Original
©2018 Dustri-Verlag Dr. K. Feistle ISSN 0946-2104DOI 10.5414/TEX01542
e-pub: ■■month ■■day, ■■year
Accepted for publication June 6, 2018
Correspondence to Assoc. Prof. Dr. Fatma Behice Serinkan Cinemre Sakarya University, Medical Faculty, Department of Medical Biochemistry, 54290 Sakarya, Turkey cinemreb@gmail.com Key words pre-eclampsia – SEPW1 gene polymorphism – selenium – selenopro-tein W
Association of selenoprotein W1 (rs3786777)
polymorphism, maternal plasma selenoprotein
W (SelW), and selenium levels in patients with
pre-eclampsia
Fatma Behice Serinkan Cinemre1, Hakan Cinemre2, Elif Erdoğan3,
Nilgun Dilaveroglu4, Abdullah Tüten5, Barıs Kaya6, Nevin Yılmaz5, Tevfik Gulyasar7,
Mustafa Yıldız7, Nurten Bahtiyar8, Ali Rıza Kızıler9, and Birsen Aydemir3
1Department of Biochemistry, 2Department of Internal Medicine, 3Department of Biophysics, Medical Faculty, Sakarya University, Sakarya, 4Medical Biochemistry, 5Department of Obstetrics and Gynecology, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, 6Department of Obstetrics and Gynecology, Faculty of
Medicine, Near East University, Lefkoşa-TRNC, Mersin, 7Department of Biophysics, Medical Faculty, Trakya University, Edirne, 8Department of Biophysics, Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, and 9Department of Biophysics, Medical Faculty, Namık Kemal University, Tekirdag, Turkey
Abstract. Objective: To investigate the
role of selenoprotein W1 (SEPW1) single nucleotide polymorphism (SNP) in etio-pathogenesis of pre-eclampsia (PE) and its association with maternal selenoprotein W (SelW) and selenium levels. Materials and methods: In this study, 98 pregnant wom-en who were diagnosed with PE and 100 healthy pregnant controls were investigated. To identify the polymorphism of the SEPW1 gene (rs3786777), allele-specific polymerase chain reaction (ASPCR) analysis was used. Serum selenium levels and plasma SelW levels were measured by graphite-furnace atomic absorption spectrophotometry and by ELISA, respectively. Results: Maternal se-lenium levels (µg/L) were 92.56 ± 6.10 and 86.26 ± 6.33 in pregnant women with and without PE, respectively (p > 0.05). On the other hand, SelW levels (ng/mL) were sig-nificantly lower in PE (72.08 ± 8.10) com-pared to controls (89.29 ± 6.99) (p < 0.01). The frequencies of the CC, CA, and AA genotypes were found to be 26%, 61%, and 13% in pregnant women with PE and 28%, 55%, and 17% in healthy pregnant controls. The distribution of the SEPW1 genotypes and alleles did not differ significantly among subjects with and without PE. In PE patients, SelW levels were lower in CC and CA gen-otypes compared to controls (p < 0.05 and p < 0.001). Conclusion: SEPW1gene poly-morphism did not seem to affect risk of PE in our population. However, SelW levels were low in some genotypes of the gene, suggest-ing that SelW might have played a role in the etiopathogenesis of PE.
Introduction
Pre-eclampsia (PE) is a hypertensive dis-order of human pregnancy and a major cause of maternal as well as perinatal mortality and morbidity [1]. It affects about 2 – 8% of preg-nancies worldwide [2, 3]. Its etiology and pathogenesis have not been explained thor-oughly, and no effective treatment has been found yet. Well-known risk factors for the occurrence of PE include medical conditions like diabetes mellitus, metabolic syndrome, renal disease, chronic hypertension, and hy-percoagulable states; obstetrical conditions including multifetal gestation and mole hy-datidiform and some genetic factors as well as nulliparity [4, 5]. Several genes have been shown to be associated with occurrence, pro-gression, and severity of PE disease.
Selenium is part of [■■■ Please check
changes made] the structure of
selenopro-teins that, in turn, play a role in oxidoreduc-tion reacoxidoreduc-tions [6]. Selenoproteins and seleni-um are important in the response to oxidative stress and redox imbalance and also play im-portant roles in the regulation of various met-abolic and developmental processes [6]. Se-lenium and selenoprotein blood levels have been found to be biomarkers for oxidative stress-associated diseases such as cardiovas-cular diseases [7, 8]. Selenium is essential in the synthesis of many selenoproteins
includ-ing the endogenous antioxidants glutathione peroxidase and thioredoxin reductase [9, 10], selenoproteins S, P, and W as well as iodo-thyronine deiodinases [11]. Several studies have shown an association of selenoproteins W (SelW) with fetal development [12]. Al-though SelW function is not completely elu-cidated yet, SelW have been reported to be expressed in fetal muscle and heart [13]. It [■■■ What?] reflects fetal selenium status, which is closely correlated with selenium content of the soil [14].
Spanning ~ 6.3 kb and comprising six exons, the human SelW locus was shown to map to chromosome 19q13.3 [15]. This lo-cus has not yet been identified to be related to any human syndrome. However, its spe-cific expression in the muscle tissue during proliferation suggests that it is involved in muscle development. Some have suggested that SelW might have a redox function. The glial cells over expressing SelW had greater survival rates compared to controls [16]. Hy-drogen peroxide exposure was reported to induce an immediate SelW-related response in proliferating myoblasts [17]. A pathophys-iological mechanism of pre-eclampsia has been suggested to be associated with oxida-tive stress, which, in turn, leads to increased incidence of maternal and fetal complica-tions in PE. Antioxidant roles of selenium and selenoproteins suggest that their circulat-ing levels and/or gene polymorphisms might play a role in the development of PE. Thus, in this study, our objective was to investigate whether SEPW1 gene polymorphism was a risk factor for pre-eclampsia and its associa-tion with maternal SelW and selenium levels.
Materials and methods
This study included 198 primiparous singleton pregnant women presenting to a
university hospital [■■■ Which one?]
Gy-necology and Obstetrics Department from July 2014 to December 2016. Among these, 98 women were diagnosed with PE and the remaining 100 women were taken as healthy controls. Gestational age was established on the basis of menstrual dates and confirmed by first-trimester ultrasonography. Differen-tial diagnosis of PE was made according to the current American College of Obstetri-cians and Gynecologists (ACOG) guidelines
[18]. These guidelines define PE as sustained pregnancy-induced hypertension with pro-teinuria. Protocol of screening and diagnosis of PE were adapted from the guidelines and protocols from the Department of Obstetrics and Gynecology, Cerrahpasa Medical Fac-ulty, Istanbul University, Istanbul, Turkey. Hypertension was defined as sustained blood pressure readings of ≥ 140/90 mmHg (with reading taking place > 6 hours apart). ACOG defines proteinuria as urine protein concen-trations of ≥ 300 mg/day (or 1+ on a urine dipstick) on two or more random specimens collected > 4 hours apart. All of the subjects were submitted to uterine artery Doppler and maternal echocardiography at 24 weeks ges-tation. All participants, patients, and healthy controls were from Istanbul and of Turkish origin. Exclusion criteria for all subjects were tobacco use, twin pregnancies, pre-existing maternal chronic medical prob-lems, chromosomal or suspected ultrasound fetal abnormalities, maternal heart disease, use of antihypertensive medication, diabe-tes mellitus, and renal disease at the 1-year follow-up visit. Patients were followed until term to verify the fetoneonatal and maternal outcomes. The evolution of gestation was followed until term by an investigator who was blinded to the results of maternal echo-cardiography. All participants were informed about the survey and freely signed and dated the consent forms. The protocol was ap-proved by the Ethics Committee of Medical Faculty in Sakarya University and was con-ducted in accordance with the Declaration of Helsinki (16214662/050.01.04/65).
Medications were ceased at least 24 hours before blood collection. Blood samples were collected in EDTA-containing tubes and plain biochemistry tubes after an overnight fast. After immediate centrifugation (3,000×g) for 10 minutes at 4 °C, plasma samples were separated in Eppendorf tubes and frozen im-mediately at –80 °C and kept so until analy-sis. Routine biochemical parameters were measured by enzymatic colorimetric meth-ods with commercially-available kits (Cobas 8000, Roche Diagnostics GmbH, Mannheim, Germany).
All reagents were of analytical reagent grade. High-purity deionized water (resistiv-ity 18.2 MΩ cm–1) obtained from a Milli-Q water purification system (Millipore,
Bed-ford, MA, USA) was used throughout. All glassware was cleaned by immersion in 20% (v/v) HNO3 for 48 hours, washed three times
with ultrapure water, and then dried before use. Se stock standard was prepared in 5% HCl (v/v) as from a stock solution contain-ing 1,000 mg/L (Merck, Darmstadt, Ger-many). The analytical curves were prepared using the standard solution in the following concentration intervals: 0.01 – 0.5 mg/L for selenium. The serum selenium levels were measured by a graphite-furnace atomic ab-sorption spectrophotometry (Shimadzu AAS-6800, Tokyo, Japan) after diluting with
3 mL of 1% HNO3 (65%) and 1 mL of 1.5%
HClO4 (70%) (Merck, Darmstadt, Germany)
and complete total volume 25 mL with ul-tra-pure water. The analytical lines of AAS [■■■Full term] determinants in selenium analyses were 196.0 nm. Results were calcu-lated as µg/L in serum samples.
Plasma SelW levels were measured by enzyme-linked immunosorbent assay (ELISA) using commercially available kit method (Prod. No: YHB3518Hu; ELISA kits from Shanghai YeHua Biological Technol-ogy Co., Ltd. Gical TechnolTechnol-ogy Co., Ltd, Shanghai, China), and the intra- and interas-say variability’s of the ELISA kits were 8.4% and 8.9%, respectively.
Blood for DNA isolation was collected into EDTA-containing tubes, and DNA was extracted from peripheral blood leukocytes using a commercial kit (Invitrogen Life Technologies Corporation, Carlsbad, CA, USA). Isolated DNA samples were stored frozen at –80 °C. Genotyping for the SEPW1 (rs3786777) gene polymorphism was
per-formed by allele-specific PCR (ASPCR) method. The primer pairs were as follows:
Common primer: 5’ – TCTGGAC-CATACTGGCTTAC – 3’
Primer C (normal allele binding primer): 5’ – ATGAACCTCAGGAACAGC– 3’
Primer A (mutant allele-binding primer): 5’ – ATGAACCTCAGGAACAGA – 3’
These primers result in a PCR product of 79 bp. Primers were synthesized at DNA Technologies A/S, Aarhus, Denmark. The PCR reaction mixture contained 50 ng DNA template, 0.4 µM of each primer, 1X PCR buffer, 0.2 mM of each dNTP, and 1 U Taq DNA polymerase (Sigma, St. Louis, MO, USA). The steps involved include an initial denaturation at 95 °C for 5 minutes, fol-lowed by 35 cycles of denaturation at 94 °C for 30 seconds, primer annealing at 55 °C for 30 seconds, and elongation at 72 °C for 30 seconds. The final amplicon extension was performed at 72 °C for 5 minutes. The amplified PCR products were separated on 3% agarose gel in 1x Tris borate EDTA buf-fer followed by staining with ethidium bro-mide solution. The rs3786777 genotypes were identified by visualization under ultra-violet light.
SPSS Statistic 17.0 program was used for the analyses of the patients and control val-ues. Hardy-Weinberg equilibrium was tested by χ2-analysis. Genotype and allele
frequen-cies were compared between cases and con-trols by χ2-analysis. Odds ratio (OR) and
respective 95% confidence intervals (CIs) were reported to evaluate the effects of any difference between allelic and genotype dis-tribution. Results are reported as mean ± SD and mean ± SE. Mann-Whitney U-test and t-test were performed for the analysis of clinical characteristics and biochemical pa-rameters. To compare the effect of SEPW1 (rs3786777) genotypes on the levels of plasma SelW and serum Se, Mann-Whitney U-test was used. A two-sided p-value ≤ 0.05 was considered statistically significant.
Results
The ages of patient and control groups were not statistically different (mean ± SD, 32.11 ± 5.98 vs. 31.87 ± 5.85 years, p > 0.05).
Table 1. Clinical characteristics and biochemical parameter values of the PE and healthy pregnant group (M ± SE).
Parameters Control group
(n = 100) PE group(n = 98) Systolic blood pressure (mmHg) 110.21 ± 5.54 151.26 ± 6.79*** Diastolic blood pressure (mmHg) 70.76 ± 3.82 109.52 ± 5.42*** Body mass index (kg/m2) 28.21 ± 1.02 32.41 ± 1.12***
Fetal weight (g) 3,216.54 ± 140.17 1,924.69 ± 430.19** Total protein (g/dL) 6.72 ± 0.22 6.12 ± 0.27** Albumin (g/dL) 3.89 ± 0.21 3.21 ± 0.39** Selenium (µg/L) 86.26 ± 6.33 92.56 ± 6.10 SelW (ng/mL) 89.29 ± 6.99 72.08 ± 8.10** PE = pre-eclampsia. **p-values (p < 0.01); ***p-values (p < 0.001) are from the t-test.
The clinical characteristics of subjects in-cluded in the present study are summarized in Table 1. We found that fetal weight, total protein, and albumin levels were significant-ly lower in pre-eclamptic pregnant women compared to healthy controls (p < 0.01, for each). Systolic and diastolic blood pressure as well as body mass index were signifi-cantly higher in the patient group compared to controls (p < 0.001, for each). Maternal selenium levels were 92.56 ± 6.10 µg/L and 86.26 ± 6.33 µg/L in PE and healthy preg-nant women, respectively (p > 0.05). SelW levels were found to be significantly higher in women with PE (72.08 ± 8.10 ng/mL) compared to controls (89.29 ± 6.99 ng/mL) (p < 0.01). However, there was no significant difference in serum selenium levels between the two groups. The SEPW1 (rs3786777) gene polymorphism was successfully geno-typed in 98 women with PE and 100 control subjects. Frequencies of SEPW1 genotypes and alleles that were observed in patients with PE and healthy pregnant women are shown in Table 2. The frequencies of the CC, CA, and AA genotypes were found to be 26%, 61%, and 13% in pregnant women with PE and 28%, 55%, and 17% in healthy preg-nant women, respectively. Our results indi-cated that the distribution of the SEPW1 gen-otypes and alleles did not differ significantly among pregnant women with and without PE (p > 0.05). On the other hand, SelW levels were lower in CC and CA genotypes of the gene in PE patients compared to their tive control (p < 0.05 and p < 0.001, respec-tively) (Figure 1). There was no significant difference in selenium levels between patient and control groups according to the same genotypes (p > 0.05) (Figure 2).
Table 2. Distribution of genotypes and allele frequencies of SEPW1 (rs3786777) polymorphism in pa-tients with PE and control group.
Gene PE patient group
n (%) Healthy pregnant womenn (%) p OR (CI 95%) SelW1 polymorphism 98 100 Genotypes CC 25 (26) 28(28) 1 CA 60 (61) 55 (55) 0.547 0.818 (0.427 – 1.570) AA 13 (13) 17 (17) 0.736 1.168 (0.474 – 2.875) Alleles C 110 (56) 111 (56) 1 A 86 (44) 89 (44) 0.901 1.026 (0.690 – 1.525)
Figure 1. The levels of SelW in subjects with pre-eclampsia (PE) and controls according to SEPW1 (rs 3786777) polymorphism. Data were presented as mean ± SE; *p-values (p < 0.05); ***p-values (p < 0.001) are from the Mann-Whitney U-test.
Figure 2. Levels of selenium in subjects with pre-eclampsia (PE) and controls according to SEPW1 (rs 3786777) polymorphism. Data were presented as mean ± SE.
Discussion
In the present study, we investigated the role of SEPW1 single nucleotide poly-morphism and its association with maternal SelW and selenium levels in etiopathogen-esis of PE. Fetal weight, total protein, albu-min levels of pre-eclamptic pregnant women were found to be lower than those of healthy pregnant women. We found that selenium levels did not change in pregnant women with PE. However, SelW levels were lower in women with PE, compared to the controls. Although SEPW1 polymorphism did not alter the risk of PE in our population, SelW levels were lower in CC and CA genotypes of the gene compared to their respective controls. In the literature, there is no study investigating the relationship between SelW levels, selenoprotein gene polymorphisms, and PE risk. To the best of our knowledge, we showed, for the first time, that SelW pro-tein levels decreased in pregnant women with PE, suggesting that SelW might play a role in the development of PE. Moreover, we found that CC and CA genotypes of SEPW1 gene polymorphism might be involved in the development of PE.
As an essential trace element, selenium is a constitutional component of selenopro-teins. In the present study, selenium levels did not differ significantly in pre-eclamptic pregnant women. There are conflicting re-sults about selenium concentration in pre-ec-lampsia. In a previous study, we investigated changes in selenium and selenoprotein K in pre-eclamptic patients [19] and reported that selenium levels did not change in PE. Ghae-mi et al [20]. found lower selenium levels in women with pre-eclampsia compared to healthy pregnant women in an Iranian popu-lation. Atamer et al. [21] have found simi-lar results among Turkish women with PE. daSilva et al. [22] reported that serum sele-nium levels were not different in PE patients compared to controls. There are several more studies in the literature reporting that seleni-um levels did not differ in PE compared to healthy pregnant women, in agreement with our study [23, 24].
Studies showed that serum selenium con-centration decreases during pregnancy [25], suggesting an increased selenium demand by the developing fetus as well as an increased
blood volume of the pregnant women [25]. Mohammadzadeh et al. [26] showed higher selenium levels in cord blood compared to that of pregnant women.
SelW is a small (87 amino acid) selenopro-tein. In the heart and muscle, SelW was found to be at the highest concentrations. These tis-sues are among those most affected in selenium deficiency disorders [27, 28, 29]. Although, the significance of its role has not been elucidated thoroughly yet, SelW, as a selenoprotein, might play an important role in these tissues [30] with its antioxidant and redox functions, as have been reported in an increasing number of stud-ies. Although the etiology of pre-eclampsia has not been fully understood yet, its relation to oxidative stress has been well demonstrated [31, 32]. It is a well-known fact that oxidative stress results from imbalances of antioxidant systems and free-radical concentrations that lead to changes in cell function. To the best of our knowledge, there are no studies in the lit-erature reporting an association between SelW and pre-eclampsia. In the present study, we found, for the first time, lower SelW levels in PE compared to controls. Furthermore, SelW levels were lower in CC and CA genotypes of the gene compared to their respective controls, even though the frequencies of SEPW1 gene polymorphism were not different in PE pa-tients. However, our study was not designed to investigate a causal relationship, and the under-lying molecular mechanisms of SelW associa-tion with PE should be investigated by further studies.
SEPW1 polymorphisms have been stud-ied in patients with colorectal and bladder cancers [33, 34]. Decreased SelW expres-sion, together with some other selenopro-teins, was found in gastric cancer [35]. Its role in etiopathogenesis of cancer may be re-lated to prevention of oxidative damage and maintenance of redox state. However, it has been reported that SEPW1 depletion induced retardation in G1/S transition of cell cycle in breast cancer and prostate epithelial cells [33, 36, 37]. This effect of SEPW1 depletion was not related with losing antioxidant pro-tection. The antioxidant role of SEPW1 may not be the main function of this selenoprotein [38]. The SEPW1 gene polymorphism was not related to risk of PE in our study.
This study has some limitations. One of them was the relatively small sample size in
the patient and control groups. Also, as the samples were recruited from the same cen-ter, the results may not be representative of the population. As the complex interaction of multiple factors play a role in the develop-ment of PE, this point should be taken into account in the interpretation of our results.
In conclusion, SEPW1 (rs3786777) poly-morphism seems to not alter the risk of PE in our study population. Although the frequen-cy of SEPW1 polymorphism and selenium levels did not change, SelW protein levels decreased in pregnant women with PE, and this suggests that SelW might play a role in etiopathogenesis of PE. Moreover, CC and CA genotypes of SEPW1 gene polymor-phism may be involved in the development of PE with a different mechanism, and this should be further studied.
Acknowledgment
This study has been partly presented in the Journal of Human Rhythm in March 2017; 3(1): pages 68-73 of the University of Sakarya, Medical Faculty, Sakarya, Turkey.
Funding
The authors have no financial relation-ships relevant to this article to disclose.
Conflict of interest
The authors declare that they have no conflicts of interest related to the publication of this manuscript.
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