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The Journal of Maternal-Fetal & Neonatal Medicine Volume 36, 2023 - Issue 2
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Review Article

Association of endothelial nitric oxide synthase gene variants in pre-eclampsia: an updated systematic review and meta-analysis

Endalamaw Tesfaa Department of Biochemistry, College of Medicine and Health Sciences, Bahir Dar University, Bahir Dar, Ethiopia;b Health Biotechnology Division, Institute of Biotechnology, Bahir Dar University, Bahir Dar, EthiopiaCorrespondence[email protected] [email protected]
ORCID Iconhttps://orcid.org/0000-0002-1554-2190View further author information
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Abaineh Munsheab Health Biotechnology Division, Institute of Biotechnology, Bahir Dar University, Bahir Dar, Ethiopia;c Department of Biology, College of Science, Bahir Dar University, Bahir Dar, EthiopiaORCID Iconhttps://orcid.org/0000-0002-1469-2189View further author information
ORCID Icon,
Endalkachew Nibretb Health Biotechnology Division, Institute of Biotechnology, Bahir Dar University, Bahir Dar, Ethiopia;c Department of Biology, College of Science, Bahir Dar University, Bahir Dar, EthiopiaORCID Iconhttps://orcid.org/0000-0002-7063-2877View further author information
ORCID Icon &
Solomon Tebeje Gizawd Department of Biochemistry, College of Health Science, Addis Ababa University, Addis Ababa, EthiopiaORCID Iconhttps://orcid.org/0000-0001-5281-8611View further author information
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Article: 2290918 | Received 27 Apr 2023, Accepted 29 Nov 2023, Published online: 12 Dec 2023

Abstract

Introduction

Three common endothelial nitric oxide synthase (eNOS) gene variants are existed such as; G-894T, T-786C, and variable number tandem repeats in intron-4 (VNTR intron-4) which has been proposed to be linked with PE. However, there is still debate regarding the findings. To address this, a review was conducted to assess the potential association of eNOS gene variants at these positions with the risk of PE.

Methods

PubMed, Scopus, Science Direct, Hinari, and African Journal Online databases and Google Scholar search engines were utilized to search studies published in English-language until 30 January 2023. The Joanna Briggs Institute Meta-Analysis instrument was used for data extraction process and the Newcastle-Ottawa Scale was used to appraise the quality of the included studies. Meta-regression analysis was conducted using Stata 14 statistical software. The pooled odds ratios (ORs) of fixed and random effect models were utilized to evaluate the association of eNOS gene polymorphism with the risk of PE at 95% CI. Publication bias was assessed using Egger’s test and a funnel plot.

Results

The study included 47 observational studies involving 13,795 pregnant women (6216 cases and 7579 controls). Pregnant women carrying TT and CC genotypes of eNOS gene at 894 and 786 positions were found to have a greater probability of developing PE as compared to GG and TT genotypes (OR = 1.54 vs. 1.43 and CI: 1.12 − 2.14 vs.1.02 – 2.00 at 95% CI), respectively. However, a significant association was not observed between aa genotype of eNOS gene in VNTR intron-4 region and risk of PE as compared to bb genotype (OR =1.26, 95% CI: 0.83 – 1.89). The allelic model of eNOS gene at all positions showed nonsignificant association with the risk of PE.

Conclusions

The women having eNOS gene variants at 894 and 786 positions showed a significant association with the risk of PE. Yet, the women having eNOS gene variant at intron-4 region showed nonsignificant association with the risk of PE. Thus, this study suggests that eNOS gene variants may play a role in the development of PE, but large-scale studies are required to inaugurate concrete evidence on the roles of eNOS gene variants in PE pathogenesis.

1. Introduction

Pre-eclampsia (PE) is a pregnancy-related metabolic disorder characterized by hypertension and proteinuria that occurs after 20 weeks of gestation. It complicates approximately 2–8% of pregnancies globally [Citation1]. While maternal deaths have decreased on a global scale from 2000 to 2020, it is still common for maternal and perinatal deaths to occur due to PE [Citation2]. This condition is responsible for approximately 50,000 to 60,000 maternal deaths and 500,000 perinatal deaths each year [Citation3,Citation4]. The incidence of PE is mainly high in low- and middle-income countries [Citation4].

The underlying mechanisms contributing to the pathophysiology of PE are poorly understood, but genetic and environmental factors play significant roles in the pathogenesis of PE [Citation5]. PE is a complex multifactorial disease that occurs at the maternal–fetal interface and affects multiple organs [Citation5]. Placenta is an integral source of PE development which is evidenced by removing the placenta usually resolves the symptoms of the disease [Citation6,Citation7]. PE is caused by placental dysfunction (stage 1), followed by release of factors from the diseased placenta into the maternal circulation (stage 2), inducing widespread endothelial dysfunction that heralds the classic manifestations of the disease [Citation6,Citation8].

Numerous studies have demonstrated that there is genetic predisposition toward PE susceptibility [Citation9,Citation10]. Both maternal and fetal genes are thought to be implicated in PE development [Citation11]. Researchers have utilized candidate gene discovery and genome-wide association studies to identify specific genes associated with PE, but it has proven challenging to establish a single gene that contributes for the disease [Citation12]. This is due to the complex nature of the disease multiple genes are involved in the pathogenesis [Citation13].

Nitric oxide (NO) is a signaling molecule that is synthesized from L-arginine by the nitric oxide synthase (NOS) and involved in endothelium-dependent vasodilation and decrease peripheral vascular resistance in pregnancy [Citation7,Citation14]. NO regulates endothelial function and maintains endothelial-dependent vasodilation in various organs [Citation15]. Maternal endothelial dysfunction is considered as crucial underlying factor that causes the clinical features of PE [Citation16]. NOS gene encodes endothelial nitric oxide synthase (eNOS) which is located in the long arm of chromosome 7 (7q35–q36 region) having 26 exons [Citation17]. There are three isoforms of NOS: neuronal (nNOS or NOS1), inducible (iNOS or NOS2), and endothelial (eNOS or NOS3) [Citation18].

Human eNOS gene is an essential gene that has been significantly associated with several diseases such as PE [Citation19], essential hypertension [Citation20], type 2 diabetes mellitus [Citation21], ischemic stroke [Citation22], coronary artery disease [Citation23], erectile dysfunction [Citation24]. Several studies have been conducted to investigate the associations of eNOS gene variant with PE. A point mutation in exon 7 at 894 position guanine by thymine and in the promoter region thymine by cytosine at 786 position and in intron-4 region 27 base pair variable number tandem repeats (VNTRs) were the common eNOS gene variants linked with PE. However, the results of individual studies were inconclusive, due to inadequate statistical power [Citation25–27]. Thus, a systematic review and meta-analysis are essential to pool the results of the individual studies.

Previously, few systematic reviews were performed to prove the association of eNOS gene variants with the risk of PE [Citation19,Citation28–30]. Yet, previous systematic reviews included the limited number of studies and due to environmental factors and the polygenic nature of the disease precipitate to continue the controversies. Therefore, this updated review was designed to generate comprehensive information regarding the associations of eNOS gene variants with PE by including more published articles to address the gaps of the previous studies.

2. Methods and materials

2.1. Study design and search strategy

A systematic review and meta-analysis of published articles was performed to evaluate the association between eNOS gene polymorphisms and PE. Five electronic databases, including PubMed, Scopus, Science Direct, Hinari, African Journals Online (AJOL), and Google Scholar search engines were utilized to retrieve relevant literatures. A literature search was performed using Medical Subject Heading (MeSH) terms separately or in combination. A literature search was performed as follows: ((("Nitric Oxide Synthase III"[Mesh]) OR eNOS OR NOS3 AND "Genes"[Mesh]) AND "Polymorphism, Single Nucleotide"[Mesh]) OR Allele OR variant OR mutation AND "Pre-Eclampsia"[Mesh] OR pregnancy-induced hypertension OR pre-eclampsia without the restriction of time period, sample size, and population. Further, we performed a manual search of the reference lists of review articles to search necessary articles that were not available in our database searches. All articles published up to 30 January 2023, were saved to evaluate their eligibility. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to conduct the review [Citation31].

2.2. Eligibility criteria

The inclusion criteria for studies were as follows: (1) independent case-control, cohort, or comparative cross-sectional studies; (2) studies that evaluated the association between eNOS gene polymorphisms and PE; (3) studies that provided complete data regarding the genotype number and allele frequencies of eNOS; and (4) studies that were published in English.

The exclusion criteria were as follows: studies with insufficient data on the genotypes and allele frequencies of eNOS, articles published in languages other than English, conference papers, editorials, systematic reviews, and meta-analyses.

2.3. Definition of outcome interest

The primary objective of this study was to evaluate the association between eNOS gene variants and the risk of PE. Hypertension was defined as blood pressure ≥ 140/90 mmHg measured on two occasions at least 4 h apart, whereas severe hypertension was defined as a measured blood pressure of ≥160/110 mmHg. Conversely, proteinuria is defined as urinary protein excretion of ≥300 mg/24 h urine samples or ≥1+ on qualitative dipstick reading and protein/creatinine ratio of ≥0.3 [Citation1,Citation32]. Pre-eclampsia is defined as new onset of hypertension plus proteinuria which diagnosed after 20 weeks of gestation [Citation32,Citation33]. Single nucleotide polymorphisms (SNPs) are variations of single nucleotide at specific positions in the genome [Citation34]. Variable number-tandem repeats (VNTRs) are class of repetitive DNA composed of short DNA sequences repeated many times in the tandem [Citation35]. Here, we evaluate the association of eNOS gene polymorphisms at three positions.

2.4. Study selection and screening

All articles identified by our search strategy were transferred to EndNote X9, and the duplicate articles were excluded. The titles and abstracts of searched studies were screened by two independent reviewers and suitable articles were included for further review. In cases of disagreement among the reviewers, a discussion was conducted to reach a consensus. The full texts of selected studies were retrieved and thoroughly read to ascertain their suitability before data extraction. The results of our search strategy are presented in PRISMA flow chart that shows the included and excluded studies with their reasons for exclusion () [Citation31].

Figure 1. PRISMA diagram shows the included studies of eNOS gene polymorphism of PE.

Figure 1. PRISMA diagram shows the included studies of eNOS gene polymorphism of PE.

2.5. Quality assessment

For case-control studies, we used the Newcastle-Ottawa Scale (NOS) to assess the quality of the studies, and a modified version of the NOS was used to evaluate the quality of the studies for inclusion. NOS were divided into three categorical criteria with a maximum score of nine. The quality of every study was appraised using the following scoring algorism: an article having quality score of ≥7 points were considered as “good” while articles having quality score between 4 to 6 points taken as “fair” and those articles having quality score of ≤3 points were considered as “poor” quality. In this study, we considered articles having good- and fair-quality scores [Citation36].

2.6. Data extraction process

Data extraction was performed using the Joanna Briggs Institute Reviewers’ Manual Data Extraction checklist [Citation37]. The abstract and full texts were reviewed by two independent reviewers. Data extraction included the author’s name, publication year, study design, sample size, country, ethnicity, age, gestational age (GA), body mass index (BMI), fetal weight, laboratory determination methods, proteinuria, systolic blood pressure (SBP), diastolic blood pressure (DBP), genotype, and allele frequency of eNOS G-894T, T-786C, and VNTR intron-4 gene variants were extracted from each article.

2.7. Data analysis and heterogeneity

The data were entered into Microsoft Excel (Microsoft, Redmond, WA, USA), and meta-analysis was performed using Stata 14 statistical software (Stata Corp, College Station, TX, USA). In this review, we used the pooled odds ratio (OR) to evaluate the strength of the association between eNOS gene SNPs and the risk of PE at 95% CI. We analyzed three (G-894T, T-786C, and 4b/a) eNOS gene polymorphisms using four genetic models: allelic model (T vs. G, C vs. T, and a vs. b), homozygote model (TT vs. GG, CC vs. TT, and aa vs. bb), heterozygote model (TG vs. GG, CT vs. TT, and ab vs. bb), additive model (TT + GT vs. GG), (CC + CT vs. TT), and (aa + ab vs. bb) or (TT vs. GT + GG), (CC vs. CT + TT), and (aa vs. ab + bb). Sensitivity and funnel plot asymmetry tests were used to evaluate heterogeneity and publication bias. I2 values of 25%, 50%, and 75% were used to declare the heterogeneity test as low, medium, and high heterogeneity, respectively. The fixed effect model was used for analysis of nonsignificant heterogeneity, while the random effect model was used for those having significant heterogeneity [Citation30]. Subgroup analysis was performed considering the ethnicity (Caucasian, Asian, African, and mixed) and laboratory genotyping methods (PCR-RFLP, PCR-ASO, TaqMan, PCR-AD, ARMS-PCR, and SBE) of eNOS gene polymorphisms in PE and normotensive pregnant women. Factors such as maternal age, GA, BMI, SBP, DBP, fetal weight, allele and genotype variations of eNOS gene polymorphisms were assessed for their association with PE. Results presented in the median and interquartile range were converted into mean and standard deviation according to the formula explained by McGrath et al. [Citation38].

3. Results

3.1. Study selection

In this study, 1318 articles were retrieved through electronic and manual searches using different search terms. After removing 312 duplicate and incomplete records, 1006 articles remained for title and abstract assessment. Out of the 1006 articles screened for eligibility, 940 records were removed by assessing their title and abstract. A total of 66 articles underwent full-text evaluation for eligibility assessment; 19 articles were excluded due to different reasons (nine articles did not report the outcome result, five studies were review articles, three studies were not retrieved, and two studies were excluded due to the absence of sufficient data).

3.2. Study characteristics

In this study, 47 articles were included, of which 44 were case-control studies, while three studies were cross-sectional [Citation17,Citation25–27,Citation39–81]. Studies published up to 30 January 2023, were included. In this review, the smallest sample size was 33 study participants, and the largest sample size was 844 study participants [Citation58,Citation73]. Thirty-nine articles (4,891 cases and 6,310 controls) were used for the evaluation of eNOS G-894T gene polymorphism, 20 articles (3,199 cases and 4,145 controls) were used for the evaluation of eNOS T-786C gene polymorphism, and 23 articles (3,627 cases and 4,099 controls) were used for the evaluation of eNOS VNTR intron-4 gene polymorphisms in PE risk. Overall, in this study, a total of 13,795 study participants (6,216 cases) and (7,579 controls) were included to evaluate the associations of eNOS gene polymorphism with PE ().

Table 1. Characteristics of research articles included in the review (n = 47).

3.3. Association of variables with PE

In this analysis, we compared the mean values of these variables between PE and normotensive pregnant women. There was no statistically significant difference between the two groups with regard to mean maternal age. However, statistically significant differences were observed in the mean values of GA, BMI, fetal weight, SBP, and DBP between cases and controls ().

Table 2. Paired sample test of variables in pre-eclamptic and normotensive pregnant women.

3.4. Association of eNOS gene polymorphism with PE

In this study, for the analysis of SNPs, four genetic models were used: allelic model (T vs. G, C vs. T, and a vs. b), homozygote model (TT vs. GG, CC vs. TT, and aa vs. bb), heterozygote model (TG vs. GG, CT vs. TT, and ab vs. bb), additive model (TT + GT vs. GG), (CC + CT vs. TT), and (aa + ab vs. bb) or (TT vs. GT + GG), (CC vs. CT + TT), and (aa vs. ab + bb). In the homozygote model, women with the TT genotype of the eNOS gene at position 894 had a higher risk of PE than women with GG and TG genotypes (OR = 1.54 and 1.35, 95% CI = 1.20 – 2.14 and 1.03 – 1.76, respectively, with POR = 0.009). In the additive model, women with TT (TT vs. GT + GG) and TT + TG (TT + GT vs. GG) genotypes of the eNOS gene at 894 positions had a higher risk of PE than women with GT + GG and GG genotypes, respectively. In the allelic model, the odds of developing PE were similar in women with T alleles than in those with G alleles of eNOS at 894 position (OR = 1.15, 95% CI = 0.97 – 1.37).

Women with the CC genotype of eNOS gene at 786 position had a higher risk of PE than women with the TT and TC genotypes (OR = 1.43 and 1.26, 95% CI = 1.0 – 2.00, and 1.05 – 1.52, respectively, with POR = 0.035). In the additive model of the eNOS gene at 786 position, women with CC genotypes showed a significantly higher risk of PE in women with TC + TT genotypes (OR = 1.32, 95% CI =1.02 – 1.72) but the odds of developing PE were similar among the women with CC + TC vs. TT genotypes. The odds of developing PE were similar in women with the C and T alleles of the eNOS gene at 786 position (OR =1.49, 95% CI = 0.96 – 2.34). No significant association was observed with the risk of PE with the women having aa genotype and a allele of eNOS gene variant at intron-4 position as compared to the bb genotype and b allele (OR = 1.26 and 1.01, 95% CI = 0.83 − 1.90, and 0.83 – 1.22), respectively. Similarly, the additive model (aa + ab vs. bb and aa vs. ab + bb) showed nonsignificant association with PE (OR =1.16 and 1.28, 95% CI = 0.98 – 1.38 and 0.99 – 1.64), respectively.

The pooled meta-regression analysis showed a statistically significant association with the risk of PE in the women having TT and CC genotypes of eNOS gene at 894 and 786 positions compared to the GG and TT genotypes (OR = 1.54 and 1.43, 95% CI = 1.20 – 2.14 and 1.0 – 2.00), respectively ( and ). Nevertheless, pooled meta-regression analysis of eNOS gene at intron-4 showed nonsignificant association with the risk of PE between aa and bb genotypes (OR =1.26, 95% CI =0.83 − 1.90 ). The allelic model showed comparable risk of PE in the women having T vs. G, C vs. T, and a vs. b alleles at three positions of eNOS gene. In this study, we used random effect model due to the presence of significant heterogeneity. ZOR and p-values of eNOS gene variant in four models at three positions were presented below ().

Figure 2. Association of eNOS G-894T gene polymorphism with PE.

Figure 2. Association of eNOS G-894T gene polymorphism with PE.

Figure 3. Association of eNOS T-786C gene polymorphism with PE.

Figure 3. Association of eNOS T-786C gene polymorphism with PE.

Figure 4. Association of eNOS VNTR intron-4 gene polymorphism with PE.

Figure 4. Association of eNOS VNTR intron-4 gene polymorphism with PE.

Table 3. Association of models of eNOS gene polymorphism in pre-eclamptic and normotensive pregnant women, 2023.

3.4.1. Association of eNOS G-894T gene polymorphism with PE

In this subcategorical analysis, 37 studies were included to evaluate the association between eNOS G-894T gene polymorphism and PE. Eight of the included studies showed a significant association between eNOS G-894T gene polymorphisms and PE [Citation17,Citation25–27,Citation39,Citation40,Citation44–61,Citation64,Citation66,Citation68–70,Citation73–75,Citation77–81]. While 26 studies [Citation26,Citation27,Citation39,Citation44–46,Citation49–54,Citation56,Citation57,Citation60,Citation61,Citation64,Citation66,Citation68–70,Citation77–81] showed nonsignificant associations between eNOS G-894T gene polymorphism and PE but three studies [Citation55,Citation58,Citation75] were excluded from the analysis due to insufficient data. Pooled meta-regression analysis showed that women with TT genotype of eNOS gene at 894 position had higher risk of PE than the women having GG genotype (OR = 1.54, 95% CI: 1.12 – 2.14) ().

3.4.2. Association of eNOS T-786C gene polymorphism with PE

In this section, 19 studies were included to evaluate the association between eNOS T-786C gene polymorphism and PE [Citation17,Citation26,Citation27,Citation39,Citation40,Citation45–47,Citation49,Citation50,Citation55,Citation67–74]. Seven of the included studies showed statistical significant association between eNOS gene at 786 variant and PE [Citation17,Citation26,Citation49,Citation50,Citation71,Citation72,Citation74], whereas 12 studies showed nonsignificant association between the eNOS gene at 786 variant and PE [Citation27,Citation39,Citation40,Citation45–47,Citation55,Citation67–70,Citation73]. Pooled meta-regression analysis showed that the women with CC genotype of eNOS gene at 786 position had higher risk of PE than the women with TT genotype (OR= 1.43, 95% CI: 1.02 – 2.00) ().

3.4.3. Association of eNOS VNTR intron-4 gene polymorphism with PE

In this subcategorical analysis, 23 studies were included to evaluate the association between eNOS gene variant at intron-4 position and PE [Citation26,Citation27,Citation39–42,Citation44–47,Citation49–51,Citation59,Citation64,Citation65,Citation67–70,Citation73,Citation74,Citation76]. Two of the included studies showed a statistically significant association between eNOS VNTR intron-4 gene polymorphism and PE [Citation40,Citation49]. While 19 studies [Citation26,Citation27,Citation39,Citation41,Citation42,Citation45–47,Citation50,Citation51,Citation59,Citation64,Citation65,Citation67–70,Citation73,Citation76] showed nonsignificant association between VNTR intron-4 polymorphism and PE but two studies [Citation44,Citation74] were excluded from the analysis due to insufficient data. The pooled meta-regression analysis of the women with aa genotype of VNTR intron-4b/a showed nonsignificant association with PE compared to the women with bb genotype (OR = 1.26, 95% CI: 0.83 – 1.89) ().

3.5. Subgroup analysis of eNOS gene polymorphism in PE

Subgroup analysis was performed to evaluate the association of eNOS gene polymorphism with the risk of PE through a random effect model using ethnicity and laboratory genotyping methods as subgrouping variables. The subgroup analysis of ethnicity did not show significant association with the risk of PE among different ethnic groups (Caucasian, Asian, African, and Mixed) in regard to the common variants of eNOS gene at 95% CI. The subgroup analysis of PCR-RFLP genotyping methods showed a higher risk of PE (eNOS G-894T and T-786C gene: TT vs. GG: OR = 1.77, 95% CI 1.18 – 2.65, p ≤ .001, and CC vs. TT: OR = 1.86, 95% CI 1.28 – 2.69, p ≤ .001, respectively) than the other genotyping methods. Instead, subgroup analysis of eNOS VNTR intron-4 gene polymorphisms using genotyping methods did not show a statistical significant association with the risk of PE at 95% CI ().

Table 4. Subgroup analysis of homozygote model of eNOS gene polymorphism in pre-eclamptic & normotensive pregnant women, 2023.

3.6. Sensitivity test and publication bias

A sensitivity test was performed by excluding each study at a time to assess the stability of the results. Hence, there was no significant change in the odds ratio after removing each study at the 95% CI. This indicates that no particular study has significantly affected the pooled effects of maternal eNOS gene variants with the risk of PE (Supporting Information S2 file). In this study, owing to high statistical heterogeneity, a random-effect model was utilized for analysis. To rule out the causes of heterogeneity, subgroup analyses by ethnicity and genotyping methods were performed. Publication bias was evaluated using Egger’s test and funnel plot. Egger’s test and funnel plot did not show evidence of publication bias among eNOS G-894T, T-786C, and VNTR intron-4 gene variants with PE (p = .098, .513, and .195), respectively ().

Figure 5. Funnel plot shows the publication bias of eNOS gene polymorphism in PE.

Figure 5. Funnel plot shows the publication bias of eNOS gene polymorphism in PE.

4. Discussion

In this study, 47 articles (6,216 cases and 7,579 controls) were included to evaluate the association of eNOS gene polymorphisms with the risk of PE. The three most common variants of eNOS (G-894T, T-786C, and VNTR intron-4) gene polymorphisms were evaluated for their association with PE risk. This updated systematic review and meta-analysis provides information on the association of eNOS gene polymorphisms with the risk of PE among pre-eclamptic and normotensive pregnant women. Maternal age was comparable between the two groups and did not show an association with PE. The mean gestational age and fetal birth weight were significantly reduced in PE cases compared to controls, but BMI, SBP, and DBP were significantly higher in cases than controls.

In humans, three isoforms of NOS have been identified that are encoded by different genes. iNOS produces high amounts of NO, which participates in host defense, inflammatory stress, and airway epithelial NO formation. However, nNOS and eNOS produce lower NO levels, which are vital for physiological processes, such as neuronal signaling, inhibition of the hemostatic system, vasodilation, and blood pressure control [Citation82]. Currently, several types of eNOS gene variants are recognized, including single nucleotide polymorphisms (SNPs), VNTRs, microsatellites, and insertions/deletions [Citation83]. eNOS is an important regulator of vascular NO production and has been extensively studied to determine their role in PE and other diseases [Citation19,Citation21,Citation22,Citation84]. Variants of exon-7 (G-894T), promoter region (T-786) and intron-4 region have been investigated in numerous studies, but the results are inconsistent [Citation19,Citation21,Citation22,Citation84].

In this study, we found a significant association between eNOS G-894T gene polymorphism and the risk of PE. Three genotypes (GG, GT, and TT) of the eNOS G-894T gene polymorphism were evaluated for their association with PE. Women with mutant TT genotype had higher risk of PE than the women having wild type GG genotype (). Similar results have been reported in previous studies [Citation19,Citation28–30]. However, other few studies have reported nonsignificant associations between eNOS G-894T gene polymorphisms and PE [Citation4,Citation85]. The difference might be attributed to inclusion of small number of studies in previous systematic review and meta-analysis. The eNOS G-894T polymorphism is located in exon 7, resulting in substitution of glutamic amino acid with aspartate amino acid at 298 position. This missense point mutation results reduced vascular NO levels, which is attributable to increased protease-mediated cleavage in endothelial cells and vascular tissue [Citation86].

The eNOS gene promoter polymorphism at the T-786C position reduces promoter activity, in turn affecting eNOS enzyme expression and activity [Citation84]. Our study demonstrated a significant association of eNOS T-786C polymorphism with the risks of PE. Three genotypes (TT, TC, and CC) of eNOS gene at T-786C position was evaluated for their association with PE. Women with CC genotype had higher risk of PE than women with TT genotype (). This may be due to the functional polymorphism of eNOS gene at T-786C positions which leads to decreased expression of the gene product. Similar findings have been reported in previous studies [Citation19]. However, other studies demonstrated that nonsignificant association was observed between CC genotypes of eNOS gene variant at T-786C position with the risks of PE [Citation28,Citation29]. This difference may be attributed to the number of included studies and environmental factors.

In the current meta-analysis, the eNOS VNTR intron-4 gene polymorphism was not significantly associated with the risk of PE in all models. Three genotypes (aa, ab, and bb) of eNOS gene variant of VNTRs were evaluated to determine their association with the risks of PE. Meta-regression analysis of aa genotypes did not show a significant association with the risks of PE compared to bb genotypes (). Similar findings were reported in previous studies [Citation19,Citation28,Citation29]. Currently, eNOS gene VNTR intron-4 polymorphism has gained more attention because of the functional relevance of eNOS activity, and it is divided into two alleles based on the number of repeats: a allele is repeated four times, and b allele is repeated five times.

Subgroup analysis was performed for eNOS gene polymorphisms at three positions based on ethnicity and laboratory genotyping methods. The subgroup analysis demonstrated nonsignificant association of eNOS gene variants with the risk of PE in different ethnic groups (Caucasian, Asian, Mixed, and African). However, previous studies showed significant association between ethnic groups and the risk of PE [Citation19,Citation30]. The subgroup analysis of genotyping methods by PCR-RFLP revealed statistical significant association between TT vs. GG and CC vs. TT genotypes of eNOS gene variant at two positions, respectively (). This might be due to large numbers of studies have been determined by PCR-RFLP methods. In addition, environmental and genetic factors would play for the discrepancy. There was evidence of statistical heterogeneity between eNOS gene variants with PE at three positions in all genetic models.

5. Strengths and limitations

This systematic review and meta-analysis provided updated information on the association of eNOS gene polymorphisms with PE risk by including 13,795 pregnant women. The other strength of this review is performing subgroup analysis by ethnicity and genotyping methods. However, the results of the study should be observed in light of the following limitations: The first limitation of this review has been the included articles lacked nutritional information about pregnant women and their living conditions, which are important components of multifactorial diseases like; PE. Second, our search strategy was limited to articles published in English, and we could not consider articles published in other languages, which could lead to reporting bias. Even though the funnel plot and Egger’s test declare the absence of publication bias, we would not completely confident the absence of publication bias in this study due to the high likelihood of publication of positive results than negative results. Moreover, the presence of high statistical heterogeneity in the included studies would have decreased the evidence.

6. Conclusion

In this study, women with TT and CC genotypes of eNOS gene variant at two positions revealed significantly higher risk of PE than women having GG and TT genotypes, respectively. Women with aa genotype of eNOS gene in the VNTR intron-4 region showed nonsignificant association with the risk of PE as compared to women with bb genotypes. Likewise, the allelic model of eNOS gene variants at three positions and subgroup analysis by ethnicity showed nonsignificant association with PE risk. Thus, we concluded that eNOS could play a role in PE development. However, concrete evidence on the role of eNOS gene polymorphisms in PE pathogenesis requires large-scale prospective studies.

Authors’ contributions

ET: Conceptualization, data curation, formal analysis, methodology, writing original draft, writing review, and editing. AM: Conceived the review topic, reviewed the protocol, supervised the review process, reviewed, and validated the final manuscript. EN and STG: Involved in analysis, software work, and reviewing and validating the final manuscript. All authors read and approved the final draft of the manuscript.

Abbreviations
BMI=

body mass index

CI=

confidence interval

DBP=

diastolic blood pressure

eNOS=

endothelial nitric oxide synthase

GA=

gestational age

JBI-MAStARI=

Joanna Briggs Institute Meta-Analysis of Statistics Assessment and Review Instrument

LDL=

low density lipoprotein

NOS=

Newcastle-Ottawa Scale, PE-Pre-eclampsia

PCR-RFLP=

polymerase chain reaction- restriction fragment length polymorphism

PRISMA=

preferred reporting items for systematic reviews and meta-analyses

RR=

risk ratio

SBP=

systolic blood pressure:

SD=

standard deviation

VNTRs=

variable number of tandem repeats.

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Acknowledgment

Not applicable.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and materials

All data pertaining to this study are contained and presented in this document and in the supplementary files.

Additional information

Funding

No fund was received for this study.

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