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.
|
|
|
|
 |
Number 27
VOL. 27 (2), 2024 |
Number 27
VOL. 27 (1), 2024 |
Number 26
Number 26 VOL. 26(2), 2023 All in one |
Number 26
VOL. 26(2), 2023 |
Number 26
VOL. 26, 2023 Supplement |
Number 26
VOL. 26(1), 2023 |
Number 25
VOL. 25(2), 2022 |
Number 25
VOL. 25 (1), 2022 |
Number 24
VOL. 24(2), 2021 |
Number 24
VOL. 24(1), 2021 |
Number 23
VOL. 23(2), 2020 |
Number 22
VOL. 22(2), 2019 |
Number 22
VOL. 22(1), 2019 |
Number 22
VOL. 22, 2019 Supplement |
Number 21
VOL. 21(2), 2018 |
Number 21
VOL. 21 (1), 2018 |
Number 21
VOL. 21, 2018 Supplement |
Number 20
VOL. 20 (2), 2017 |
Number 20
VOL. 20 (1), 2017 |
Number 19
VOL. 19 (2), 2016 |
Number 19
VOL. 19 (1), 2016 |
Number 18
VOL. 18 (2), 2015 |
Number 18
VOL. 18 (1), 2015 |
Number 17
VOL. 17 (2), 2014 |
Number 17
VOL. 17 (1), 2014 |
Number 16
VOL. 16 (2), 2013 |
Number 16
VOL. 16 (1), 2013 |
Number 15
VOL. 15 (2), 2012 |
Number 15
VOL. 15, 2012 Supplement |
Number 15
Vol. 15 (1), 2012 |
Number 14
14 - Vol. 14 (2), 2011 |
Number 14
The 9th Balkan Congress of Medical Genetics |
Number 14
14 - Vol. 14 (1), 2011 |
Number 13
Vol. 13 (2), 2010 |
Number 13
Vol.13 (1), 2010 |
Number 12
Vol.12 (2), 2009 |
Number 12
Vol.12 (1), 2009 |
Number 11
Vol.11 (2),2008 |
Number 11
Vol.11 (1),2008 |
Number 10
Vol.10 (2), 2007 |
Number 10
10 (1),2007 |
Number 9
1&2, 2006 |
Number 9
3&4, 2006 |
Number 8
1&2, 2005 |
Number 8
3&4, 2004 |
Number 7
1&2, 2004 |
Number 6
3&4, 2003 |
Number 6
1&2, 2003 |
Number 5
3&4, 2002 |
Number 5
1&2, 2002 |
Number 4
Vol.3 (4), 2000 |
Number 4
Vol.2 (4), 1999 |
Number 4
Vol.1 (4), 1998 |
Number 4
3&4, 2001 |
Number 4
1&2, 2001 |
Number 3
Vol.3 (3), 2000 |
Number 3
Vol.2 (3), 1999 |
Number 3
Vol.1 (3), 1998 |
Number 2
Vol.3(2), 2000 |
Number 2
Vol.1 (2), 1998 |
Number 2
Vol.2 (2), 1999 |
Number 1
Vol.3 (1), 2000 |
Number 1
Vol.2 (1), 1999 |
Number 1
Vol.1 (1), 1998 |
|
|
