FREQUENCIES OF SINGLE-NUCLEOTIDE POLYMORPHISMS
AND HAPLOTYPES OF THE SLCO1B1 GENE IN SELECTED
POPULATIONS OF THE WESTERN BALKANS Daka Grapci A1, Dimovski AJ2, Kapedanovska A2, Vavlukis M3, Eftimov A2, Matevska
Geshkovska N2, Labachevski N4, Jakjovski K4, Gorani D5, Kedev S3, Mladenovska K2,* *Corresponding Author: Professor Kristina Mladenovska, Faculty of Pharmacy, Center for Biomolecular Pharmaceutical
Analyses, University “Ss Cyril and Methodius” in Skopje, Blv. “Mother Theresa” 47, 1000 Skopje,
Republic of Macedonia. Tel: +389-2-3126-032. Fax: +389-2-3132-015. E-mail: krml@ff.ukim.edu.mk page: 5
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DISCUSSION
It is clearly evident that the mutations in the SLCO1B1
gene and their clinical significance for a large
number of endogenous and xenobiotic substrates transported by OATP1B1 is a persistent motivation
for scientific research. To the best of our knowledge,
this is the first study in which polymorphisms contained
in the SLCO1B1 gene were studied in the populations
living in the Western Balkan Peninsula. For
this reason, commonly seen mutations (c.388A>G,
c.521T>C, c.571T>C, c.597C>T, c.*439 T>G) as
well as coding region SNPs that were not identified
in the Caucasian (European) population (c.1086C>T,
c.1463G>C) were selected for genotyping. Our data
confirmed that SLCO1B1 is highly polymorphic and
that several variants appear at a high frequency, both
in the Macedonian and Albanian populations. The
SNPs c.388A>G (Asn130Asp), c.571T>C (Leu-
191Leu), c.597C>T (Phe199 Phe) and c.*439T>G,
all occurred with an allelic frequency between 40.0
and 65.0%. The non synonymous c.521T>C SNP,
which has been constantly associated with a reduced
OATP1B1 activity, was found with an allele
frequency of approximately 14.0 and 12.0% in the
Macedonian and Albanian population, respectively,
which is nearly equal to that reported for Caucasians
(15.0%) [32], slightly lower than that reported previously
for Dutch (18.0%) [33], Finish (20.0%) [13], Algerian (17.0%) [11], Israeli (20.0%) [11], Japanese
(16.0-19.0%) [11,34] and Korean (25.0%) [35]
ethnic groups, and much higher than that reported
for African Americans (2.3%) [12] and Sub-Saharan
Africans (1.9%) [11] (Table 4). So far, literature
data point to equal allele frequency for this SNP in
Macedonians and European Americans [12] and Han
Chinese [29], although a lower number of subjects
in the last two groups was included in the study. The
same was observed in Albanian and Turkish subjects,
with an equal number of subjects in the study [36].
Compared to studies with Native Americans, Caucasian
Europeans, Sub-Saharan Africans, Japanese and
Israeli subjects [11], the variant alleles found in the
Macedonian and Albanian subjects were lower for
c.388A>G (41.0-42.0% vs. 46.0-79.0%), higher for
c.571 T>C (62.0-65.0% vs. 13.0-61.0%) and nearly
equal for c.597C>T (40.0-45.0% vs. 42.0-50.0%),
with the exception of Native Americans in which a
much lower allele frequency was observed (28.0%).
The allele frequency for SNP c.*439T>G was lower in
comparison with Sub-Saharan Africans (47.0-50.0%
vs. 76.0%), higher than that of Caucasian Europeans
(30.0%) and almost equal to the frequency of other
ethnic groups, where a variant G allele existed with
a frequency between 41.0% (Native Americans) and
55.0% (Israeli) (Table 4). No variant alleles were
found for c.1086C>T and c.1463G>C SNPs in the
Macedonian and Albanian populations and the same
was observed in German, Finish, Japanese, Israeli and
Turkish subjects [11,36], while in the studied Native
American and Sub-Saharan African, Ugandan and
Pakistani ethnic groups, a low frequency of variant
alleles was observed, between 1.0 and 7.0% for variant T in c.1086C>T and 0.5 and 3.0% for variant C
in c.1463G>C [11].
For all SNPs, the distributions of the genotypes
did not differ significantly (p >0.05) between healthy
subjects and patients and between male and female
subjects. These data are partly in accordance with the
results obtained in the study of Hubacek et al. [37],
in which no difference for genotype distributions of
rs4149056 variant between male and female subjects
was observed. However, the results of the same study
pointed to possible gender-dependent effects of this
SNP within the SLCO1B1 gene on statin treatment
efficacy.
It is increasingly evident that the most relevant
variants, the SNPs 388A>G and 521C>T, have a
major effect on OATP1B1 activity. However, their
association and other SNPs in LD with these functionalities
may modify the respective phenotype and
explain the discrepant effects of some SNPs on OATP1B1
activity in vivo. Most of the literature data point
to a strong association between this SNP pair and its
effect on drug response [20,29]. In the actual study,
the association between c.388A>G and c.521 T>C
was relatively weaker compared to other SNP pairs,
especially those in the Albanian population. These
data and generally, the differences between the two
populations in LD data, are probably explained by
the significantly smaller number of Albanian subjects
included in the study and random sampling variation.
The c.521T>C SNP showed the strongest correlation
with the c.597C>T in both populations and the similar
results have been obtained in the study of Pasanen et
al. [13], in which a large sample (468) of Caucasian
subjects was included. Compared with the analysis performed with
single SNPs, haplotypes often better predict the associated
phenotype. In the present study, the most
common SLCO1B1 haplotype, *IJ/*IK/*IL, contained
the synonymous c.571 T>C SNP as compared
with the reference sequence. It occurred at a frequency
(35.6%) similar to that reported in the study
of Pasanen et al. [13]. The c.521T>C SNP existed
in two (*5 and *15/*16/*17) major haplotypes in
the Macedonian and Albanian populations and one
new, identified in the Albanian population only. Both
common haplotypes, with a frequency of 2.0 and
3.7% (for *5) and 2.4 and 8.6% (for *15/*16/*17) in
the Macedonian and Albanian subjects, respectively,
contained the c.597C>T and c.439T>G SNPs. In the
new haplotype identified in the Albanian population,
instead of variant G allele in the c.439T>G SNP, variant
C allele of c.571T>C existed, with referent alleles
in other SNPs. Considering the significantly smaller
number of subjects in the Albanian population, as
potential limitation of this study, this result should
be confirmed in a study in which a larger number of
Albanian subjects would be included. The frequencies
of the major haplotype *15/*16/*17 containing
the variant alleles of the functionally most significant
SNP pair c.388A>G/ c.521T>C (8.6 and 2.4%
for Macedonians and Albanians, respectively) were
lower than the frequency of haplotype *15 reported
for Chinese (14.0%) and Japanese (15.8%), higher
for Macedonians and comparable for Albanians with
that of Caucasians (2.4%) and significantly higher
than the one of African Americans (0.0%) [13,29].
In conclusion, this study presents an extensive
analysis of SLCO1B1 variant genotype and haplotype
distribution in selected populations living in
the Western Balkan Peninsula, Macedonians and
Albanians for the first time. No significant differences
(p >0.05) in allelic frequencies and genotype
distributions of the analyzed SNPs were observed
between the two ethnic groups and the data are similar
to those for Caucasians. About 8.6 and 2.4% of the
Macedonians and Albanians, respectively, carrying
the SLCO1B1*15 or SLCO1B1*16 or SLCO1B1*17
variant may exhibit altered/impaired transport activity
of OATP1B1.
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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