” [8]. Poor metabolizers inherit two null CYP2D6 alleles that include at least 22 different alleles which do not encode a functional protein and show no detectable residual enzymatic activity. This leads to accumulation of high levels of unmetabolized drugs that are CYP2D6 substrates, greater potential for adverse effects and drug-drug interactions, and lower efficacy of drugs that require CYP2D6 activation [9]. The UM phenotype is caused by amplification of active CYP2D6 genes, primarily the CYP2D6*1 and CYP 2D6*2 alleles. Individuals with this phenotype metabolize drugs at an ultrarapid rate, which may lead to loss of therapeutic efficacy at standard doses [10]. Individuals who are heterozygous for a defective and a fully active CYP2D6 allele or are homozygous for an allele with decreased activity, for example alleles *10, *17, *36 and *41, often demonstrate an IM phenotype [11]. Previous genetic studies showed high levels of CYP2D6 polymorphism, both within and between populations [12], and a surprisingly high frequency of null and reduced function variants. Poor metabolizers account for 5.0 to 10.0% of the Caucasian population and less than 1.0% of the Asian population [13]. In Caucasians, common deficient alleles include CYP2D6*3, *4, *5 and *6, accounting for about 98.0% of PMs [14]. On the other hand, the decreased activity allele *41 is predominantly present in the Middle East, with frequencies reaching up to 22.5% [15]. In contrast to PMs, UMs usually carry a duplicated, or even multiduplicated (up to 13 copies of CYP2D6) active CYP2D6 allele (CYP2D6*xN). The frequencies of CYP 2D6*xN vary greatly between races [16]. Both CYP2D6*5 and CYP2D6*xN result from CYP2D6 gene rearrangement [17] and comprise CYP2D6 gene copy number variations. The CYP2D6 genotyping to predict metabolic status is considered a valid alternative to traditional phenotyping methods [18]. Assessing the CYP2D6 genotype also offers several distinct advantages over the experimental determination of a CYP2D6 phenotype [19]. Genotyping usually requires only a blood sample and can be done before a drug is given to a patient. It therefore may facilitate improved drug efficiency and diminished risk for adverse drug reactions [20]. The aim of this study was to investigate the allele distribution of CYP2D6 variants in Macedonian, Albanian and Romany populations as well as to implement our findings in the clinical practice in the Republic of Macedonia.



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