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
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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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