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

DISCUSSION

The CYP2D6 gene is of great interest for clinical practice because it is responsible for the metabolism of many commonly used drugs and its genetic polymorphism can have a strong effect on the substrate and lead to wide inter-individual variation. Variation in CYP2D6 activity has important therapeutic consequences and can play a significant role in the development of adverse events or therapeutic failure in susceptible individuals. The knowledge of how a drug is metabolized and which enzymes are involved helps to predict drugdrug interactions and how fast an individual patient may metabolize a specific drug. Because CYP2D6 metabolizes at least 25.0% of the marketed drugs, including selective serotonin reuptake inhibitors (SSRI), tricylic antidepressants (TCA), β blockers, opiates, neuroleptics, tamoxifen and antiar-rhythmics, there are possible issues of drug interaction in vivo which are of clinical significance. The CYP2D6*3, CYP2D6*4 and CYP2D6*6 are the most important non functional alleles that are predominantly responsible for the poor metabolizing capacity. These alleles are found in 90.0-95.0% of the PMs in Europe [23]. The results obtained in our study showed that the prevalence of the CYP2D6*4 allele frequency is in accordance with that of other European populations, which vary between 12.0 and 21.0%. The frequency values for the allele *4 range between 15.0% in Romanies, 17.0% in Macedonians and 22.5% in Albanians (Table 4). From the alleles with severely reduced activity, the results we acquired show an increased frequency of allele *41 (23.0%) in Romanies. These frequencies are in correlation with the values obtained from several studies conducted in the Middle East [24- 26]. These results are not surprising given the Indian origin of the Romany population and their migration through the Middle East, before they reached the Balkans. Our results showed similar percentages of deletions and duplications in comparison with the other European populations. In the Albanian ethnic group we noticed the highest number of deletions, reaching frequency of 2.5% and in the Macedonian ethnic group the highest number of duplication (2.5%) (Table 4). Our study is not the first one that has reviewed the frequency distribution of the CYP2D6 alleles in the Republic of Macedonia, still it is the first one that was conducted for each ethnicity separately. The prevalence values for the polymorphic alleles CYP2D6*3, *4, *6, *9 and *10 (0.008, 0.187, 0.0, 0.016 and 0.027, respectively) reported by Kapedanovska Nestorovska et al. [27] are in agreement with our results. However, the results for deletions and duplications in the two studies were not in concordance. Kapedanovska Nestorovska et al. [27] reported high frequencies of deletions and duplications (0.091 and 0.059, respectively) which are not in concordance with our study (Table 4). The method that Kapedanovska Nestorovska et al. [27] used for detection of the duplications and deletions was the quantitative real-time PCR method, using TaqMan Copy Number Assay (Thermo Fisher Scientific, Waltham, MA, USA). One of the main limitations of real-time PCR is the increased risk of false positive results, so this discordance is probably due to the lack of specificity and sensitivity of the method used. The metabolizing classes that are of pharmacological interest include the group of PMs and UMs. It is important to point out that the Albanians topped the list as the group with the highest number of PMs (7.0%), due to the accumulation of the *4 allele in their population, followed by the Romanies (6.0%) and the Macedonians (4.0%). The Macedonians stood out as the ethnic group with the highest number of UMs (5.0%), followed by the Albanians (1.0%) and the Romanies (1.0%) (Figure 3). Concordant genotype-phenotype correlation provides a basis for predicting the phenotype based on genetic testing, which has the potential to achieve optimal pharmacotherapy. Predictive CYP2D6 genotyping is estimated to be beneficial for treatment of about 30.0-40.0% of CYP2D6 drug substrates, that is for about 7.0-10.0% of all drugs clinically used. A study conducted in a psychiatric setting in the USA has shown that the CYP2D6 polymorphisms can have an effect on the cost of treating a patient; patients with ultrarapid and poor metabolizing capacity were found to cost between $4,000 and $6,000 per year more to treat than EM or IM individuals [28]. Thus, genotyping for individuals receiving single or multiple drugs that are metabolized by CYP2D6 may help clinicians to avoid adverse drug-drug interactions and to individualize better treatment with medications. In addition, the Food and Drug Administration (FDA) approved testing is now available and an increasing number of medical centers provide this service to patients under their care. It will be increasingly important for doctors, physicians, pharmacists, and other care providers to be able to provide coherent therapeutic recommendations to patients with predetermined pharmacogenetic data. Following the global trends in pharmacogenetics and the recommendations from the FDA, we decided to conduct this study in order to help with the introduction of pharmacogenetic testing for certain drugs in clinical practice, thus avoiding detrimental drug reactions, facilitating improved drug efficiency and moreover individualizing treatment for each patient. Our study is the first to assess the frequency distribution of the CYP2D6 alleles in the three major ethnic groups living in the Republic of Macedonia, with our findings displaying a genuine correspondence between the prevalence of CYP2D6 allele variants and genotypes in the Republic of Macedonia to other European populations. Declaration of Interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.



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