THE 3’ END PROTHROMBIN GENE VARIANTS IN SERBIAN
PATIENTS WITH IDIOPATHIC THROMBOPHILIA
Aradjanski M1, Djordjevic V1, Pruner I1,*, Tomic B1, Gvozdenov M1, Kovac M2,3, Radojkovic D1
*Corresponding Author: Dr. Iva Pruner, Institute of Molecular Genetics and Genetic Engineering, Vojvode Stepe
444A, PO Box 23, 11010 Belgrade, Serbia. Tel: +381-11-397-6658. Fax: +381-11-397-5808. E-mail: iva.pruner@
gmail.com
page: 43
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DISCUSSION
In order to identify potential thrombophilic risk
factors in these patients, we chose to sequence the 3’
end of the FII gene, since it has been shown that this
region is very susceptible to gain-of-function mutations
[13-15]. We detected two variants in the 3’ end
of the FII gene, A19911G and C20068T, in both the
patients and control groups.
The A19911G gene mutation is located in the
last intron of the FII gene and functional analyses
showed that the presence of this variant enhances
splicing efficiency by altering a known functional
pentamer motif [24]. In our study, the frequency of
the A19911G gene variant in patients was similar to
the frequencies in the control group. The frequency of
the G allele in our study was 0.44, which is very similar
to the frequencies that were reported for thrombophilia patients in other populations: Italian (0.51),
Spanish (0.52) and Dutch (0.48) [22-23]. According
to our results, A19911G does not represent a risk factor
for idiopathic thrombophilia (Table 2). A recent
study by Martinelli et al. [23] that investigated the
risk of cerebral sinus-venous thrombosis in patients
with A19911G, also showed that this variant does not
represent a significant risk factor for this thrombotic
disorder. However, the MEGA study [25], which included
over 5000 patients and 5000 controls showed
that the presence of the 19911GG genotype represents
1.43-fold greater risk for thrombotic occurrence (95%
CI 1.27-1.67) compared to the 19911AA genotype.
The C20068T gene variant is located in the last
exon of the FII gene. As it does not result in a change
of the amino acid sequence of a protein, it is considered
as a synonymous variant. In vitro functional
assays revealed that constructs with the C20068T
gene variant increased expression level 1.64 times
compared to the wild type construct [27]. However,
further studies are needed in order to clarify the exact
mechanism of overexpression. In our study, we
detected this variant only in the heterozygous state,
with a higher frequency in patients than in controls.
Moreover, further studies in a larger group of subjects
are needed in order to elucidate the importance of this
gene variant for etiology of idiopathic thrombophilia.
To the best of our knowledge, there are no studies
considering the prevalence of C20068T in patients
with thrombophilia or any other disease.
In our study, 4.0% of the patients were carriers
of a combined 20068CT/19911AG genotype. These
patients experienced more severe clinical manifestations
of throm-bophilia. This result alludes to the
possible role of the association of C20068T and
A19911G in pathogenesis of thrombophilia. Nevertheless,
functional studies are needed to yield more
precise conclusions.
Other variants in the 3’ end of the FII gene
(C20211T, T20219A, A20218G and C20209T) that
were reported in previous studies were not detected
in our study. Our data indicate that the prevalence of
these variants is less than 1.0% in the patients with
idiopathic thrombophilia in a population originating
from the geographic area of Serbia.
In order to obtain a well-defined group of patients
with idiopathic thrombophilia, we applied very strict
selection criteria as described in the Materials and
Methods section, which led to a relatively small size
of the patient group. Also, the results that we obtained
can be attributed to the specific criteria we used.
In conclusion, our study showed the first results
for the prevalence of variants at the 3’ end of the FII
gene in patients with idiopathic thrombophilia. These
results indicate that the A19911G gene variant is not
a significant risk factor in our study group. On the
other hand, the C20068T polymorphism could be a
potential risk factor in idiopathic thrombophilia and
therefore, further studies in a larger group of patients
should be conducted.
Declaration of Interest. This study was supported
by grant No. 173008 from The Ministry of Education,
Science and Technological Development of the Republic of Serbia, Belgrade, Serbia. The authors
report no conflicts of interest. The authors alone are
responsible for the content and writing of this article.
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