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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INTRODUCTION
Membrane influx and efflux transporters have
a significant role in facilitating or preventing drug
movement through biological membranes. Drug responses
are largely dependent on their interplay with phases I and II metabolism and the physicochemical
properties of a drug. They function in the selective
absorption and elimination of drugs, mediate tissuespecific
drug distribution and are also targets of many
clinically used drugs. In addition, they play a critical
role in the development of resistance to anticancer
drugs, anticonvulsants and antiviral agents. When
considering drug transport, two major super-families,
ABC (ATP binding cassette) and SLC (solute carrier)
transporters attract the highest scientific attention.
The SLC super family includes genes that encode
facilitating transporters and ion-coupled secondary
active transporters that reside in various cell
membranes. Genes of the solute carrier organic anion
transporter (SLCO) family encode organic aniontransporting
polypeptides (OATPs), membrane influx
transporters identified mostly in the intestine,
liver, kidney, lung, testes, placenta and blood-brain
barrier among other organs. The OATP1B1 [previously
OATP2, OATP-C and liver specific transporter
1 (LST-1)], expressed in the sinusoidal membrane of
the hepatocytes, is known to be involved in the hepatic
uptake of a broad array of endogenous compounds
(e.g., steroid conjugates, bile acids, eicosanoids and
thyroid hormones) and drugs such as methotrexate,
fexofenadine, repaglinide and statins [1-6]. Examples
of in vitro OATP1B1 drug substrates include several
HMG-CoA reductase inhibitors, angiotensin-converting
enzyme inhibitors and angiotensin II receptor antagonists
[6-8]. Many drugs have also been identified
in vitro as OATP1B1 inhibitors and there are some
in vivo interactions where OATP1B1 inhibition can
be regarded as an important mechanism. Examples
include cyclosporine, atorvastatin, gemfibrozil and
rifampicin [9,10].
The OATP1B1 protein is a 691-amino acid glycoprotein
with 12 putative membrane-spanning domains
and a large fifth extracellular loop. Its encoding
gene, solute carrier organic anion transporter family
member 1B1 (SLCO1B1), is located on chromosome
12 (gene locus 12p12) [11]. A large number of single
nucleotide polymorphisms (SNPs), both non synonymous
and synonymous, have been discovered in the
SLCO1B1 gene, and several of these have proven
to affect a substrate-dependent transport function
in vitro and in vivo [12,13]. While no firm evidence
for association between these SNPs and development
of certain diseases (e.g., gallstone development,
essential hypertension) due to dysregulation
of endogenous compounds transport exists, there are
numerous research data pointing to their effects on
drugs responses.
The SNPs 388 (A>G) (*1b, rs2306283) and
521 (C>T) (*5, rs4149056) are considered to be the
most prevalent and most relevant variants, encoding
a substitution of alanine for valine at amino acid
174 (p.Val174Ala), and amino acid change at position
130 (p.Asn130Asp), respectively. Increased
transport activity of pravastatin as well as decreased
plasma concentration of ezetimibe in carriers of the
SLCO1B1*1b allele was observed [14,15], unlike
reduced uptake of all statins except fluvastatin in
hepatocytes and increased area under curve (AUC)
of fexofenadine, repaglinide and irinotecan in carriers
of SLCO1B1*5 [3,4,16,17]. The carriers of the
c.521T>C variant were also highlighted by a genomewide
association study as a population with an increased
risk for simvastatin-induced myopathy because
of the increased plasma and muscle exposure to
statins [18]. These findings were further confirmed by
Santos et al. [19], who suggested that the SLCO1B1
genetic risk depends on the specific drug that was
used. It was also shown that subjects carrying the
SLCO1B1 c.388GG genotype exhibit significantly
higher low-density-lipoprotein cholesterol reduction
relative to c.388AA+ c.388AG carriers, pointing out
that the SLCO 1B1 c.388A>G polymorphism may
be used as an important marker for predicting the
efficacy of a lipid-lowering therapy [20].
Recent data point out that these two variants are
in linkage disequilibrium (LD) and exist in variable
SLCO 1B1 haplotypes; AT, a haplotype known as *1A
(reference haplotype), GT as *1B, AC as *5 and GC as
*15, for c.388 A>G and c.521T>C, respectively [13].
The *15 haplotype has been consistently associated
with a decreased transport activity, while controversial
results have been reported for the*1B haplotype
[21]. It was also demonstrated that the SLCO1B1*17
haplotype (g.-11187G>A, c.388G>A and c.521T>C)
was associated with increased plasma concentrations
of pravastatin in humans [22], while the *14 haplo
type (c.388G-c.463A-c.521T) was characterized with
enhanced response to fluvastatin [23].
It is becoming evident that the incidence of sequence
variations in the SLCO1B1 gene is largely
dependent on the ethnic background. The c.521T>C
variant showed an allele frequency of approximately
10.0-15.0% in Asian populations, 10.0-20.0% in Caucasians and 1.0-2.0% in African-American
populations. The c.388A>G SNP showed an allele
frequency of approximately 30.0-45.0% in Caucasians,
70.0-80.0% in African-American/Sub-Saharan
African populations and 60.0-90.0% in Asian populations
[12,22,24-26]. Therefore, characterization of
the genetic variation in this transporting gene is an
important step towards understanding the individual
variation in drugs-substrates responses and developing
a personalized and safer drug therapy.
To the best of our knowledge, there is no evidence
about genotyping of OATP1B1 in the populations
living in Western Balkans. Also, there is no
evidence when considering the populations living in
the whole Balkan Peninsula, with exception of one report
evaluating association between three SLCO1B1
SNPs and statin response in the Greek population
[27]. In this respect, there has not been any report on
the genotype of SLCO1B1 allelic variants in Macedonian
and Albanian populations who are considered
Caucasians. The origin of the Macedonians and Albanians
is a continuing matter of discussion among
historians; they also showed unequivocal signs of a
common genetic history. In addition, Western Balkan
countries have always been a historical crossroads
between Asia, Africa and Europe. Considering all the
above, the overall aim was to analyze the diversity
of the SLCO1B1 gene in selected ethnically diverse
populations living in the Western Balkans [Republic
of Macedonia (RoM) and Republic of Kosovo
(RoK)]. In this article, the results from the allele and
genotypic frequencies of the several known SNPs in
the SLCO1B1 gene and the haplotypes they form are
presented. The results from this study could serve
as a baseline clinical data for dosing of all drugs
substrates of OATAP1B1 and avoiding the adverse
drug reactions.
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