ASSOCIATION OF CYP2C19*2 C.681G>A (RS4244285) LOSS-OF-FUNCTION ALLELE WITH CARDIOVASCULAR DISEASE RISK IN THE KOSOVO POPULATION
Elshani N1*, Ukella K1, Staninova Stojovska M2, Naumovska Z2, Kurshumliu M3, Gorani D4, Kapedanovska Nestorovska A
*Corresponding Author: Corresponding Author: Nora Elshani, Glloku te Shelgjet “Veternik” 10000-Prishtinë, Kosova. Phone: +38344601032. E-mail: nora.elshani1@gmail.com; nora.elshani@rezonanca-rks.com.
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DISCUSSION
The worldwide implementation of pharmacogenet-
ics highlighted population-specific differences in allelic
and genotype/phenotype frequencies of genes coding for
drug-metabolizing enzymes. One significant challenge
in translating treatment-associated polymorphisms into
routine clinical use is the lack of knowledge regarding its
frequency in the targeted population in comparison to the
population frequency. In the context of clopidogrel treat-robability of CVD. This association appeared to be inde-
pendent of the type and number of comorbidities as well
as patients’ previous history on MI (STEMI or NSTEMI).
Notably, the proportion of poor metabolizers (PMs) identi-
fied in our patient cohort was significantly higher than the
reported in studies of other European populations (4.67%
vs. 2.4%, respectively) [11, 29, 31].
This study is the first to report this correlation
within the Balkan population. Comparable research con-
ducted in Macedonia [32], Serbia [33] and Croatia [34] has
demonstrated that CYP2C19*2 functions as an independ-
ent risk factor for adverse treatment outcomes, defined
by the occurrence of MACE in patients receiving dual
antiplatelet therapy with aspirin and clopidogrel. Notably,
this is the first investigation that explores the relationship
between the CYP2C19*2 allele and the risk of CVD among
the Balkan population. The potential mechanism by which
CYP2C19*2 may contribute to an increased risk of cardio-
vascular disease (CVD) extends beyond its pharmacoge-
netic role, encompassing disruptions in the metabolism of
critical endogenous substrates, such as eicosanoids (arachi-
donic acid derivatives) and steroids. These substrates are
integral to maintaining vascular homeostasis, modulating
inflammatory processes, and regulating oxidative stress.
Impaired CYP2C19 activity could alter the metabolism
of these molecules, leading to endothelial dysfunction,
compromised vascular function, and dysregulated blood
pressure. Such metabolic disruptions may exacerbate con-
ditions like hypertension and atherosclerosis, ultimately
contributing to the pathophysiology of CVD [35, 36].
These preliminary findings highlight the importance
of investigating intra-population genetic variations to
identify specific genetic markers or health risks prevalent
within a particular ethnic group. They supplement the
growing body of evidence linking the CYP2C19*2 LOF
allele with the occurrence and development of CAD, CVD
and CHD. The results align with previously published
studies suggesting that the CYP2C19 LOF allele may be
involved in CVD susceptibility [37-41]. Rothenbacher et
al. (2013) reported that stable CHD patients, carriers of
the homozygous CYP2C19*2 LOF allele are at increased
risk for subsequent CVD events during the long follow up,
independent of other risk factors [37]. Similarly, Zhang et
al. (2019) found that CYP2C19*2 not only increased the
risk of CHD, but also worsened clinical outcomes in CHD
patients during an extended follow-up period [38]. Cai
et al. (2023) observed that among the Hakka population,
carriers of the CYP2C19 LOF alleles, both heterozygous
and homozygous, exhibited increased susceptibility to
hypertension [39]. In Martínez-Quintana’s study (2017),
patients with an acute coronary event and poor or normal
CYP2C19 metabolizer phenotype were more likely to have
insulin-dependent diabetes mellitus than those with rapid
or ultrarapid metabolizer phenotypes [40]. More recently,
Chen et al. (2024) reported that carriers of CYP2C19 LOF
alleles are at increased risk for premature coronary artery
disease, particularly when combined with other risk factors
such as overweight, smoking, hypertension and diabetes
mellitus [41].
When addressing the observed intra-population dif-
ferences in CYP2C19*2 frequencies, it is important to
acknowledge that relying on previously published data
may introduce potential variability due to differences in
study design, methodology, or population characteristics
and recruitment between historical genotype controls and
the study cohort might affect the validity of direct compari-
sons. However, we recognize this limitation arising from
the lack of a contemporaneously recruited healthy control
group, as well as the small sample size and absence of
demographic data for the healthy population. Despite these
limitations, the internal validity of our findings remains
intact. Importantly, there were no differences in the sample
collection, handling and storing, DNA extraction or geno-
typing procedures, and both studies used DNA extraction
kits comparable in terms of sensitivity and specificity and
employed the same PCR-based methods and genotyping
assays. Additionally, both the patient cohort and the his-
torical control group primarily consist of ethnic Albanians
from all parts of Kosovo. Nevertheless, it is essential to
consider that differences in exposure to environmental
factors, diet, or healthcare access between the cohorts
could act as confounding variables, potentially mask-
ing genetic associations. Overall, these results provide
valuable insights into the allele, genotype, and phenotype
frequencies of the CYP2C19 drug-metabolizing enzyme
in Kosovar patients indicated for clopidogrel treatment.
They add to the growing evidence advising the need for
careful consideration of CYP2C19 genetic diversity as
a population-specific factor when recommending PGx-
guided clopidogrel therapy [25, 26], particularly in popu-
lations like Kosovo’s, where genetic determinants are not
yet fully elucidated. The observed association between the
CYP2C19*2 LOF allele and increased probability of devel-
oping CVD for clopidogrel treatment in our study hinders
the ability to conclusively demonstrate a clinical benefit
of CYP2C19*2 PGx guided treatment in the population
of Kosovo. Variability in treatment outcome, if identified
during the study follow up period, could potentially be
attributed to additional patient-specific determinants (such
as comorbidities, concomitant drug treatments or as-yet
undiscovered population-specific genetic factors). Future
studies incorporating a broader range of demographic and
clinical variables are needed to better elucidate the role
of CYP2C19*2 PGx guided therapy in optimizing clopi-dogrel treatment strategies for this population. Moreover,
additional investigations should evaluate whether the car-
riage of the CYP2C19*2 allele itself is associated with an
adverse outcome in patients not taking clopidogrel.
ment, understanding the prevalence of CYP2C19 LOF
variants within a population is critical for assessing their
clinical implications. Careful consideration is necessary
when interpreting studies on the association between CY-
P2C19 metabolizer phenotype and clopidogrel treatment
outcomes. Evidence supporting this association primarily
stems from studies involving ACS patients (with at least
50% undergoing PCI) and settings where clopidogrel was
compared with an alternative P2Y12 inhibitor [28]. Con-
versely, studies opposing this association often focus on
lower risk, non-PCI patients or data that did not strongly
justify the utility of PGx guided clopidogrel treatment
for secondary stroke prevention or ACS patients [13, 16].
The presented study primarily aimed to determine the
frequency of CYP2C19*2 LOF allele in clopidogrel treated
patients with cardiovascular disease indications (CVDI)
and other concurrent risk factors in Kosovo and to evalu-
ate the prognostic value and association of CYP2C19 PM
phenotype with the risk of MACE in this cohort during
two-year term follow-up under routine clinical care. The
prevalence of the CYP2C19*2 allele in this cohort of Ko-
sovo patients (19%) and the historical genotype control
group of healthy population (13%) was consistent with
the range reported in other European populations [29,
30], with latter falling within the 9-18% range observed
across the population from the Balkan region, including
Turkey (12%), Greece (13%), Macedonia (14.4%), Serbia
(11%), Republic of Srpska (16%) in Bosnia and Hercego-
vina) Croatia (15%) and Slovenia (16%). Intra-population
comparisons, however revealed a significantly higher fre-
quency of the CYP2C19*2 LOF allele in the patient cohort
compared to the healthy Kosovo population reported by
Krasniqi et al. (2017), suggesting a possible association
between the CYP2C19*2 LOF allele and increased overall
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