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Ashurova Umida, Najmutdinova Dilbar, Republican Specialized Scientific and Practical Medical Center of Obstetrics and Gynecology Tashkent, Uzbekistan E-mail: [email protected]
GENETIC PREDISPOSITION FOR PREGNANCY HYPERTENSIVE DISORDERS OF UZBEK WOMEN
Abstract: In this study was evaluated the association ofAGT T704C polymorphisms with pregnancy hypertensive disorders among Uzbek women. Two hundred and one women with PHDs and 110 age-matched controls were included in the study. Among 201 PHDs patients, 41 women were with chronic hypertension, 110 women with gestational hypertension and 50 women with preeclampsia. The mutant heterozygous genotypes C/T were found more common in women with chronic hypertension. The homozygous mutant C/C genotypes ofAGT polymorphism also were found common in preeclamsia patients compared to controls. In our study, we have found out predisposition to chronic hypertension and pre-eclampsia of AGT polymorphism, but not to gestational hypertension.
Keywords: pregnancy hypertensive disorders, chronic hypertension, gestational hypertension, preeclampsia, angiotensinogen, gene polymorphism.
Introduction. Pregnancy hypertensive disorders (PHDs), mainly including gestational hypertension (GH), pre-eclampsia (PE), severe pre-eclampsia and eclampsia, are a major contributor to maternal, fetal, and neonatal morbidity and mortality [1]. PHDs have been estimated to complicate 5% of all pregnancies and 11% of first pregnancies, half associated with PE, and accounting for up to 40,000 maternal deaths annually [2]. Previous studies showed that PHDs were the cause of16.1% of maternal deaths in developed countries, 9.1% in Africa, 9.1% in Asia, and 25.7% in Latin America and the Caribbean, respectively [3].
Many risk factors (genetic, nutrition, immunologic, and infectious origins) and their pathologic mechanisms (abnormal placentation, oxidative stress, and endothelial dysfunction) have been proposed, yet this disorder has remained as a ''disease of theories' [4].
The renin-angiotensin-aldosterone system (RAAS) contributes to blood pressure regulation and body fluid through a series of enzymatic reactions induced by its primary components: renin, angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin I (ANG I), angiotensin II (ANG II), angiotensin a receptor type I (AT1R), and angiotensin receptor type 2 (AT2R). In response to low blood pressure and low circulating sodium chloride, renin, synthesized and secreted by juxtaglomerular cells of the afferent renal arterioles, catalyzes the cleavage ofAGT made in the liver to ANG I. This is the rate-limiting step of the renin- angiotensin system (RAS) cascade [5].
Angiotensinogen is an important component of the RAAS system, which is a powerful regulatory system with an effec-
tive influence on salt and water metabolism and blood pressure. AGT is the precursor protein to angiotensin II, which plays a primary role in the regulation of blood pressure by the renin-angiotensin system [6]. The M235T angiotensinogen gene mutation is a single base pair substitution of thymine (T) with cytosine (C) at nucleotide 704 (T704C) in exon 2 of the angiotensinogen gene (chromosome 1q42-43), leading to the substitution of methionine with threonine at amino acid position 235 in the pre proangiotensinogen molecule (M235T). In addition, T235 allele represents the mutant allele, while M235 allele represents the wild type [7, 8]. Jeunemaitre et al. showed that increased concentration of plasma or tissue angiotensinogen in women with variants of angiotensinogen, (for example M235T), can lead to increased baseline or reactive production of angiotensin II, which is final effector hormone of the RA system [8, 9].
In our study, we decided to evaluate the association of AGT T704C polymorphisms with PHDs among Uzbek women.
Methods. This was a case-control study that recruited patients from Republican Specialized Scientific and Practical Medical Center of Ob&Gy in Tashkent, Uzbekistan between June 2015 and June 2017. All patients were Uzbek nationals. For detection of gene polymorphism Q-PCR genotyping was done by DT-Prime 384. A 5 ml of venous blood sample was drawn in ethylene diamine tetra acid vials and DNA was extracted using phenol chloroform method. The genotype analysis was performed at the Scientific Research Institute of Immunology of the Republic of Uzbekistan.
Two hundred and one women with PHDs and 110 age-matched controls were included in the study. Among 201 PHDs patients, 41 women were with chronic hypertension (CH), 110 women with GH and 50 women with PE. They are all were Uzbek nationals. CH was diagnosed as hypertension, which existed before pregnancy or appeared before 20 weeks of gestation, without proteinuria. GH was classified as hypertension after 20 weeks of gestation, systolic blood pressure 90 and more mm Hg and diastolic 140 mm Hg and more, 24h proteinuria less than 0.3 g/L. PE was classed if one of the following were presented: blood pressure more than 140/90 mm Hg, 24h proteinuria > 0.3 g/L, cerebral or visual disturbances, epigastric or right upper quadrant pain, impaired liver function and thrombocytopenia.
Table 1. - Demographic and
Controls included normotensive women with normal pregnancy outcome. Women with concomitant diabetes, gestational diabetes, with renal diseases and multiple pregnancies were excluded. A thorough medical, obstetric and menstrual history were taken, and general physical and obstetrical examination was carried out and recorded in the case questionnaire.
For statistical analysis, we performed chi-square test using SPSS software 13. The genotype and allele frequencies in the cases and controls were compared and a P-value < 0.05 was considered significant.
Results
The demographic and laboratory data of the patients included in this study are shown in (Table1).
laboratory features of patients
Characteristics CH GH PE Controls
n = 41 n = 110 n = 50 n = 110
Age 28.9 ± 5.5 28.7 ± 4.4 28.11 ± 5.1 25 ± 5.1
Elevation of BP at gestational age 12.8 ± 5.16 31.7 ± 5 29.5 ± 8.1 -
GA at delivery 31.7 ± 9 37.24 ± 3 34.7 ± 3 38.2 ± 3
BMI 32.7 ± 4.1 32.9 ± 4.2 31.7 ± 4 30.7 ± 3.1
SBP (mm Hg) 150.8 ± 13.3 145.1 ± 9.7 150.8 ± 10 120.4 ± 10
DBP (mmHg) 99 ± 8 99.8 ± 11 101.2 ± 7.3 75.6 ± 7
Abdominal girth 105.4 ± 13.4 122.4 ± 7.8 105.7 ± 17.1 100.5 ± 9
Proteinuria/24h 0.03 ± 0.07 0.22 ± 0.06 1.43 ± 1.7 -
Infant birthweight 3017.95 ± 862 2981.52 ± 786.8 2140±739 3369±557
Apgar score 7.94 ± 2 7.59 ± 1.97 7.74 ± 2.1 8.2 ± 1.1
Information about parity, history and mode of delivery for CH, GH and PE groups are as follows: nulliparous were 24.4% vs 44.5% vs 52% respectively; uterine scar had 22% vs 23.6% vs 4% women respectively; normal delivery rates were 68.3% vs 56.3% and 14% respectively; C-section were performed to 31.7% vs 43,6% vs 72% respectively; preterm labor were in 17% vs 6.4% vs 60% cases respectively. In our study, hypertension in history was more often for women who developed chronic hypertension compared to patients with GH and PE
Table 2. - Genotype and allelic distributions of the
(29.3% vs 118% vs 4% respectively). This can indicate that women who had PE in her previous pregnancy can developed CH in following gestation. However, for further conclusions there is a need for extensive randomized controlled trials.
The genotype and allelic frequency data for all studied groups are given in (Table 2). The differences in genotype and allelic frequencies of polymorphisms for all groups were unpredic table.
AGT (T704C) polymorphisms examined in the study
Groups Allelic frequency Genotype frequency
C T C/C C/T T/T
n % n % n % n % n %
1. CH (n = 41) 49 59.76 33 40.24 14 34.15 21 51.22 6 14.63
2. GH (n = 110) 160 72.73 60 27.27 63 57.27 34 30.91 13 11.82
3. PE (n = 50) 88 88.0 12 12 39 78.0 10 20.0 1 2.0
4. Controls (n = 110) 172 78.2 48 21.8 71 64.5 30 27.3 9 8.2
The mutant heterozygous genotypes C/T were found more common in women with chronic hypertension (OR2.8, RR1.9, P-value 0.006), compared to controls, which was statistically significant. The same thing were observed with
homozygous genotypes C/C in-group of CH compared to controls (ORO.3, RR0.5, P-value < 0.05). The mutant allele frequencies for AGT gene were also slightly higher in patients with CH, this was proven by statistical significance (OR2.4,
RR2.1, P-value 0.001). As to GH group, there was not found any differences either mutant or wild allelic and genotype distributions compared to controls. Moreover, the homozygous mutant C/C genotypes of AGT polymorphism also were found common in PE patients compared to controls, but this was not statistically significant (OR1.9, RR1.7, P-value 0.09).
In our study, we have found out predisposition to chronic hypertension and pre-eclampsia of AGT polymorphism, but not to gestational hypertension.
Discussions. We found that with T allele and C/T genotype of AGT (T704C) are almost 2 times more likely to develop CH compared with normotensive pregnant women, and C/C genotype predispose to PE, but was not statistically proven. The studies performed by Song et al. in Chinese women [10], Radkov et al. [11], Bouba et al. [12] in NorthWest Greece women and Afshariani et al. [9] in Iranian preeclamptic women revealed an obvious association between AGT (M235T) gene and PE. These workers also found that TT genotype could be considered as high risk genotype for the development of PE. Zafarmand et al. [13] also reported that the allele T and TT genotype of AGT (M235T) were associated with elevated blood pressure during pregnancy in Dutch women. This finding contraindicates to ours, because we find correlation with C/C homozygous genotype and PE. In addition, Procopciuc et al. (2011) proved that the risk of
preeclampsia increased significantly for women homozygous for Met235Thr AGT polymorphisms. Chengweng S. et al. also show that pregnant women carrying the TT genotype of the AGT gene are more at risk for development of PE. This is possibly because RAS in the local tissue can also generate angiotensin in addition to the classic circulation system [14]. The AGT gene, as part of the uterine spiral artery RAS, may be involved in spiral artery remodeling [15]. Therefore, the AGT gene may be a marker for PE pathophysiological changes, suggesting that PE is genetically determined. A meta-analysis involving 17 studies concluded that C allele homozygotes had a 1.62 times higher risk of developing PE [16]. In population-based study of Zafarmand et. al. among women aged 49 to 70 years, they found that individuals with the TT genotype were more likely to have had a history of elevated BP during pregnancy than those with the M genotype. Furthermore, under dominant and additive inheritance models, the AGT M235T polymorphism was associated with increased risk of BP elevation in pregnancy. The AGT T235T genotype may represent a genetic "susceptibility" for hypertensive disorders in pregnancy, chronic hypertension and atherosclerosis in later life [13]. Eventhough, our results controversial with the results of different researches, we can explain it that this may be national identity of Uzbek population. However, we clearly observed genetic predisposition for PHDs among Uzbek women.
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