Candidate Genes and Clinical-Laboratory Indices in Pregnant Women Depending on the Development of Preeclampsia

Author Name: Evgenii A. Reshetnikov, Vladimir F. Kulikovskii, Irina V. Batlutskaia, Tatiana I. Iakunchenko, Aleksei V. Polonikov, Mikhail I. Churnosov
Author Email: reshetnikov@bsu.edu.ru

Abstract

Objectives: The relationship between polymorphic variants of folate metabolism genes with clinical (blood pressure level before and at the end of pregnancy) and clinical and laboratory indicators (proteinuria, fibrinogen, total protein, urea and creatinine in the blood, activated partial thromboplastin time, thrombin time) were studied in pregnant women with preeclampsia. Materials and Methods: The study group included 322 pregnant women diagnosed with preeclampsia and 179 women with normal pregnancy. Polymorphisms of the folate cycle genes (MТHFR +677С>Т (rs1801133), MТHFR +1298 A>С (rs1801131), MТRR +66 A>G (rs1801394), MТR +2756 A>G (rs1805087)) were studied by real-time polymerase chain reaction (PCR) of DNA synthesis (Real-time-PCR). Results: Polymorphic markers +2756 AA MТR and +1298 AС, +1298СС MТHFR are associated with an increased level of diastolic and systolic blood pressure, respectively, in women with pre-eclampsia prior to pregnancy. The genotypes +677ST and + 677TT MTHFR are associated with an increased level of proteinuria, and the genetic variants of +2756 AA MTR and +66GG MTRR are associated with a lower protein content in the blood and a high proteinuria level in pregnant women with preeclampsia. Conclusions: Thus, as a result of this study, significant associations of genetic polymorphisms MТHFR +677С>Т, MТHFR +1298 A>С, MТR +2756 A>G, MТRR +66 A>G with indices of blood pressure, protein content in the blood, proteinuria level in pregnant women with preeclampsia were determined.

Introduction

Preeclampsia is a multisystem pathological condition that occurs in the second half of pregnancy (after the 20th week) characterized by hypertension in combination with proteinuria, often with edema and multiple organ dysfunction (Williams et al, 2011, Sidorova, 2016). The frequency of PE is 8-20% among all pregnant women (Suhih, Murashko, 2010). During the last decade, preeclampsia is one of the main factors of perinatal morbidity in the world and stably ranks 3rd-4th in the structure of the causes of maternal morbidity and mortality (Ajlamazyan, Mozgovaya, 2010, Sidorova, 2016).

Analysis of modern literature indicates that PE is a multifactorial disease. Genetic component of PE development can account for up to 50% of all risk factors (Baranov, 2009; Reshetnikov et al., 2017).

An important role in the etiology and pathogenesis of preeclampsia belongs to the candidate genes for folate metabolism (Vorozhishcheva, 2014; Zhou et al., 2016). Mutations in the genes of folate metabolism, which lead to a decrease in the activity of methyltetrahydrofolate reductase enzymes and methionine synthase reductase, lead to an excessive accumulation of homocysteine in the blood and, as a result, disruption of methylation processes in cells (Vorozhishcheva, 2014). Deficiency of folic acid causes the formation of hypertension in pregnant women, the development of total angiopathy, microthrombosis, increased insulin resistance. It should be noted that the role of candidate genes for folate metabolism in the formation of PE has been actively studied, but these studies often give conflicting results in different populations of the world (Obolenska et al., 2011; Pavlova et al., 2011; Williams et al., 2011; Valenzuela et al., 2012; Reilly et al., 2014; Vorozhishcheva, 2014;).

Conclusion

The data obtained as a result of the research broaden the understanding of the mechanisms of preeclampsia development, and also allows predicting the nature of the clinical course of the disease, which will ensure optimization of the treatment and diagnostic process for each patient. The polymorphisms MТR +2756 A>G, MТHFR +1298 A>С, MТHFR +677С>Т, MТRR +66 A>G can be used to predict blood pressure levels, proteinuria levels, and protein content in pregnant women with preeclampsia. MТHFR +677С>Т (rs1801133), MТHFR +1298 A>С (rs1801131), MТRR +66 A>G (rs1801394), MТR +2756 A>G (rs1805087))

References

  1. Ajlamazyan, E.K., Mozgovaya, E.V., 2008. Gestosis: theory and practice. М.: Publishing house MEDpress-inform.
  2. Baranov, V.S., 2009. The genetic passport is the basis of individual and predictive medicine. StP.: Publishing House N-L.
  3. Baranova, E.I., Bolshakova, O.O., 2004. Clinical significance of homocysteinemia (literature review). Arterial hypertension, 1:12-15.
  4. Bailey, L., Gregory, J., 1999. Polymorphisms of methylenetetrahydrofolatereductase and other enzymes: metabolic signifi – cance, risks and impact on folate requirement. J Nutr, 129: 919-922.
  5. Churnosov, M.I., Pesik, V.Yu., Rudyh, N.A., 2005. Materials of the study of the structure of the gene pool of the Russian population of Central Russia. Medical Genetics, 6(4): 289a-289.
  6. Friedman, G., Goldschmidt, N., Friedlander, Y., Ben-Yehuda, A., Selhub, J., Babaey, S., Mendel, M., Kidron, M., Bar-On, H., 1999. Acommon mutation A1298C in human methylenetetrahydrofolatereductase gene: association with plasma total homocysteine and folate concentrations. J Nutr, 129: 1656-1661.
  7. Halford-Knyazeva, I.P., 2013. Genetic markers for the prediction of preeclampsia: Author’s abstract, PhD Medicine. M., 16.
  8. Matos, A., da Silva, A.P., Maia, H., Ferreira, J., Clode, N., Areias, M.J., Bicho, M.C., Bicho, M., Rebelo, I., 2013. The polymorphism C677T of methylenetetrahydrofolate reductase (MTHFR), may increase risk for future higher blood pressure in women with previous hypertension in pregnancy. Pregnancy Hypertens, 3(2): 69.
  9. Obоlens’k a, M.I., Rоdrihes, R.R.,2011. M artseniuk О.P. Fоlate-related prосesses in human plaсenta: gene expressiоn, aminоthiоls, prоliferatiоn and  apоptоsis. Ukr Biоkhim Zh, 83(1): 5-17.
  10. Pavlova, K.K., Trifonova, E.A., Gotovceva, L.V., Maksimova, N.R., Nogovicyna, A.N., Stepanov, V.A., 2010. Role of polymorphisms of eNOS, ACE and MTHFR genes in the development of gestosis in the Yakut population. The Yakut Medical Journal, 3(31): 28-31.
  11. Rebrova, O.Yu., 2006. Statistical analysis of medical data. The use of STATISTISA application package. M.: Publishing House Media Sfers.
  12. Reilly, R., MсNulty, H., Pentiev a, К., Strain, J.J., Ward, M., 2014. MTHFR 677TT genоtype and disease risk: is there a mоdulating rоle fоr B-vitamins? Prос Nutr Sос, 73(1): 47-56.
  13. Reshetnikov, E.A., Yakunchenko, T.I., Aristova, I.K., Polonikov, A.V.,  Churnosov, M.I., 2017. Associations of Insertion-deletion Polymorphism of Angiotensin-converting Enzyme with the Risk of Preeclampsia Development among Pregnant Women in Central Russia. Asian Journal of Pharmaceutics, 11(3): 635-639.
  14. Sidorova, I.S., 2016. Preeclampsia. М.: Publishing house “Medical information agency”.
  15. Sorokina, I.N., Churnosov, M.I., Balanovskaya, E.V., 2007. Gene pool of the population of the Belgorod region II. “Familial portraits” in groups of regions with different levels of division and the role of migrations in their formation. Genetics, 8(43): 1120-1128.
  16. Strizhakov, A.N., Makacariya, A.D., Timohina, E.V., Bajmuradova, S.M., Kozlova, U.A., 2009. Clinical significance of acquired and hereditary forms of thrombophilia in the pathogenesis of fetal growth retardation syndrome. Questions of gynecology, obstetrics and perinatology, 8(2): 16-21.
  17. Suhih, G.T., Murashko, L.E., 20010. Preeclampsia. M.: Pulishing house GEOTAR-media.
  18. Suhovol’skaya, M.A., Subbotina, T.N., Ol’hovskij, I.A., Bazarin, K.P., 2012. Mutations in the genes of methylenetetrahydrofolate reductase (MTHFR) and methiotine synthase (MTR) and risk factors for hyperhomocysteinemia in athletes. Clinical laboratory diagnostics, 9: 65.
  19. Valenzuela, F.J., Pérez-Sepúlveda, A., Torres, M.J., Correa, P., Repetto, G.M., Illanes, S.E., 2012. Pathogenesis of preeclampsia: the genetic component. J Pregnancy, 2012: 632732.
  20. Vorozhishcheva, A.Yu., 2014. Genetic factors of development of preeclampsia in populations of different ethnic origins: Author’s abstract, PhD Medicine. Tomsk; 24Zainulina M.S., Glotov A.S., Korniushina M.L. Thrombophilia in obstetrical practice. StP.: Publishing house N-L. 2009.
  21. Williams, P.J., Broughton, Pipkin, F., 2011. The genetics of pre-eclampsia and other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet Gynaecol, 25(4): 405-417.
  22. Zhou, L., Cheng, L., He,Y., Gu, Y., Wang, Y., Wang, C., 2016. Association of gene polymorphisms of FV, FII, MTHFR, SERPINE1, CTLA4, IL10, and TNFalpha with pre-eclampsia in Chinese women. Inflamm Res, 65(9): 717-724.

 

223 total views, 1 views today

Download File

About the author: admin