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

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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