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Section 6. Medical science
9. Beydon N., Davis S. D., Lombardi E., et al. An official American Thoracic Society/European Respiratory Society statement: pulmonary function testing in preschool children.//Am.J. Respir. Crit. Care Med. 2007. V. 175, № 12. P. 1304-1345.
10. Devulapalli C. S., Carlsen K. C., Haland G. et al. Severity of obstructive airways disease by age 2 years predicts asthma at 10 years of age//Thorax. 2008. V. 63. № 1. P. 8-13.
11. Hedlund U., Eriksson K., Ronmark E. Socoeconomic status is related to incidence of asthma and symptoms in adults//Eur.Respir. J.-2006. - Vol. 28, N 2. - P. 303-210.
12. Investigation of factors associated with difficult to control asthma/A. C. Araujo, E. Ferraz, M.de Borges et al//J. Braz. Pneumol. - 2007. - Vol. 33, N 5. - P. 495-501.
13. Khaptkhaeva G, Zykov K, Chuchalin A. et al. Role of respiratory infection in the control and severity of asthma.//Eur Respir J 2008; P. 2228; 388 p.
14. Martinez F. D. Genes, environments, development and asthma: a reappraisal. Eur. Respir. J. 2007; 29 (1): 179-184.
15. Martin P., Matheson M., Gurrin L., et al. Childhood eczema and rhinitis predict atopic but not nonatopic adult asthma: A prospective cohort study over 4 decades//JACI. 2011. V. 127. P. 1473-1479.
Yuldasheva Dilchehra Yusuphonovna, assistant of the Tashkent Medical Academy, Republic of Uzbekistan Sadykova Dilfuza Ravshanovna, Associate Professor of the Tashkent Medical Academy,
Republic of Uzbekistan E-mail: evovision@bk.ru
Studying the frequency of genotypes and allelic variants of the polymorphism rs1042522 gene TP53 in women with cervical intraepithelial neoplasia
Abstract: One of the earliest identified polymorphisms in the TP53 gene was Ex4 + 119 G> C (Arg72 Pro, rs1042522), the caller an amino acid substitution of arginine (p53Arg) proline (p53Pro) in protein p53 (1).It was subsequently found that the polymorphic variants Arg and Pro possess different abilities to activating transcription of target genes p53 and p53 startup-mediated processes.
Keywords: cervical intraepithelial neoplasia, polymorphism, allelic imbalance.
Thanks to functional differences between the polymorphic variants like p53Arg and p53Pro, in the world widely studied the role of this polymorphism in forming of diseases of various pathology.
The p53 protein has an increased affinity to the interaction with HPV E6 protein, leading to the degradation of the first and, respectively, a high risk of developing cervical cancer and with greater sensitivity to ultraviolet (skin cancer) [2].
We have studied frequency of genotypes and allelic variants of the polymorphism rs1042522 in gene TP53 in patients with CIN and their possible association with the formation and with course of the disease. The distribution of genotype frequencies of this polymorphism and their conformity population equilibrium Hardy-Weinberg (HVE) was carried out separately in the study and control groups.
It was found that the genotypic diversity of TP53 gene polymorphism Arg72Pro among patients and the control group, which was estimated based on the magnitude of the observed heterozygosity was close to the maximum possible dinucleotide loci.
Patients of the main group were found close to statistically significant difference observed distribution of genotypes of the expected under HVE (^2 = 3.6; P = 0.06).
This indicates a possible "allelic imbalance" in the locus of the gene TP53, underlying malignant transformation and appears as a genetic mechanism by which lost "functionally unfavorable" and selected the most "favorable" for the tumor growth of alleles (or accumulation in patients with relevant genotypes and their possible protective effect on the formation of the disease).
The population sample was a statistically significant deviation of the observed distribution of genotypes of the expected under Hardy-Weinberg equilibrium (HWE) by reducing the number of homozygotes.
Thus, the observed increase in the observed heterozygosity compared to their expected value. Such variations are due to the specifics of the control group: it included only provisionally healthy women — without of endometrial hyperplastic processes and cervical pathology. In the subgroups of patients with increasing stage ofdisease observed accumulation ofheterozygote from 45.6% (subgroup — A) to 53.3% (subgroup — B) due to a decrease frequency ofhomozygotes ofboth forms (wild and mutant). The frequency distribution of genotypes in both groups of patients with a statistically insignificant has deviated irom the expected under HWE (P> 0.05).
Analysis of the relationship associations of alleles and genotypes of the polymorphism rs1042522 gene TP53 at risk of developing CIN showed that the frequency of allele polymorphism rs1042522 gene TP 53 statistically significant differences between samples of patients with CIN and control was not (^2 = 0.6; P = 0.4; OR = 2.2; 95% CI 0.7692, 1.921). Since the analysis of the association of the allele does not give a complete picture of the nature of interconnection examined polymorphisms with predisposition to disease, we investigated the effect of the genotypes polymorphism rs1042522 TP53 gene on the develop risk of CIN. Statistically significant differences in the genotype frequencies between groups were found (P> 0.05) [6].
Studying the frequency of genotypes and allelic variants of the polymorphism rs1042522 gene TP53 in women with cervical.
However, in both groups of patients with CIN, compared to controls significantly reduced the proportion of Arg/Arg genotype and increased proportion of homozygous genotype Pro/Pro amid tall frequency of heterozygous genotype Arg/Pro. The risk of CIN in the presence of a genotype Pro/Pro increases by more than by 4 times (x2 = 2,0; F = 0.1; OR=4,3; 95% CI 0.4739, 39.42). Despite the high odds ratio (OR=4,3), such a difference was not statistically significant. Since the lower limit of the confidence interval (95% CI of the relative risk) is very far from unity (95% CI 0,4739-39,42), in this case we can assume that the result is a trend, not a pattern. To concretize the values of genotypic frequencies necessary to increase the sample size, patients and population groups, reducing the value of the confidence interval and will make more accurate conclusions.
Research of association polymorphism rs1042522 gene TP53 separately in subgroups A and B statistically significant differences between them and the control were not found (P> 0.05).
Analysis of association of polymorphism rs1042522 gene TP53 has not allowed us to establish interconnection of this locus detection with the risk of CIN in Uzbekistan. Predictive efficiency polymorphism rs1042522 gene TP53 in patients according to the values of the AUC, was also very low — 0.54, indicating that the low efficiency of detection of this locus for predicting the risk of developing CIN (OR = 1,2; P> 0.05 95% CI0, 7692, 1,921).
We can assume that in the course of tumor formation adverse genotypic variants (contributing to the launch of the p53-mediated processes) polymorphism rs1042522 gene TP53 inactivated as a result of the phenomenon loss ofheterozygosity. The activity ofthe
remaining allele may be inhibited by the mutation or epigenetic modifications [5].
In addition, there are data of another mechanism for the in-activation of the p53 gene — by binding with the E6 oncoprotein of human papillomavirus types 16 and 18, which leads to loss of control of proliferation, DNA damage and chromosomal instability.
Cellular protein E6-AP (associatedprotein) complexed with inactivates p53 oncoprotein E6, and also possibly, reduces the expression level shortens the life cycle of the protein product of p53 gene in HPV-immortalized cells [4].
Accordingly, it can be assumed that when infecting HPV and carriers adverse genotypes polymorphism rs1042522 gene TP53 probably likely to have an increased risk of cervical cancer development only in the presence of additional genetic modifications in the gene TP53, due to epigenetic modifications of allelic imbalance (loss of heterozygosity) and somatic mutations.
Exactly similar disturbances underlie the malignant transformation of cells [3].
Conclusion: We concluded that the polymorphism rs1042522 gene TP53 does not make an independent contribution to the risk of developing CIN in the Uzbek population. Taking into account the above concept, as well as considering of a possible pleiotropic influence of p53 gene on carcinogenesis (in conjunction other mutations) interpopulation differences ofpolymorphism
rs1042522 gene TP53, and genetic heterogeneity of the disease,
consider it necessary to continue research on the possible involvement of this gene in the formation of predisposition to CIN.
References:
1. Ara S., Lee P. S., Hansen M. F., Saya H. Codon 72 polymorphism of the TP53 gene//Nucleic Acids Res. -1990. - Vol.18, № 16. - P.4961.
2. Jerry D. J., Dunphy K. A., M. J. Hagen. Estrogens, regulation of p53 and breast cancer risk: a balancing act//Cell Mol Life Sci. - 2010.
3. Imyanitov E., Togo A., Hanson K. Searching for cancer associated genepolymorphisms: promises and obstacles//Cancer Lett. - 2004. -Vol. 204, № 1. - P. 3-14.
4. Huibregtse J. M., Beaudenon S. L.//Semin. Cancer Biol. - 1996. Vol. 7. № 6. - P. 317.
5. Tucker T., Friedman J. M. Pathogenesis ofhereditary tumors: beyond the "twohit" hypothesis//Clin Genet. - 2002. - Vol.62, № 5. - P. 345-357.
