The connections of polymorphic variants of the gene of vasoactive hormones with the level of arterial pressure in pregnant women, depending on the development of preeclampsia (PE), have been studie

Batlutskaya, I. V.

Krikun, E. N.

Orlova, V. S.

Reshetnikov, E. A.

Rudyh, N. A.

English

DSpace at Belgorod State University

Asian Journal of Pharmaceutics • Oct-Dec 2018 (Suppl) • 12 (4) | S1320Genetic Determinants of Complicated PregnancyEvgeny A. Reshetnikov, Nataliya A. Rudyh, Irina V. Batlutskaya, Evgeny N. Krikun, Valentina S. Orlova, Inna N. SorokinaDepartment of Medico-Biological Studies, Belgorod State University, 308015, Belgorod, Pobeda Street, 85, RussiaAbstractObjectives: The connections of polymorphic variants of the gene of vasoactive hormones with the level of arterial pressure in pregnant women, depending on the development of preeclampsia (PE), have been studied. Materials and Methods: The study group included 382 pregnant women diagnosed with PE and 205 women with normal pregnancy. Polymorphisms of the endothelin-1 gene rs5370 (G>T EDN1) and guanine-binding protein β3 subunit gene rs2301339 (G>A GNB3) were studied by real-time polymerase chain reaction (PCR) of DNA synthesis (real-time PCR). Results: Women with PE with genotype TT EDN1 have lower values of systolic, diastolic, and mean arterial pressure at the end of pregnancy compared to those with G EDN1 allele (genotypes GG and GT, P = 0.01–0.04). Conclusions: Thus, as a result of this study, significant associations of genetic polymorphisms with blood pressure indicators in pregnant women with PE were established.Key words: Blood pressure, Genetic polymorphism, Preeclampsia, PregnancyINTRODUCTIONRecently, there has been a tendency to increase in the frequency of the pathological course of pregnancy, childbirth, the postpartum period in women, and perinatal morbidity and mortality in newborns.[1]In this regard, the number of research devoted to molecular genetic studies of the complications of pregnancy has been constantly increasing.[2-4]Preeclampsia (PE) is a complication of pregnancy, characterized by the development of endothelial dysfunction, multiple organ failure, disruption of coagulation and anticoagulation systems, microcirculation, metabolic processes, and immune response.[5]According to the world literature and the WHO, the incidence of PE is 2–8%.[6,7] PE remains an important cause of maternal, perinatal, and neonatal morbidity and mortality.[7]Severe PE and eclampsia cause the risk of complications such as hemorrhages and cerebral edema, placental abruption, disseminated intravascular coagulation syndrome, massive obstetric hemorrhages, HELLP syndrome, hemorrhage and rupture of the liver capsule, pulmonary edema, adult respiratory distress syndrome, and acute renal and hepatic insufficiency.[4,7]According to a number of studies, this complication of pregnancy has a multifactorial nature.[3,8] Local gene networks of PE include endothelial dysfunction genes, vascular reaction genes, growth factor and cytokine genes, and major histocompatibility genes.[9-15]MATERIALS AND METHODSThe study involved 587 women living in the territory of Central Russia (Belgorod region). The age of women ranged from 20 to 43 years (mean age 27.98 ± 4.50 years). Clinical and laboratory studies of women were conducted in the Perinatal Center of the Belgorod Regional Clinical Hospital (Department of Pathological Pregnancy). Criteria ORIGINAL ARTICLEAddress for correspondence:  Evgeny A. Reshetnikov, Department of Medico-Biological Studies, Belgorod State University, 308015, Belgorod, Pobeda Street, 85, Russia. E-mail: reshetnikov@bsu.edu.ruReceived: 22-11-2018 Revised: 09-12-2018 Accepted: 14-12-2018Reshetnikov, et al.: Genetic Determinants of Complicated PregnancyAsian Journal of Pharmaceutics • Oct-Dec 2018 (Suppl) • 12 (4) | S1321for inclusion in the study group were (a) Russian nationality, (b) gestational age 37–40 weeks, and (c) informed consent for the study. Pregnant women with diabetes and liver or kidney failure, as well as pregnant women with diabetes with a gestation period of <37 weeks and over 40 weeks, were excluded from the study. Blood pressure was measured 3 times according to the recommendations of the American Heart Association.[16] Data on blood pressure before pregnancy were obtained from case records of every woman. Mean blood pressure (MBP, mmHg) was calculated using the Hickam formula: MBP = (SBP + 2DBP)/3, where SBP is the systolic blood pressure and DBP is the diastolic blood pressure. Among 587 pregnant, 205 patients were with a physiological course of gestation and 382 women with a pregnancy complicated by PE.PE was defined as the presence of hypertension, accompanied by proteinuria, as defined by a 24 h urine protein excretion more 300 mg.[17]Molecular genetic methodsVenous blood (8–9 ml) was drawn from the ulnar vein of each woman. Genomic DNA was isolated using the method proposed Miller et al.[18] All women underwent typing of molecular genetic markers of endothelin-1 (G>T EDN1 [rs5370]) and β3 subunits of guanine-binding protein (G>A GNB3 [rs2301339]).The selection of polymorphisms was made in accordance with the criteria set forth in the paper by Ponomarenko.[19]Loci genotyping was produced using real-time polymerase chain reaction (PCR) by the method of TaqMan probes detection according to relative fluorescence unit values of each probe on the thermocycler IQ5 with detecting system in real time. “Bio-Rad IQ5-Standart Edition” program was used for the alleles discrimination.Statistical analysisAllele frequencies of the genes polymorphism were estimated by the gene counting method, and the Chi-square test was used to identify significant departure from Hardy–Weinberg equilibrium. The distribution of allele and genotype frequencies between the study groups was compared by the Chi-square test for 2 × 2 contingency tables. The distribution of the quantitative traits such as SBP, DBP, MAP, and pulse pressure (the pressure difference between the systolic and diastolic pressures, PBP) before and at the end of pregnancy was analyzed by the Shapiro–Wilks test. Since the values of the quantitative traits did not follow the normal distribution, median (Me) and interquartile range (Q25-Q75) were used for their description and intergroup comparisons were done using the Mann–Whitney U-test. All statistical analyses were performed using STATISTICA for Windows v. 6.0 (StatSoft, USA).RESULTSThe biomedical and clinical characteristics of the study women are shown in Table 1.As a result of studying the relationship of polymorphism of endothelin gene 1 G>T EDN1 rs5370 with BP levels in women at the end of pregnancy, significant associations were established only for pregnant women with PE [Table 2]. Women with PE with genotype TT EDN1 have lower values of systolic, diastolic, and mean arterial pressure at the end of pregnancy compared to those with G EDN1 allele (genotypes GG and GT, P = 0.01–0.04).The study of the relationship between the polymorphism of the guanine-binding protein β3 subunit of rs2301339 and the blood pressure levels in pregnant women revealed no significant associations.DISCUSSIONThe results of this study suggest that G>T EDN1 rs5370 polymorphism is associated with the level of arterial pressure in pregnant women with PE (37–40 weeks). The genotype TT EDN1 is associated with lower rates of systolic, diastolic, and MBP.Gene EDN1 is located on the chromosome 06p24. The polymorphism studied is due to the replacement of guanine with thymine at position 5665 in exon 5 and leads to the replacement of the amino acid lysine with asparagine in the 198th codon of Table 1: The biomedical and clinical characteristics of the study womenVariables Value variables, Ме (Q25‑Q75)Pregnant women without preeclampsiaPregnant women with preeclampsiaNumber 205 382Age, year 26.7 (24.0–30.0) 27.2 (25.0–31.0)Height, m 1.57 (1.54–1.60) 1.65 (1.62–1.68)Weight, kg 70.0 (59.0–81.7) 79.3 (71.6–90.4)BMI, kg/m2 23.0 (21.2–26.9) 29.2 (26.4–33.8)SBP, mmHg 110.0 (110.0–120.0) 140.0 (135.0–150.0)DBP, mmHg 70,0 (70.0–75.0) 90.0 (85.0–100.0)PBP, mmHg 40.0 (40.0–40.0) 50.0 (50.0–60.0)MAP, mmHg 85.0 (83.3–90.0) 106.7 (103.3–116.7)∆MAP, mmHg 5.0 (0.0–10.0) 25.0 (20.0–35.0)∆SBP, mmHg 0.0 (0.0–10.0) 20.0 (10.0–25.0)∆DBP, mmHg 3.3 (0.0–8.3) 20.0 (13.3–28.3)BMI: Body mass index, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, PBP: Pulse blood pressure, MAP: Mean arterial pressure, Δ MAP: Change of mean arterial pressure, ΔSBP: Change of systolic blood pressure, ΔDBP: Change of diastolic blood pressureReshetnikov, et al.: Genetic Determinants of Complicated PregnancyAsian Journal of Pharmaceutics • Oct-Dec 2018 (Suppl) • 12 (4) | S1322the polypeptide encoded by the gene (rs5370).[20] As some studies show, this polymorphism is associated with the plasma content of endothelin 1 in women during pregnancy.[21,22] It has been established that carriers of the allele T EDN1 have a higher level of endothelin 1 in the blood plasma compared to subjects with the genotype GG EDN1. In contrast, the study by Tanaka et al.[23] showed that plasma amounts of endothelin-1 in patients with essential hypertension do not differ in individuals with the allele T EDN1 and the genotype GG EDN1.[23]Perhaps, the polymorphism of the gene EDN1 rs5370 is in close adherence to another SNP that provides an impact on blood pressure values.The study conducted on the Mexican population has established the protective effect of this polymorphism on the development of PE.[24] Similar results were obtained in a study on the polish population.[25]The observed inconsistency in the above results may be related to interpopulation and interethnic differences in the frequencies of alleles of polymorphism EDN1 rs5370.[26,27]CONCLUSIONSThus, as a result of the study, the relationships of the genetic polymorphisms of vasoactive hormones with the level of blood pressure in women with PE were revealed. Women with genotypes GG and GT EDN1 (rs5370) have higher values of systolic, diastolic, and mean arterial pressure at the end of pregnancy.Data obtained as a result of the research broaden the understanding of the mechanisms of preeclampsia development, and also allows prediction the nature of the clinical course of the disease, which will ensure the optimization of the treatment and diagnostic process for each patient.REFERENCES1. Sidorova IS, Nikitina NA. Pre-eclampsia in the practitioner’s focus. Obstet Gynecol 2014;6:4-9.2. Gureev VV, Martynova OV, Anciferova OE, Martynov MA, Pokrovskaya TG, Malorodova TN, et al. Correction of adma-induced preeclampsia with the use of phosphodiesterase 5 and selective inhibitor of arginase II ZB49-0010. Res Result Series Med Pharm 2015;4:66-8.3. Zhou L, Cheng L, He Y, Gu Y, Wang Y, Wang C. Association of gene polymorphisms of FV, FII, MTHFR, SERPINE1, CTLA4, IL10, and TNFalpha with pre-eclampsia in Chinese women. Inflamm Res 2016; 65;717-24.4. Simanaov IV. Timing of the main clinical symptoms of Table 2: Association rs5370 polymorphism of the endothelin 1 gene with indicators of blood pressure in women at the end of pregnancy, Me (Q25‑Q75)Values of blood pressure Genotypes РGG+GT TTPregnant women without preeclampsia (PE) (n=205)N 195 10SBP, mmHg 110.0 (110.0–120.0) 110.0 (110.0–115.0) 0.3DBP, mmHg 70.0 (70.0–80.0) 70.0 (70.0–75.0) 0.8PBP, mmHg 40.0 (40.0–45.0) 40.0 (30.0–40.0) 0.3MAP, mmHg 85.0 (83.3–90.0) 83.3 (83.3–83.3) 0.4∆MAP, mmHg 3.3 (0.0–8.3) 0.8 (0.0–6.6) 0.4∆SBP, mmHg 5.0 (0.0–10.0) 0.0 (0.0–10.0) 0.3∆DBP, mmHg 0.0 (0.0–10.0) 0.0 (0.0–5.0) 0.7Pregnant women with PE (n=382)N 377 5SBP, mmHg 140.0 (135.0–150.0) 130.0 (130.0–140.0) 0.04DBP, mmHg 90.0 (85.0–100.0) 80.0 (80.0–80.0) 0.02PBP, mmHg 50.0 (50.0–60.0) 50.0 (50.0–55.0) 0.8MAP, mmHg 106.7 (103.3–116.7) 100.0 (96.7–103.3) 0.01∆MAP, mmHg 20.0 (13.3–28.3) 20.0 (6.7–20.0) 0.2∆SBP, mmHg 25.0 (20.0–40.0) 20.0 (20.0–20.0) 0.1∆DBP, mmHg 20.0 (10.0–25.0) 15.0 (5.0–20.0) 0.2BMI: Body mass index, SBP: Systolic blood pressure, DBP: Diastolic blood pressure, PBP: Pulse blood pressure, MAP: Mean arterial pressure, Δ MAP: Change of mean arterial pressure, ΔSBP: Change of systolic blood pressure, ΔDBP: Change of diastolic blood pressureReshetnikov, et al.: Genetic Determinants of Complicated PregnancyAsian Journal of Pharmaceutics • Oct-Dec 2018 (Suppl) • 12 (4) | S1323pre-eclampsia at the present stage. Res Result Series Med Pharm 2017;3:51-6.5. Eiland Е, Nzerue C. Marquetta faulkner. Preeclampsia 2012. J Pregnancy 2012;2012:576-86.6. Duley L. The global impact of pre-eclampsia and eclampsia. Semin Perinatol 2009;33:130-7.7. Abalos E, Cuesta C, Carroli G, Qureshi Z, Widmer M, Vogel JP, et al. Pre-eclampsia, eclampsia and adverse maternal and perinatal outcomes: A secondary analysis of the world health organization multicountry survey on maternal and newborn health. BJOG 2014; 121 Suppl 1:14-24.8. Pinheiro MB, Gomes KB, Ronda CR. Severe preeclampsia: Association of genes polymorphisms and maternal cytokines production in Brazilian population. Cytokine 2015;71:232-7.9. Uma R, Forsyth JS, Struthers AD, Fraser CG, Godfrey V, Murphy DJ. Polymorphisms of the angiotensin converting enzyme gene in relation to intrauterine growth restriction. Acta Obstet Gynecol Scand 2010;89:1197-201.10. Bell MJ, Roberts JM, Founds SA, Jeyabalan A, Terhorst L, Conley YP. Variation in endoglin pathway genes is associated with preeclampsia: A case-control candidate gene association study. BMC Pregnancy Childbirth 2013;1:82.11. Alpoim PN, Gomes KB, Pinheiro MB, Godoi LC, Jardim LL, Muniz LG, et al. Polymorphisms in endothelial nitric oxide synthase gene in early and late severe preeclampsia. Nitric Oxide 2014;15:19-23.12. Mistry HD, Gill CA, Kurlak LO, Seed PT, Hesketh JE, Méplan C, et al. SCOPE consortium, association between maternal micronutrient status, oxidative stress, and common geneticvariants in antioxidant enzymes at 15 weeks׳ gestation in nulliparous women who subsequently develop preeclampsia. Free Radic Biol Med 2015;78:147-55.13. Polonikov AV, Ushachev DV, Ivanov VP, Churnosov MI, Freidin MB, Ataman AV, et al. Altered erythrocyte membrane protein composition mirrors pleiotropic effects of hypertension susceptibility genes and disease pathogenesis. J Hypertens 2015;33:2265-77.14. Reshetnikov EA, Akulova LY, Dobrodomova IS, Dvornyk VY, Polonikov AV, Churnosov MI. The insertion-deletion polymorphism of the ACE gene is associated with increased blood pressure in women at the end of pregnancy. J Renin Angiotensin Aldosterone Syst 2015;16:623-32.15. Polonikov AV, Bushueva OY, Bulgakova IV, Freidin MB, Churnosov MI, Solodilova MA, et al. A comprehensive contribution of genes for aryl hydrocarbon receptor signaling pathway to hypertension susceptibility. Pharm Genomics 2017;27:57-69.16. Pickering TG, Hall JE, Appel LJ. Recommendations for blood pressure measurement in humans and experimental animals. Part 1: Blood pressure measurement in humans a statement for professionals from the subcommittee of professional and public education of the American heart association council on high blood pressure research. Hypertension 2005;45:142-61.17. ACOG Committee on Practice Bulletins-Obstetrics. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Obstet Gynecol 2002;99:159-67.18. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 1988;16:1215.19. Ponomarenko IV. Otbor polimorfnykh lokusov dlya analiza assotsiatsiy pri genetiko-epidemiologicheskikh issledovaniyakh [Selection of polymorphic loci for association analysis in genetic-epidemiological studies]. Res Result Med Pharm 2018;4:38-52.20. Ahmed M, Rghigh A. Polymorphism in endothelin-1 gene: An overview. Curr Clin Pharm 2016;11:191-210.21. Barden AE, Herbison CE, Beilin LJ, Michael CA, Walters BN, van Bockxmeer FM. Association between the endothelin-1 gene Lys198Asn polymorphism blood pressure and plasma endothelin-1 levels in normal and pre-eclamptic pregnancy. J Hypertens 2011; 19:1775-82.22. Aggarwal PK, Jain V, Srinivasan R, Jha V. Maternal EDN1 G5665T polymorphism influences circulating endothelin-1 levels and plays a role in determination of preeclampsia phenotype. J Hypertens 2009;27:2044-50.23. Tanaka C, Kamide K, Takiuchi S, Kawano Y, Miyata T. Evaluation of the Lys198Asn and -134delA genetic polymorphisms of the endothelin-1 gene. Hypertens Res 2004;27:367-71.24. Galaviz-Hernandez C, Arámbula-Meraz E, Medina-Bastidas D, Sosa-Macías M, Lazalde-Ramos BP, Ortega-Chávez M, et al. The paternal polymorphism rs5370 in the EDN1 gene decreases the risk of preeclampsia. Pregnancy Hypertens 2011;6:327-32.25. Seremak-Mrozikiewicz A, Barlik M, Perlik M, Kurzawińska G, Drews K. Genetic variability of endothelin-1 system in gestational hypertension and preeclampsia. Ginekol Pol 2011;82:363-70.26. Litovkina O, Nekipelova E, Dvornyk V, Polonikov A, Efremova O, Zhernakova N, et al. Genes involved in the regulation of vascular homeostasis determine renal survival rate in patients with chronic glomerulonephritis. Gene 2014;546:112-6.27. Rudyh NA, Sirotina SS. Geneticheskie sootnosheniya russkih i ukrainskih populyaciy Belgorodskoy oblasti [Genetic interrelations of Russian and Ukrainian populations of Belgorod region]. Res Result Med Pharm 2015;1:72-9.Source of Support: Nil. Conflict of Interest: None declared.

Genetic determinants of complicated pregnancy

http://dspace.bsu.edu.ru/bitstream/123456789/28286/1/Reshetnikov_Genetic_deter_18.pdf

Genetic determinants of complicated pregnancy

Abstract

Similar works

Full text

Available Versions

DSpace at Belgorod State University