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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RESULTS
Genotypes and Allele Frequencies. Genetic
variation of SLCO1B1 was studied in 360 subjects
in total, both patients with hyperlipidemia type IIa
or IIb and healthy subjects, of which 266 were of
Macedonian and 94 of Albanian ethnicity. Observed
genotypes and allelic frequencies of SLCO1B1 gene
polymorphisms did not differ significantly (p >0.05)
when comparing the data obtained from patients and
healthy subjects (Table 1). In addition, the observed
frequency distributions did not show significant deviations
from HWE (p >0.05) in both populations of
the two ethnic groups, the population of both patients
and healthy subjects, confirming the random selection
of the individuals, i.e., representativeness of the
population samples being studied. Taking all this into
consideration, genotype and allele frequencies for
the total population of Macedonians and Albanians
were estimated and the data are presented in Table 2.
Data for distribution of genotypes and allele
frequencies of SLCO1B1 gene polymorphisms between
females and males, including both patients
and healthy subjects within each ethnic group, are
presented in Table 3. No significant differences for
all SLCO1B1 gene polymorphisms were observed
between female and male subjects, both within each
and between the two ethnic groups. All SNPs, except c.1463G>C and c.1086C>T,
occurred at an allele frequency higher than 12.0%.
Variant alleles of SLCOB1 c.1463G>C and
c.1086C>T polymor- phisms were not identified in
either ethnic group in this study. The frequency of
the c.521T>C SNP was the lowest, 13.7 and 12.2%
for Macedonians and Albanians, respectively, while
the frequencies of all other SNPs alleles were above
40.0%, with frequency of the c.571T>C variant allele
being highest in both populations (65.0 and 62.2%
for Macedonians and Albanians, respectively). No
significant differences (p >0.05) in allelic frequencies
and genotype distributions of the analyzed SNPs
were observed between the two ethnic groups. The
SNP variant allele frequencies in the ethnic groups
separately compared to data reported from various
ethnic groups are presented in Table 4.
Pairwise Linkage Disequilibrium. Pairwise
LD profiles for single SNPs using r2 and D’ values
for Macedonians and Albanians separately, are
shown in Figures 1 and 2, respectively. Generally,
the correlations of SNP pairs in the Albanian population
were weaker than those of the Macedonian
population. The most strongly correlated (r2 ≥0.33)
SNP pair in the Macedonian population was c.597
C>T/c.388A>G (r2 = 0.531, D’ = 0.740), followed
by c.597C>T/c.*439T>G (r2 = 0.373, D’ = 0.699).
Other pairs showing a significant association were
c.388A>G/c.*439 T>G (r2 = 0.289, D’ = 0.613) and
c.521T>C/c.571T>C (r2 = 0.233, D’ = 0.919). The
correlation of the most common SNP pair, c.388A>G/
c.521T>C, in the Macedonians was relatively weaker
compared to other SNP pairs, with r2 = 0.113 and D’
= 0.698. The c.521T>C showed the strongest correlation
with c.571T>C, followed by c.597 C>T (r2 =
0.178, D’ = 0.872), c.388A>G and c.*439 T>G (r2
= 0.072, D’ = 0.645).
In the Albanian population, the same SNP pairs,
c.597C>T/c.388A>G and c.597C>T/c.*439T>G,
showed the strongest correlation with r2 = 0.221,
D’ = 0.498 and r2 = 0.214, D’ = 0.505, respectively.
The correlation between c.388 A>G and c.521T>C
in the Albanian population was weaker (r2 = 0.009,
D’ = 0.219) compared to the same SNP pairs in the
Macedonian population. Similar data for the LD of
c.521T>C with other SNPs were obtained, with the
strongest correlation of this SNP with c.571T>C (r2
= 0.091, D’ = 0.635), followed by c.597C>T (r2 =
0.097, D’ = 0.746), c.388A>G and c.*439T>G (r2 =
0.008, D’ = 0.238).
Haplotypes. The haplotype analysis revealed 20
different haplotypes in the Macedonian population
and 21 in the Albanian population (Tables 5 and 6).
Nine haplotypes in each of the two populations were
designated as new. Nine other haplotypes that occurred
in the Macedonian and Albanian populations
had the same sequence of the actually investigated
SNPs as in the newly identified haplotypes presented
in the study of Pasanen et al. [13].
In the Macedonian population, eight haplotypes
occurred at a frequency equal to or greater than 3.0%
(Table 5). The most common haplotype in this ethnic
group, *1J/ *1K/*1L, had a frequency of 39.0%, containing
variant allele C at position c.571 and having
referent nucleotides at all other investigated positions.
The variant allele C at position c.571 existed
in eight haplotypes, with a frequency between 0.3
and 39.0%. The variant allele G at position c.388 and
T at c.597C>T SNP existed in 11, while the variant
allele G at c.*439T>G in 12 haplotypes, all occurring
with frequencies between 0.3 and 11.6%. The
c.521T>C SNP existed in six haplotypes, with a frequency
between 0.3 and 8.6%. The variant alleles of
the functionally most distinguished SNPs, c.388A>G and c.521T>C, were present in four haplotypes, of
which the dominant haplotype *15/*16/*17 had a
frequency of 8.6%.
In the Albanian population, 10 haplotypes occurred
at a frequency equal or greater than 3.0%
(Table 6). The most common haplotype was the same
as in the Macedonian ethnic group, *1J/*1K/*1L,
with a frequency of 26.6%. The variant allele C at
position c.571 existed in nine haplotypes with a frequency
between 1.4 and 26.6%. The variant allele
G at position c.388 existed in 10 haplotypes, while
c.597C>T SNP in 11 haplotypes, both occurring at
frequencies between 1.0 and 12.4%. The c.*439T>G
occurred in 10 haplotypes, with a frequency between
0.6 and 12.4%, and the c.521T>C SNP existed in
seven haplotypes, with a frequency between 0.6 and
3.7%. Three of the haplotypes contained the variant
alleles of the c.388A>G and c.521 T>C SNPs
with a frequency ≥1.0%, with the major haplotype
*15/*16/*17 having a frequency of 2.4%.
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