Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine
Analysis of F2, F5 and MTHFR genes SNPs allelic variants in population of Ukraine. Polymorphic variants were analyzed in 172 unrelated individuals using PCR followed by RFLP analysis.
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irk-123456789-667212014-07-22T03:01:17Z Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine Tatarskyy, P. Kucherenko, A. Livshits, L. Оригинальные работы Analysis of F2, F5 and MTHFR genes SNPs allelic variants in population of Ukraine. Polymorphic variants were analyzed in 172 unrelated individuals using PCR followed by RFLP analysis. Проанализировано распределение полиморфных вариантов генов по SNP F2 G20210A, F5 G1691A и MTHFR C677T среди населения Украины. Аллельные варианты SNP анализировали среди 172 неродственных индивидуумов методами ПЦР- и ПДРФ-анализа. Проаналізували розподіл алельних варіантів генів за SNP F2 G20210A, F5 G1691A та MTHFR C677T серед населення України. Алельні варіанти SNP аналізували серед 172 неспоріднених індивідів методом ПЛР- та ПДРФ-аналізу. 2010 Article Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine / P. Tatarskyy, A. Kucherenko, L. Livshits // Цитология и генетика. — 2010. — Т. 44, № 3. — С. 3-8. — Бібліогр.: 28 назв. — англ. 0564-3783 http://dspace.nbuv.gov.ua/handle/123456789/66721 575.11+577.21 en Цитология и генетика Інститут клітинної біології та генетичної інженерії НАН України |
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Оригинальные работы Оригинальные работы Tatarskyy, P. Kucherenko, A. Livshits, L. Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine Цитология и генетика |
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Analysis of F2, F5 and MTHFR genes SNPs allelic variants in population of Ukraine. Polymorphic variants were analyzed in 172 unrelated individuals using PCR followed by RFLP analysis. |
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Article |
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Tatarskyy, P. Kucherenko, A. Livshits, L. |
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Tatarskyy, P. Kucherenko, A. Livshits, L. |
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Tatarskyy, P. |
| title |
Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine |
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Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine |
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Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine |
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Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine |
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Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine |
| title_sort |
allelic polymorphism of f2, f5 and mthfr genes in population of ukraine |
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Інститут клітинної біології та генетичної інженерії НАН України |
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2010 |
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Оригинальные работы |
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http://dspace.nbuv.gov.ua/handle/123456789/66721 |
| citation_txt |
Allelic polymorphism of F2, F5 and MTHFR genes in population of Ukraine / P. Tatarskyy, A. Kucherenko, L. Livshits // Цитология и генетика. — 2010. — Т. 44, № 3. — С. 3-8. — Бібліогр.: 28 назв. — англ. |
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Цитология и генетика |
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AT tatarskyyp allelicpolymorphismoff2f5andmthfrgenesinpopulationofukraine AT kucherenkoa allelicpolymorphismoff2f5andmthfrgenesinpopulationofukraine AT livshitsl allelicpolymorphismoff2f5andmthfrgenesinpopulationofukraine |
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УДК 575.11+577.21
P. TATARSKYY, A. KUCHERENKO, L. LIVSHITS
Institute of Molecular Biology and Genetics
National Academy of Sciences of Ukraine, Kyiv
E�mail: tatarskyy@yahoo.com
ALLELIC POLYMORPHISM
OF F2, F5 AND MTHFR GENES
IN POPULATION OF UKRAINE
]
Analysis of F2, F5 and MTHFR genes SNPs allelic vari�
ants in population of Ukraine. Polymorphic variants were
analyzed in 172 unrelated individuals using PCR followed by
RFLP analysis. Following genotypes have been identified: GG
(97 %), GA (3 %) for F2 gene G20210A SNP, GG (96.5 %),
GA (3.5 %) for F5 gene G1691A SNP and CC (49.5 %), CT
(43 %), TT (7.5 %) for MTHFR gene C677T SNP. Following
combined genotypes have been detected. We observed 1.7 %
heterozygous carriers of MTHFR gene 677T SNP which were
heterozygous for one of the alleles of F5 1691A or F2 20210A
genes. On the other hand, the 7.5 % MTHFR gene 677T SNP
homozygous individuals carried wild type alleles only of
F5 and F2 genes. None of the individuals was carrying F5
1691A and F2 20210A genes polymorphic variants simultane�
ously. The data about F2, F5 and MTHFR genes SNPs allel�
ic frequencies in the population of Ukraine have been obtained.
Thus, distribution of F2, F5 and MTHFR genotypes based on
analysis of SNP in those three genes simultaneously has been
detected.
Introduction. Taking into account the growing
interest to the genetic aspects of complex diseases
the era of whole genome association studies
(WGAS) started in the last decade. Many single
nucleotide polymorphisms (SNPs) have been dis�
covered in different genes. Nevertheless there are
contradictory conclusions regarding their contri�
bution to the pathogenesis of different complex
disorders. In different publications the newly
described SNPs have been studied in many com�
plex pathological conditions.
Methylenetetrahydrofolate reductase (MTHFR)
is a key regulatory enzyme involved in folate
metabolism, DNA synthesis and remethylation
reactions [1]. Homocysteine is a metabolic product
of remethylation and trans�sulphuration reactions
involving methionine [1–4]. A common polymor�
phism in the MTHFR gene (C677T) results in a
thermolabile phenotype associated with high levels
of homocysteine [1–4]. It has been shown that
homozygosity for the C to T substitution at nucleo�
tide 677 of the MTHFR gene is associated with a
30–50 % reduction of this enzyme activity and is
the most common inherited cause of moderate
hyperhomocysteinemia [1, 2]. In the last publica�
tions there are evidences that the C677T MTHFR
gene variation is a risk factor for ischemic stroke
[2], infertility [1], primary closed�angle glaucoma
(PCAG) [3], presence of anti�hepatitis B virus
(HBV) antibodies [4], cytomegalovirus infection
(CMV) [4], Huntington disease [5], cancer [6],
coronary artery disease (CAD) [7], neural tube
defects (spina bifida) and venous thrombosis [6, 8,
9], but the association of the C677T MTHFR gene
variation and the risk of primary open�angle glau�
coma (POAG) is still conflicting [3].
Factor V gene which encodes coagulation mol�
ecule responsible for blood coagulation through
activation of protein C (APC) was discovered in
1987. APC is a serine protease with potent anti�
coagulant properties, which is formed in blood on
the endothelium from an inactive precursor [10].
The point mutation of factor V (guanine is replaced
by adenine in position 1691) led to the structural
change in factor V molecule (F5 Q506, or FV Leiden)
that is not properly inactivated by APC and shifts
the balance toward thrombosis in the clotting cas�
cade [2, 9–15] and may increase the risk of sys�
temic lupus erythematosus (SLE) [12], type 2 dia�
betes [16], recurrent pregnancy loss (RPL) [17–
21], stroke [2, 22], venous thrombosis and myocar�
dial infraction [2, 22].
ІSSN 0564–3783. Цитология и генетика. 2010. № 3 3
Оригинальные работы
© P. TATARSKYY, A. KUCHERENKO, L. LIVSHITS, 2010
Prothrombin is the precursor of the serine pro�
tease thrombin, a key enzyme in the processes of
hemostasis and thrombosis, that exhibits procoag�
ulant, anticoagulant, and antifibrinolytic activi�
ties [20, 23, 24]. The G to A transition at
nucleotide position 20210, in the 3'�untranslated
region of factor II (prothrombin) gene (F2) plays a
regulatory role in gene expression [11, 20, 23]. It
has been shown that F2 gene G20210A SNP is
associated with higher plasma prothrombin con�
centrations and augmented thrombin generation
[11, 17, 20, 23, 24]. Patients carrying the 20210A
allele have been demonstrated to be at risk for
venous thrombosis [9, 11, 15, 17, 20], RPL and
ischemic stroke [18–20].
Several studies argued that F5 G1691A and F2
G20210A were maintained at polymorphic frequen�
cies among Caucasians, because they conferred an
evolutionary advantage of reduced bleeding [25].
The high frequency of 677T allele MTHFR gene
suggests that it may be of some benefit to the host.
A survival advantage for homozygous fetuses is
hypothesized in environment, in which folic acid
consumption is adequate [25]. F5 gene G1691A,
F2 gene G20210A and MTHFR gene C677T are
three SNPs common among Caucasians. Therefore
the study of their frequencies in various popula�
tions provides perspectives for both clinical medi�
cine and population genetics.
This study aimed to analyze the F5 gene
G1691A, F2 gene G20210A and MTHFR gene C677T
alleles distribution in the population of Ukraine.
Materials and methods. The study subjects were
recruited between 2007 and 2008. An informed
consent was obtained from each participant prior
to blood collection and DNA extraction. This study
was approved by the Institute of Molecular Biology
and Genetics of the National Academy of Sciences
of Ukraine Ethical Committee. We studied 172
unrelated individuals (men – 85, women – 87),
having an age range of 25 to 45 years old, who
were randomly selected from different regions of
Ukraine from the general population.
Venous blood samples were collected into vacu�
tainer tubes containing EDTA and stored frozen
at –70 °С until using.
DNA was extracted from the peripheral blood
leukocytes by standard phenol�chloroform extraction
method [27] and stored at +4 °С until being used.
The F5 gene G1691A, F2 gene G20210A alle�
les were genotyped by multiplex polymerase chain
reaction (PCR) with the use of specific oligonu�
cleotide primers followed by MnlI restriction
enzyme digestion as described by Koksal [9].
The PCR reaction was performed in a final vol�
ume of 15 μL containing 1 � PCR buffer, 1.5 mM
MgCl2, 200 μM of each dNTP, 5 μM of each of the
relevant primer (made on an Biosset ASM
800 DNA synthesizer), 0.2 units of Taq�DNA
polymerase and 50–200 ng of the DNA template.
The cycling conditions on the PCR�amplificator
for alleles of F5 and F2 genes were as follows: ini�
tial denaturation at 95 °С for 5 min, 30 cycles con�
sisting of denaturation at 95 °С for 30 sec, annealing
at 60 °С for 30 sec, extension at 72 °С for 30 sec
and a final elongation step at 72 °С for 5 min.
The MTHFR gene C677T allele was genotyped
by PCR with the use of specific oligonucleotide
primers followed by HinfI restriction enzyme
digestion by Michael [3].
ISSN 0564–3783. Цитология и генетика. 2010. № 34
P. Tatarskyy, A. Kucherenko, L. Livshits
Fig. 1. RFLP analysis of F5 (factor V Leiden G1691A) and
F2 (prothrombin G20210A) genes endonuclease restric�
tion MnlI (7 % polyacrylamide gel electrophoresis): 1 – F2
(GG – wild type) and F5 (GG – wild type) genes; 2 – F2
(GA – heterozygote) and F5 (GG – wild type) genes; 3 –
F2 (GG – wild type) and F5 (GA – heterozygote) genes; 4 –
undigested PCR product of F2 and F5 genes, М – marker
of molecular mass
ІSSN 0564–3783. Цитология и генетика. 2010. № 3
The cycling conditions for MTHFR gene C677T
allele were as follows: initial denaturation at 95 °С
for 5 min, 30 cycles consisting of denaturation at
95 °С for 30 sec, annealing at 66 °С for 30 sec,
extension at 72 °С for 30 sec and a final elongation
step at 72 °С for 3 min. Electrophoresis of the
PCR products was performed in a 1.8 % agarose
gel with EtBr followed by visualization under UV.
PCR products 169, 221 and 294 bp long corre�
spondently were digested and run on 7 % PAGE.
The G to A transition in position 1691 of exon
10 F5 gene results in a disappearance of restriction
site for MnlI endonuclease. With a purpose to
detect G to A transition in position 20210 of the
F2 gene 3'�untranslated region detection, a single
mismatch nucleotide has been introduced in the
reverse primer [9]. This mismatch results in the
generation of a new MnlI restriction site in the
wild type allele. The C to T transition in position
677 of exon 4 MTHFR gene creates a restriction
site for HinfI endonuclease.
Digestion was performed in 15 μL reaction vol�
ume containing 1 � reaction buffer, 0.5 units of the
restriction enzyme and 10 μL of purified PCR prod�
uct, incubated at 37 °С for 3 hours or overnight.
The digested products with 100 bp leader were
electrophoresed on 7 % PAGE gel with EtBr and
photographed under UV.
Statistical analysis was performed by χ2 test,
using GENEPOP [28] package.
Results and discussion. In wild type alleles MnlI
digestion of F5 and F2 genes amplicons yielded
fragments of 17, 37 and 115 bp for F5 gene (Fig. 1),
the 17 bp fragment was a result of an invariant
MnlI site. For digested F2 gene amplicon 29 and
192 bp fragments were observed (Fig. 1). In wild
type allele HinfI digestion of MTHFR gene ampli�
cons yielded fragment of 294 bp (Fig. 2).
Digestion of the F5 gene G1691A SNP homozy�
gote gave fragments of 17 and 152 bp, and the
F2 gene G20210A SNP homozygote yielded frag�
ment of 221 bp (Fig. 1). Digestion of MTHFR gene
C677T SNP homozygote yielded fragments of
126 and 168 bp (Fig. 2). The small 17, 29 and
37 bp fragments has run out from the gel (Fig. 1).
5
Allelic polymorphism of F2, F5 and MTHER genes in population of Ukraine
Fig. 2. RFLP analysis of MTHFR (C677T) gene endonu�
clease restriction HinfI (7 % polyacrylamide gel electro�
phoresis): 1 – undigested PCR product of MTHFR gene;
2, 3 – CT (heterozygote); 4 – TT (mutant variant); 5, 6 –
CC (wild type); М – marker of molecular mass
Table 1
Genotype and allele frequencies distribution of F5 G1691A, F2 G20210A
and MTHFR C677T gene variants in Ukraine
Note . n – group size.
SNPs
F2 G20210A
F5 G1691A
MTHFR C677T
167(GG)
166(GG)
85(CC)
97
96.5
49.5
5(GA)
6(GA)
74(CT)
3
3.5
43
0(AA)
0(AA)
13(TT)
0
0
7.5
0.015
0.017
0.29
n % n
Homozygote
(wild type) Heterozygote
Homozygote
(mutant allele)
% n %
Mutant allele
frequency
Genotypes and allele frequencies of the three
polymorphisms are presented in Table 1. Of the
172 analyzed samples from the present study, we
have found 5 to have F2 gene 20210A (mutant
allele frequency 0.015), 6 to have F5 gene 1691A
(mutant allele frequency 0.017) and 87 to have at
least one MTHFR gene 677T allele (mutant allele
frequency 0.29). The genotype distribution of the
three analyzed SNPs is in Hardy�Weinberg equi�
librium χ2 = 0.0374, P > 0.05, χ2 = 0.0542, P >
> 0.05 and χ2 = 0.3222, P > 0.05 for F2 G20210A,
F5 G1691A and MTHFR C677T genes SNPs cor�
respondently. Expected heterozygosity for the
studied loci corresponded to the observed one.
To our knowledge this is the first published data
regarding research of F5 gene G1691A SNP,
F2 gene G20210A SNP and MTHFR gene C677T
SNP combined genotype distribution in the gener�
al population of Ukraine.
The frequency of allelic variants of F2 gene
20210A, F5 gene 1691A and MTHFR gene 677T in
our study is in agreement with the published data
obtained in other countries (Table 2). The excep�
tion appears to be the Japanese population in
which the F5 gene G1691A and F2 gene G20210A
were not detected yet [21]. The expected frequen�
cy of homozygotes in our study is 0.017 % for
F2 gene 20210A and 0.026 % for F5 gene 1691A.
ISSN 0564–3783. Цитология и генетика. 2010. № 36
P. Tatarskyy, A. Kucherenko, L. Livshits
Table 2
Frequencies of F5 G1691A, F2 G20210A and MTHFR C677T genes alleles in different countries
Note. n – group size; FII*A – 20210A; FV*A – 1691A; MTHFR*T – 677T.
Population
Gene/mutant allele
FII*A n FV*A n MTHFR*T n
Reference
Russia
Japan
Turkey
Italy
Greece
Cyprus
Jordan
Lebanon
Tunisia
Bahrain
Saudi�Arabia
Iran�west
Morocco
Palestinians
Pakistan
China
Brazil
Indian
Canadian
United States
Finland
Germany
Australia
United Kingdom
France
Azerbaijan
Spain
Ireland
Netherlands
Sweden
–
–
0.013
0.0199
0.022
0.039
0.010
0.014
0.013
0.005
0.003
0.017
0.012
0.033
–
–
0.0052
–
–
–
–
0.0098
–
–
–
0.0136
–
–
–
–
–
–
311
1429
160
90
200
697
313
191
884
180
124
107
–
–
384
–
–
–
–
102
–
–
–
110
–
–
–
–
–
0
0.041
0.0187
0.025
0.072
0.085
0.079
0.035
0.016
0.007
0.014
0
0.082
–
0
0.00826
–
0.0266
0.0298
0.0198
0.0274
0.0198
0.0227
0.0133
–
–
–
0.0156
–
–
386
387
1415
160
90
200
697
313
191
902
180
159
581
–
99
484
–
356
704
303
510
126
352
300
–
–
–
641
–
0.259
–
0.325
0.432
0.353
0.400
0.160
0.304
0.292
0.126
0.148
0.278
0.289
0.322
0.0928
0.5707
–
0.4
–
–
–
–
–
0.186
–
–
0.545
0.286
0.270
0.338
599
–
1885
1504
160
90
200
697
313
191
884
180
162
284
70
99
–
200
–
–
–
–
–
94
–
–
33
947
318
6644
7, 26
21
25
25, 26, 19
25
25
25
25
25
25
25
25
25
25
3
2
20, 14
1
14
14
14
21, 18, 14
14
14, 26
14
24
26
8, 26
14, 26
26
Therefore, the absence of homozygous individuals
in our study is not surprising. From all the 27 possi�
ble combinations of F2 20210A, F5 1691A and
MTHFR 677T genes SNPs combined genotypes, we
observed only 7 (Table 3). None of the individuals
was carrying F5 gene 1691A and F2 gene 20210A
alleles simultaneously. We observed 3 heterozygous
individuals for MTHFR gene 677T allele who at the
same time carried one of the F5 gene 1691A or
F2 gene 20210A alleles. On the other hand, the
MTHFR gene 677T allele homozygous individuals
carried F5 and F2 genes wild type alleles only. The
obtained allelic frequencies in the current study
were in the lower range frame of the world distribu�
tion. Obtained results from our study add to the
world distribution data concerning F2 20210A,
F5 1691A and MTHFR 677T genes allelic variants.
Although further studies based on population data
as controls are required to clarify their involvement
in different complex disorders, increased awareness
of this genetic risk factors is warranted.
П.Ф. Татарский,
А.М. Кучеренко, Л.А. Лившиц
АЛЛЕЛЬНЫЙ ПОЛИМОРФИЗМ ГЕНОВ F2,
F5 И MTHFR СРЕДИ НАСЕЛЕНИЯ УКРАИНЫ
Проанализировано распределение полиморфных
вариантов генов по SNP F2 G20210A, F5 G1691A и
MTHFR C677T среди населения Украины. Аллельные
варианты SNP анализировали среди 172 неродствен�
ных индивидуумов методами ПЦР� и ПДРФ�анализа.
Выявлены следующие генотипы: GG (97 %), GA (3 %)
для гена F2 G20210A, GG (96,5 %), GA (3,5 %) для ге�
на F5 G1691A и CC (49,5 %), CT (43 %), TT (7,5 %) для
гена MTHFR С677Т. Идентифицированы следующие
комбинированные генотипы: 1,7 % гетерозиготных но�
сителей 677Т аллеля гена MTHFR одновременно были
носителями одного из полиморфных аллелей генов
F2 20210А или F5 1691А. Вместе с тем 7,5 % гомозигот�
ных носителей 677Т аллеля гена MTHFR были гомози�
готами по аллелям дикого типа генов F2 и F5. Ни у
одного из индивидов в генотипе не выявлены иссле�
дуемые аллели 20210А и 1691А генов F2 и F5 одновре�
менно. Получены данные о частоте аллельных вари�
антов SNP по генам F2, F5 и MTHFR среди населения
Украины. На основании комплексного анализа SNP
этих трех генов было установлено распределение ком�
бинированных генотипов.
П.Ф. Татарський,
А.М. Кучеренко, Л.А. Лівшиць
АЛЕЛЬНИЙ ПОЛІМОРФІЗМ ГЕНІВ F2,
F5 ТА MTHFR СЕРЕД НАСЕЛЕННЯ УКРАЇНИ
Проаналізували розподіл алельних варіантів генів
за SNP F2 G20210A, F5 G1691A та MTHFR C677T се�
ред населення України. Алельні варіанти SNP аналізу�
вали серед 172 неспоріднених індивідів методом ПЛР�
та ПДРФ�аналізу. Виявлено наступні генотипи: GG
(97 %), GA (3 %) для гена F2 G20210A, GG (96,5 %),
GA (3,5 %) для гена F5 G1691A та CC (49,5 %), CT
(43 %), TT (7,5 %) для гена MTHFR С677Т. Було іден�
тифіковано наступні комбіновані генотипи: 1,7 % ге�
терозиготних носіїв 677Т алеля гена MTHFR водночас
виявились носіями одного з поліморфних алелів гена
F2 20210A чи гена F5 1691A. Разом з тим 7,5 % гомо�
зиготних носіїв 677Т алеля гена MTHFR були гомози�
готами за алелями дикого типу генів F2 та F5. У жод�
ного з індивідів в генотипі не виявлені досліджувані
алелі 20210A та 1691A генів F2 та F5 одночасно. Отри�
манo дані про частоти алельних варіантів SNP за генами
F2, F5 та MTHFR серед населення України. На основі
комплексного аналізу SNP цих трьох генів було вста�
новлено розподіл комбінованих генотипів.
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ІSSN 0564–3783. Цитология и генетика. 2010. № 3 7
Allelic polymorphism of F2, F5 and MTHER genes in population of Ukraine
Table 3
Combined genotypes frequencies of F5 G1691A,
F2 G20210A and MTHFR C677T genes variants
in Ukraine
Note. n – group size; FII: A – 20210A; G – 20210G, FV:
A – 1691A; G – 1691G, MTHFR: T – 677T, C – 677C.
FII
GG
GG
GA
GG
GG
GA
GG
GG
GA
GG
GG
GA
GG
GG
TT
CT
CT
CT
CC
CC
CC
13
1
2
71
5
3
77
7.5
0.5
1.2
41.3
2.9
1.8
44.8
FV MTHFR
n
Genotype
%
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Received 01.12.09
ISSN 0564–3783. Цитология и генетика. 2010. № 38
P. Tatarskyy, A. Kucherenko, L. Livshits
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