Search

Background: Preeclampsia and eclampsia are severe pregnancy disorders marked by hypertension and potential organ damage. The etiological basis of preeclampsia and eclampsia is not fully understood. Previous studies have revealed a link between sleep abnormality and preeclampsia/eclampsia, but the causal relationship remains unclear. In this study, we explored the genetic links between sleep and preeclampsia/eclampsia using genome-wide association study (GWAS) summary data and Mendelian randomization (MR) analysis., Methods: RNA sequence dataset GSE114691 was downloaded from the Gene Expression Omnibus database, comprising placental tissues from patients with preeclampsia and controls. Differential expression analysis was conducted with R (v4.2.3) and DESeq2 (v1.38.3). Gene set enrichment analysis (GSEA) was carried out using HTSanalyzeR2. GWAS summary data on preeclampsia/eclampsia and genetic markers for sleep abnormality were sourced from the FinnGen Consortium and IEU genetic databases. The Mendelian randomization analysis was conducted with TwoSampleMR (v0.6.2), and the inverse variance weighted (IVW) approach was employed as the principal method., Results: GSEA analysis revealed that the orexin receptor pathway showed heightened expression in the preeclampsia group versus controls. The random-effects IVW results showed that sleeplessness/insomnia has a genetic causal relationship with preeclampsia (OR = 2.08, 95% CI: 1.07-4.06, p  = 0.0318), while sleep duration has evidence of regulating eclampsia (OR = 0.09, 95% CI: 0.01-0.67, p  = 0.0187)., Conclusion: This study provides significant evidence for a genetic causal association between sleep abnormalities and preeclampsia/eclampsia. [Figure: see text].

Introduction: Hypertensive disorders of pregnancy are associated with adverse feto-maternal outcomes. Existing evidence is mostly limited to observational studies, which are liable to confounding and bias. This study investigated the causal relevance of component hypertensive indices on multiple adverse pregnancy outcomes using Mendelian randomization., Methods: Uncorrelated ( r2  < 0.001) genome-wide significant ( P  < 5 × 10 -8 ) single-nucleotide polymorphisms associated with SBP, DBP and pulse pressure (PP) were selected as instrumental variables. Genetic association estimates for outcomes of preeclampsia or eclampsia, preterm birth, placental abruption and hemorrhage in early pregnancy were extracted from summary statistics of genome-wide association studies in the FinnGen cohort. Two-sample, inverse-variance weighted Mendelian randomization formed the primary analysis method. Odds ratios (OR) are presented per-10 mmHg higher genetically predicted hypertensive index., Results: Higher genetically predicted SBP were associated with higher odds of preeclampsia or eclampsia [OR 1.81, 95% confidence interval (CI) 1.68-1.96, P  = 5.45 × 10 -49 ], preterm birth (OR 1.09, 95% CI 1.03-1.16, P  = 0.005) and placental abruption (OR 1.33, 95% CI 1.05-1.68, P  = 0.016). Higher genetically-predicted DBP was associated with preeclampsia or eclampsia (OR 2.54, 95% CI 2.21-2.92, P  = 5.35 × 10 -40 ). Higher genetically predicted PP was associated with preeclampsia or eclampsia (OR 1.68, 95% CI 1.47-1.92, P  = 1.9 × 10 -14 ) and preterm birth (OR 1.18, 95% CI 1.06-1.30, P  = 0.002)., Conclusion: This study provides genetic evidence to support causal associations of SBP, DBP and PP on multiple adverse outcomes of pregnancy. SBP and PP were associated with the broadest range of adverse outcomes, suggesting that optimized management of blood pressure, particularly SBP, is a key priority to improve feto-maternal health., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Beta-blocker (BB) and calcium channel blocker (CCB) antihypertensive drugs are commonly used in pregnancy. However, data on their relative impact on maternal and foetal outcomes are limited. We leveraged genetic variants mimicking BB and CCB antihypertensive drugs to investigate their effects on risk of pre-eclampsia, gestational diabetes and birthweight using the Mendelian randomization paradigm., Methods: Genetic association estimates for systolic blood pressure (SBP) were extracted from summary data of a genome-wide association study (GWAS) on 757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs) associated with SBP (p < 5 × 10 -8 ) in BB and CCB drug target gene regions were selected as proxies for drug target perturbation. Genetic association estimates for the outcomes were extracted from GWASs on 4743 cases and 136,325 controls (women without a hypertensive disorder in pregnancy) for pre-eclampsia or eclampsia, 7676 cases and 130,424 controls (women without any pregnancy-related morbidity) for gestational diabetes, and 155,202 women (who have given birth at least once) for birthweight of the first child. All studies were in European ancestry populations. Mendelian randomization estimates were generated using the two-sample inverse-variance weighted model., Results: Although not reaching the conventional threshold for statistical significance, genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per 10 mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p = 0.08) and increased risk of gestational diabetes (OR per 10 mmHg SBP reduction 2.01, 95%CI 0.91-4.42, p = 0.08), and significantly associated with lower birthweight of first child (beta per 10 mmHg SBP reduction - 0.27, 95%CI - 0.39 to - 0.15, p = 1.90 × 10 -5 ). Genetically-proxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR 0.62, 95%CI 0.43-0.89, p = 9.33 × 10 -3 ), and was not associated with gestational diabetes (OR 1.05, 95% CI 0.76-1.45, p = 0.76) or changes in birthweight of first child (beta per 10 mmHg SBP reduction 0.02, 95%CI - 0.04-0.07, p = 0.54)., Conclusions: While BB and CCB antihypertensive drugs may both be efficacious for lowering blood pressure in pregnancy, this genetic evidence suggests that BB use may lower birthweight. Conversely, CCB use may reduce risk of pre-eclampsia and eclampsia without impacting gestational diabetes risk or birthweight. These data support further study on the effects of BBs on birthweight., (© 2022. The Author(s).)

Objective: We aimed to explore the associations of the ATP2B1 gene polymorphisms with eclampsia., Patients and Methods: A total of 150 patients with eclampsia (disease group) and 150 healthy pregnant women (control group) were taken as the subjects of study. The peripheral blood of the two groups of subjects was collected to extract deoxyribonucleic acids (DNAs), and the ATP2B1 gene rs71454161, rs73196661 and rs73196675 polymorphisms were detected by sequencing the Polymerase Chain Reaction (PCR) products, and then, analyzed combined with gene expression determined via Reverse Transcription-quantitative Polymerase Chain Reaction (RT-qPCR) and clinical indicators, such as 24-h urine protein, platelets, and LDH., Results: A difference was observed in the allele distribution of ATP2B1 gene rs71454161 (p=0.000) and rs73196661 (p=0.011) between the disease group and control group. Disease group exhibited higher frequencies of allele G of rs71454161 and allele T of rs73196661 than control group. Besides, there was a difference in the genotype distribution of ATP2B1 gene rs71454161 (p=0.000), rs73196661 (p=0.000) and rs73196675 (p=0.000) between disease group and control group. Disease group exhibited higher frequencies of genotype GG of rs71454161, genotype TT of rs73196661 and genotype CG of rs73196675 than control group. Moreover, a difference in the distributions of ATP2B1 gene rs71454161 (p=0.000) and rs73196661 (p=0.014) was found between the two groups in the dominant model. Disease group exhibited lower frequencies of AA+AG of rs71454161 and CC+CT of rs73196661 than control group in the dominant model. Differences in the distributions of haplotypes ACC (p=0.000), ATC (p=0.047) and GTC (p=0.000) of ATP2B1 gene rs71454161, rs73196661 and rs73196675 were observed between disease group and control group. Furthermore, a high degree of linkage disequilibrium was detected between rs71454161 and rs73196661 (D'=0.329). The ATP2B1 gene rs73196675 polymorphism was evidently correlated with the gene expression of ATP2B1 (p<0.05), and the patients with genotype GG had a lower expression level of ATP2B1. The ATP2B1 gene rs71454161 was evidently correlated with the 24-h urinary protein in eclampsia patients (p=0.021), and the patients with genotype AG had a higher level of 24-h urinary proteins. The rs73196661 polymorphism was significantly correlated with LDH (p=0.000), and the patients with genotype CC had a higher level of LDH., Conclusions: The ATP2B1 gene polymorphism was significantly correlated with the occurrence and progression of eclampsia.

Background: Preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome share many clinical and biologic features with thrombotic microangiopathy syndromes caused by complement abnormalities. Our hypothesis was that similar functional and genetic alterations in the complement alternative pathway (CAP) are present in these disorders of pregnancy., Methods: We conducted quantitative analysis of proteins involved in CAP using ELISA and nephelometry on prospectively collected blood samples from patients with severe phenotype preeclampsia (defined as delivery ≤34 weeks due to preeclampsia), HELLP syndrome, or eclampsia, and matched normotensive controls ( n =25 in each arm) between 2011 and 2016. Sequencing was performed to interrogate 14 genes encoding CAP components., Results: Both groups were similar in age, gravidity, parity, marital status, and race. The study group had a higher BMI (mean±SD, 32±8 versus 25±4 kg/m 2 ; P =0.002) and earlier gestational age at delivery (32.5±3.6 versus 40.3±1 weeks; P <0.001). Serologic studies demonstrated elevated Bb subunit (median [range], 1.2 [0.5-4.3] versus 0.6 [0.5-1] μ g/ml; P<0.001), complement C5 concentration (28 [18-33] versus 24 [15-34] mg/dl; P =0.03), and sMAC (371 [167-761] versus 184 [112-249] ng/ml; P<0.001) concentrations in patients with preeclampsia. Two thirds of patients with preeclampsia had at least one nonsynonymous sequence variant in CAP genes., Conclusion: Patients with severe phenotype preeclampsia manifest functional alterations in CAP activation. Genetic variants in the CAP genes were detected in several patients, but a larger population study is necessary to fully evaluate genetic risk. Genetic screening and complement-targeted treatment may be useful in risk stratification and novel therapeutic approaches., Competing Interests: V.D. Garovic reports being the inventor of the technology “Markers for preeclampsia.” The technology has not been licensed. M.L. Gonzalez Suarez reports receiving research funding from Gilead. M.J. Wick reports serving on the board of Informed DNA. M.A.V. Willrich reports serving on the Clinical Chemistry and Laboratory Medicine (published by De Gruyter) editorial board, as chair of the Clinical Diagnostic Immunology Division of the American Association for Clinical Chemistry, and as vice-chair of the Diagnostic Immunology and Flow Cytometry Committee of the College of American Pathologists; having consultancy agreements with Sebia Inc.; and receiving research funding from Sebia Inc., Siemens Healthineers, and The Binding Site. All remaining authors have nothing to disclose., (Copyright © 2021 by the American Society of Nephrology.)

This research aimed at exploring the predictive value of 4-Hydroxyglutamate and miR-149-5p on eclampsia. Preeclampsia patients admitted to our hospital (n = 204), with 112 mild patients and 92 severe patients. Thereinto, pregnant women who underwent physical examination were regarded as a normal group (NG) (n = 100). Serum 4-Hydroxyglutamate levels and miR-149-5p in each group were detected. The serum 4-Hydroxyglutamate level in pregnant women in the NG was markedly lower than that in preeclampsia, while the miR-149-5p level was higher (p = 0.001). The serum 4-Hydroxyglutamate level in severe preeclampsia was higher than that in mild preeclampsia, while the miR-149-5p level was lower (p = 0.001). Partial thromboplastin time (APTT) and prothrombin time (PT) of preeclampsia patients were lower than those of the NG, while Fibrinogen (Fib) was higher (p = 0.001). With the aggravation of the condition of patients, PT, APTT decreased and Fib index increased. In preeclampsia patients, serum 4-Hydroxyglutamate was negatively correlated with PT and APTT, positively correlated with Fib content (p < 0.001); serum miR-149-5p was dramatically positively correlated with PT and APTT, negatively correlated with Fib content (p < 0.001). 4-Hydroxyglutamate and miR-149-5p were relevant to the occurrence time of preeclampsia; 4-Hydroxyglutamate, miR-149-5p and their combination could be used for preeclampsia diagnosis. According to the situation of newborn, they were divided into good and poor groups. The 4-Hydroxyglutamate level in the good group was lower than that in the poor group, while the miR-149-5p level was higher. The adverse prognosis of preeclampsia patients was predicted by 4-Hydroxyglutamate and miR-149-5p. 4-Hydroxyglutamate is highly expressed in preeclampsia, while miR-149-5p is low. Single and combined detection of 4-Hydroxyglutamate, miR-149-5p can be used for preeclampsia diagnosis and prediction., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The clinical spectrum of hypertensive disorders of pregnancy (HDP) is determined by the interplay between environmental and genetic factors, most of which remains unknown. ERAP1, ERAP2 and LNPEP genes code for multifunctional aminopeptidases involved with antigen processing and degradation of small peptides such as angiotensin II (Ang II), vasopressin and oxytocin. We aimed to test for associations between genetic variants in aminopeptidases and HDP. A total of 1282 pregnant women (normotensive controls, n = 693; preeclampsia, n = 342; chronic hypertension with superimposed preeclampsia, n = 61; eclampsia, n = 74; and HELLP syndrome, n = 112) were genotyped for variants in LNPEP (rs27300, rs38034, rs2303138), ERAP1 (rs27044, rs30187) and ERAP2 (rs2549796 rs2927609 rs11135484). We also evaluated the effect of ERAP1 rs30187 on plasma Ang II levels in an additional cohort of 65 pregnant women. The genotype C/C, in ERAP1 rs30187 variant (c.1583 T > C, p.Lys528Arg), was associated with increased risk of eclampsia (OR = 1.85, p = 0.019) whereas ERAP2 haplotype rs2549796(C)-rs2927609(C)-rs11135484(G) was associated with preeclampsia (OR = 1.96, corrected p-value = 0.01). Ang II plasma levels did not differ across rs30187 genotypic groups (p = 0.895). In conclusion, ERAP1 gene is associated with eclampsia whereas ERAP2 is associated with preeclampsia, although the mechanism by which genetic variants in ERAPs influence the risk of preeclampsia and eclampsia remain to be elucidated.

Objective: We aimed to study the correlations of angiotensin II receptor type 1 (AGTR1) gene polymorphisms with the occurrence and development of eclampsia., Patients and Methods: A total of 200 pregnant women with eclampsia admitted to our hospital from January 1, 2017 to September 30, 2019 were collected as observation group and 200 normal pregnant women during the same period were recruited in the control group. Genome sequencing was performed to detect the AGTR1 gene polymorphisms in the two groups. Expression level of AGTR1 in both groups was detected. The influences of AGTR1 on clinical data of pregnant women with eclampsia were analyzed., Results: There were no significant differences in age (p=0.545), height (p=0.738), weight (p=0.695) and hypertension (p=0.372) between observation group and control group. However, significant differences were found in the distributions of alleles at AGTR1 rs1799870 (p=0.002) and AGTR1 rs52936049 (p=0.047) between groups. The frequencies of T allele at rs1799870 and rs52936044 in observation group were higher than those in the control group. In addition, the distributions of AGTR1 gene genotypes at rs1799870 (p=0.012), rs144520513 (p=0.008) and rs529360494 (p p =0.036) in observation group differed from those in control group. Observation group had higher frequencies of TT genotype at rs1799870, GG genotype at rs144520513 and TG genotype at rs529360494 than those in control group. Besides, the frequency of CGG haplotype (p=0.008) of AGTR1 gene in observation group was notably lower than that in the control group, while the frequency of TGT haplotype (p=0.012) of AGTR1 gene in the former was remarkably higher than that in the latter. Moreover, the linkage disequilibrium between rs529360494 and rs144520513 of AGTR1 gene was relatively high (D'=0.623). AGTR1 gene polymorphism rs529360494 showed an evident relationship with the expression of AGTR1 gene, and the expression of AGTR1 in pregnant women with eclampsia who carried TG genotype was markedly reduced (p<0.05). Furthermore, AGTR1 gene polymorphism rs1799870 was associated with prothrombin time (PT) in pregnant women with eclampsia (p=0.046), and PT in those carrying genotype TC was shorter. Rs144520513 was related to the levels of triglyceride (TG) (p<0.001) and low-density lipoprotein (LDL) (p<0.001) in pregnant women with eclampsia, and TG and LDL levels were significantly lower., Conclusions: AGTR1 gene polymorphisms are closely associated with the onset and progression of eclampsia.

Objective: The aim of this study was to explore the relationship between CYP11B2 gene polymorphisms and eclampsia., Patients and Methods: A total of 400 pregnant women treated in our hospital were enrolled in this study, including 200 normal pregnant women (pregnancy group) and 200 pregnant women with eclampsia (eclampsia group). Peripheral blood was collected from subjects of the two groups. Subsequently, genomic deoxyribonucleic acids (DNAs) were extracted and amplified via polymerase chain reaction (PCR) for detection of CYP11B2 rs4543, rs3802228 and rs104894072 polymorphisms. The expression level of CYP11B2 gene was measured as well. Additionally, the correlations of CYP11B2 gene polymorphisms with blood pressure and coagulation and renal function indexes were analyzed., Results: The distribution of alleles of rs4543 locus in CYP11B2 gene was significantly different between eclampsia group and pregnancy group (p=0.027). The frequency of the allele C was significantly lower in eclampsia group than that of pregnancy group (p<0.05). There was a statistically significant difference in the genotype distribution of CYP11B2 rs3802228 (p=0.000) and rs104894072 (p=0.000) between eclampsia group and pregnancy group (p<0.05). Meanwhile, the frequency of AA genotype of rs3802228 and TG genotype of rs104894072 was remarkably higher in eclampsia group than that in pregnancy group (p<0.05). The distribution of the locus rs104894072 (p=0.044) in dominant model and rs3802228 (p=0.002) in recessive model in eclampsia group was different from that in pregnancy group (p<0.05). Eclampsia group showed remarkably elevated frequency of TT + TG of the locus rs104894072 in dominant model and lowered frequency of AG + GG of the locus rs3802228 in recessive model (p<0.05). Similarly, a significant difference was observed in the distribution of the haplotypes CGG (p=0.001) and TGT (p=0.048) in CYP11B2 gene between eclampsia group and pregnancy group (p<0.05). The linkage disequilibrium of the loci rs3802228 and rs104894072 was relatively high (D'=0.382). The polymorphism of the locus rs104894072 in CYP11B2 gene had an evident relation to CYP11B2 gene expression (p<0.05). Meanwhile, the expression of CYP11B2 gene was markedly higher in patients with GG genotype in eclampsia group (p<0.05). The polymorphism of CYP11B2 rs4543 was notably associated with PT level of patients in eclampsia group (p=0.000). Conversely, rs3802228 polymorphism was correlated with 24 h urine protein level (p=0.000). Besides, the proportion of patients with CGG haplotype was significantly larger among patients with systolic blood pressure of 140-160 mmHg (p<0.05). In addition, the proportion of patients with TGT haplotype was evidently greater among patients with systolic blood pressure >180 mmHg in eclampsia group (p<0.05)., Conclusions: CYP11B2 gene polymorphisms are significantly correlated with the development and progression of eclampsia.

Objective: The aim of this study was to analyze the association of ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) gene polymorphism with the incidence of eclampsia, and to investigate the possible underlying mechanism., Patients and Methods: ATP2B1 genotype and allele distributions in umbilical venous blood cells were analyzed in 50 control subjects and 117 eclampsia patients via Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and TaqMan genotyping technique. Meanwhile, the differences in the single nucleotide polymorphisms at rs2681472 and rs17249754 in the case group and control group were analyzed using the χ2-test. The risk factors for eclampsia were analyzed via univariate, multivariate, and Logistic regression analyses. Furthermore, the associations of rs2681472 gene polymorphism with risk factors for eclampsia (hypertension and lower extremity edema) were verified via χ2-test., Results: The statistically significant differences were observed in the gestational week, body mass index, blood pressure, and incidence rates of proteinuria and lower extremity edema of pregnant women between the case group and the control group (p<0.05). Meanwhile, the genotype and allele distributions at rs2681472 in the case group were remarkably different from those of the control group (p<0.05). However, no evident differences were observed at rs17249754 between the two groups (p>0.05). According to univariate, multivariate, and logistic regression analyses, hypertension, and lower extremity edema were significantly associated with the incidence of eclampsia (p<0.05). In addition, the gene polymorphism at rs2681472 showed significant differences among subjects with and without hypertension and lower extremity edema (p<0.05)., Conclusions: ATP2B1 gene polymorphism at rs2681472 shows significant differences between eclampsia patients and normal controls. Moreover, its gene polymorphism is closely related to the occurrence of hypertension and lower extremity edema.

Objective: To explore the association between preeclampsia/eclampsia and maternal and fetal angiotensinogen SNPs. Methods: From January 2008 to October 2015, a case-parents/mother-control designed study was conducted among 347 preeclampsia/eclampsia cases and 700 controls to collect related information on their demographic characteristics and to detect the related angiotensinogen SNPs' genotypes. Both log-linear and unconditional logistic regression methods were employed to investigate the genetic effects of maternal/fetal angiotensinogen SNPs on preeclampsia/eclampsia. Multivariate binary unconditional logistic regression model and covariance were used to analyze the relationship between BMI before pregnancy, weight gain during pregnancy and overweight and obesity in preschool children. Results: Both fetal angiotensinogen rs3789679 GA and AA genotype were associated with the reduced risks of preeclampsia/eclampsia, with OR s as 0.73 (95 %CI : 0.55-0.96) and 0.62 (95 %CI : 0.39-0.98), respectively. For fetal angiotensinogen rs2493132, individuals that carrying the TT genotype, presented a positive association with the risk of preeclampsia/eclampsia, with OR as 1.60 (95 %CI : 1.08-2.37). However, these associations were not statistically significant after the correction of the false discovery rate. It was observed that fetal rs3789679 could reduce the risk of preeclampsia/eclampsia ( OR =0.73, 95 %CI : 0.55-0.96) under the dominant model (GA+AA/GG) while fetal rs2493132 increased the risk of preeclampsia/eclampsia ( OR =1.66, 95 %CI : 1.13-2.44) under the recessive model (TT/CC+CT). Maternal rs5051 presented an association with preeclampsia/eclampsia ( OR =1.33, 95 %CI : 1.01-1.76) under the dominant model (TC+CC/TT). Conclusions: Results from the dominant model showed that both fetal rs3789679 GA and AA genotype reduced the risk of preeclampsia/eclampsia and maternal rs5051 TC while CC genotype increased the risk of preeclampsia/eclampsia. Fetal rs2493132 TT genotype seemed to be associated with the risk of preeclampsia/eclampsia under the recessive model.

Objective: To explore the correlations of endothelial nitric oxide synthase (eNOS) G894T and endothelin-2 (ET-2) A985G gene polymorphisms with eclampsia., Patients and Methods: A total of 110 eclampsia patients in our hospital from July 2014 to August 2017 were enrolled as the observation group and 100 healthy pregnant women in the same period as the control group. The polymorphisms of eNOS G894T and ET-2 A985G genes in the two groups were analyzed via polymerase chain reaction (PCR), and their correlations with eclampsia risk were investigated., Results: The distribution frequency of eNOS G894T genotype TT and GT and T allele, as well as the ET-2 A985G genotype GG and AG and G allele, were evidently higher in the observation group than in the control group (p<0.05). ENOS G894T genotype TT and ET-2 A985G genotype GG were significantly associated with the occurrence of eclampsia., Conclusions: The polymorphisms of eNOS G894T and ET-2 A985G genes are correlated with the occurrence of eclampsia.

Objective: The aim of this study was to investigate the expression of cyclooxygenase-2 (COX-2) in eclampsia patients, and to explore the correlation between COX-2 polymorphism and incidence of eclampsia., Patients and Methods: From January 2016 to January 2018, a total of 280 pregnant women diagnosed in the Obstetrics and Gynecology Department of our hospital were selected for this study. All patients were divided into two groups, including normal pregnancy control group (n=120) and eclampsia group (n=160). The expression of COX-2 in placenta and umbilical cord tissues of eclampsia group and normal group was detected via Reverse Transcription-Polymerase Chain Reaction (RT-PCR), Western blotting and immunohistochemical staining. The single-nucleotide polymorphisms (rs1526172, rs1245231 and rs2198532) in the promoter region of the COX-2 gene were typed via conformation difference gel electrophoresis. Whether the distribution frequency of COX-2 genotypes met Hardy-Weinberg equilibrium law was detected via the Chi-square test. Meanwhile, the correlation between COX-2 alleles and gene polymorphisms and the incidence of eclampsia was analyzed., Results: The messenger ribonucleic acid (mRNA) and protein expression levels of COX-2 in the eclampsia group were significantly higher than those of the normal group (p<0.05). According to the analysis, three polymorphisms of COX-2 gene were all in line with Hardy-Weinberg equilibrium distribution (p>0.05). Gene association analysis revealed that only polymorphisms (rs1526172 and rs1245231) and alleles were correlated with the incidence of eclampsia (p<0.05). However, polymorphism rs2198532 and alleles were not correlated with the incidence of eclampsia (p>0.05)., Conclusions: Rs1526172 and rs1245231 in the promoter region of COX-2 are correlated with the incidence of eclampsia, while rs2198532 has no correlation with eclampsia.

Eclampsia is a hypertensive disorder of pregnancy that is defined by the new onset of grand mal seizures on the basis of pre-eclampsia. Until now, the mechanisms underlying eclampsia were poorly understood. Brain edema is considered a leading cause of eclamptic seizures; aquaporins (AQP4 and AQP9), the glial water channel proteins mainly expressed in the nervous system, play an important role in brain edema. We studied AQP4 and AQP9 expression in the hippocampus of pre-eclamptic and eclamptic rats in order to explore the molecular mechanisms involved in brain edema. Using our previous animal models, we found several neuronal deaths in the hippocampal CA1 and CA3 regions after pre-eclampsia and that eclampsia induced more neuronal deaths in both areas by Nissl staining. In the current study, RT-PCR and Western blotting data showed significant upregulation of AQP4 and AQP9 mRNA and protein levels after eclamptic seizures in comparison to pre-eclampsia and at the same time AQP4 and AQP9 immunoreactivity also increased after eclampsia. These findings showed that eclamptic seizures induced cell death and that upregulation of AQP4 and AQP9 may play an important role in this pathophysiological process., Competing Interests: The authors declare no conflict of interest.

The etiological pathways and pathogenesis of preeclampsia have rendered difficult to disentangle. Accumulating evidence points toward a maladapted maternal immune system, which may involve aberrant placental expression of immunomodulatory human leukocyte antigen (HLA) class Ib molecules during pregnancy. Several studies have shown aberrant or reduced expression of HLA-G in the placenta and in maternal blood in cases of preeclampsia compared with controls. Unlike classical HLA class Ia loci, the nonclassical HLA-G has limited polymorphic variants. Most nucleotide variations are clustered in the 5'-upstream regulatory region (5'URR) and 3'-untranslated regulatory region (3'UTR) of HLA-G and reflect a stringent expressional control. Based on genotyping and full gene sequencing of HLA-G in a large number of cases and controls (n > 900), the present study, which to our knowledge is the largest and most comprehensive performed, investigated the association between the HLA-G 14-bp ins/del (rs66554220) and HLA-E polymorphisms in mother and newborn dyads from pregnancies complicated by severe preeclampsia/eclampsia and from uncomplicated pregnancies. Furthermore, results from extended HLA-G haplotyping in the newborns are presented in order to assess whether a combined contribution of nucleotide variations spanning the 5'URR, coding region, and 3'UTR of HLA-G describes the genetic association with severe preeclampsia more closely. In contrast to earlier findings, the HLA-G 14-bp ins/del polymorphism was not associated with severe preeclampsia. Furthermore, the polymorphism (rs1264457) defining the two nonsynonymous HLA-E alleles, HLA-E*01:01:xx:xx and HLA-E*01:03:xx:xx, were not associated with severe preeclampsia. Finally, no specific HLA-G haplotypes were significantly associated with increased risk of developing severe preeclampsia/eclampsia., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To analyze methylation profiles of known preeclampsia/eclampsia (PE) candidate genes in normal (NL) and preeclamptic (PE) women at delivery., Methods: A matched case-control study comparing methylation in 79 CpG sites/33 genes from an independent gene set in maternal leukocyte DNA in PE and NL (n = 14 each) on an Illumina BeadChip platform. Replication performed on second cohort (PE = 12; NL = 32)., Results: PE demonstrates differential methylation in POMC, AGT, CALCA, and DDAH1 compared with NL., Conclusion: Differential methylation in four genes associated with PE may represent a potential biomarker or an epigenetic pathophysiologic mechanism altering gene transcription.

A line of investigations indicate that genes in the human leukocyte antigen (HLA) complex are involved in a successful acceptance of the semiallogeneic fetus during pregnancy. In this study, associations between specific HLA class Ia (HLA-A and -B) and class II (HLA-DRB1, -DQA1, -DQB1, -DPA1 and -DPB1) alleles and the risk of developing severe preeclampsia/eclampsia were investigated in a detailed and large-scale study. In total, 259 women diagnosed with severe preeclampsia or eclampsia and 260 matched control women with no preeclampsia, together with their neonates, were included in the study. HLA genotyping for mothers and neonates was performed using next-generation sequencing. The HLA-DPB1*04:01:01G allele was significantly more frequent (Pc=0.044) among women diagnosed with severe preeclampsia/eclampsia compared with controls, and the DQA1*01:02:01G allele frequency was significantly lower (Pc=0.042) among newborns born by women with severe preeclampsia/eclampsia compared with controls. In mothers with severe preeclampsia/eclampsia, homozygosity was significantly more common compared with controls at the HLA-DPB1 locus (Pc=0.0028). Although the current large study shows some positive results, more studies, also with a functional focus, are needed to further clarify a possible role of the classical HLA genes in preeclampsia.

Objective: To investigate the association between cigarette use during pregnancy and pregnancy-induced hypertension/preeclampsia/eclampsia (PIH) by maternal race/ethnicity and age., Methods: This retrospective cohort study was based on the U.S. 2010 natality data. Our study sample included U.S. women who delivered singleton pregnancies between 20 and 44 weeks of gestation without major fetal anomalies in 2010 (n = 3,113,164). Multivariate logistic regression models were fit to estimate crude and adjusted odds ratios and the corresponding 95% confidence intervals., Results: We observed that the association between maternal smoking and PIH varied by maternal race/ethnicity and age. Compared with non-smokers, reduced odds of PIH among pregnant smokers was only evident for non-Hispanic white and non-Hispanic American Indian women aged less than 35 years. Non-Hispanic Asian/Pacific Islander women who smoked during pregnancy had increased odds of PIH regardless of maternal age. Non-Hispanic white and non-Hispanic black women 35 years or older who smoked during pregnancy also had increased odds of PIH., Conclusion: Our study findings suggest important differences by maternal race/ethnicity and age in the association between cigarette use during pregnancy and PIH. More research is needed to establish the biologic and social mechanisms that might explain the variations with maternal age and race/ethnicity that were observed in our study.

Pre-eclampsia is a devastating multi system syndrome and a major cause of maternal, fetal, neonatal morbidity and mortality. Pre-eclampsia is associated with oxidative stress in the maternal circulation. To have an insight on the effect of pre-eclampsia/eclampsia on the neonates, the study was made to explore the oxidative status by quantification of byproducts generated during protein oxidation and oxidative DNA damage and deficient antioxidant activity in umbilical cord blood of pre-eclamptic/eclamptic mothers during fetal circulation. Umbilical cord blood during delivery from neonates born to 19 pre-eclamptic mothers, 14 eclamptic mothers and 18 normotensive mothers (uncomplicated pregnancy) as control cases was collected. 8-OHdG (8-hydroxy-2-deoxyguanosine), protein carbonyl, nitrite, catalase, non-enzymatic antioxidants (vitamin A, E, C), total antioxidant status and iron status were determined. Significant elevation in the levels of 8-OHdG, protein carbonyl, nitrite and iron along with decreased levels of catalase, vitamin A, E, C, total antioxidant status were observed in the umbilical cord blood of pre-eclamptic and eclamptic pregnancies. These parameters might be influential variables for the risk of free radical damage in infants born to pre-eclamptic/eclamptic pregnancies. Increased oxidative stress causes oxidation of DNA and protein which alters antioxidant function. Excess iron level and decreased unsaturated iron binding capacity may be the important factor associated with oxidative stress and contribute in the pathogenesis of pre-eclampsia/eclampsia which is reflected in fetal circulation., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Objective: Genetic variants associated with venous thromboembolism (VTE) have been suggested to be involved in the pathogenesis of pre-eclampsia/eclampsia (PEC/EC). This nationwide study aimed to determine whether VTE shares familial susceptibility with PEC/EC., Design: Population-based cohort study., Setting: Sweden., Sample: A total of 941 841 Swedish women delivering their first child between 1987 and 2008., Methods: Data from the Swedish Multigeneration Register were linked to the Swedish Hospital Discharge Register. The risk of PEC/EC was determined in primiparous women with a family history of VTE (in parents and/or siblings), compared with primiparous women without a family history of VTE. Odds ratios (ORs) were calculated by logistic regression., Main Outcome Measure: PEC/EC in first pregnancy., Results: In total, 43 621 women had PEC/EC in association with their first pregnancy. The OR for PEC/EC in women with a family history of VTE was 1.06 (95% CI 1.01-1.11); however, a family history of VTE was associated with higher odds of PEC/EC among women with previous hypertension (OR 1.38, 95% CI 1.25-1.52)., Conclusion: A family history of VTE is weakly associated with PEC/EC risk, and is not clinically useful for the prediction of PEC/EC. The results of the present study suggest that it is unlikely that strong disease-causing mutations shared by VTE and PEC/EC are common in the Swedish population. The novel association between family history and PEC/EC among the subgroup with previous hypertension needs further confirmation in future studies., (© 2013 The Authors BJOG An International Journal of Obstetrics and Gynaecology © 2013 RCOG.)

Background: Cytokine imbalance and endothelial dysfunction are suggested to have a pivotal role in eclampsia. Pathophysiological processes are influenced by genetic factors and nitric oxide (NO) synthases seem to play important roles, although their role is still unclear. Endothelial NO synthase (eNOS) gene polymorphism may affect cytokine production. The aim of this study was to test the hypothesis that inflammatory cytokines impairs endothelium-dependent relaxation and NO production gets vitiated due to eNOs Glu298Asp gene polymorphism causing endothelial dysfunction in eclampsia., Methods: This cross-sectional study included 100 women with eclampsia and 100 healthy pregnant women. Their blood samples were analyzed for NO (indirectly), and inflammatory cytokines and eNOS (Glu298Asp) gene polymorphism were determined by DNA extraction, followed by restriction fragment length polymorphism., Results: Decreased NO metabolites and increased cytokines (tumor necrosis factor-α; interleukin-2, -6; and interferon-γ) levels were found in eclampsia (p < 0.001). Significant differences were found in genotype/allele distribution between the two groups. Occurrence of "T" allele frequency was found to be 0.27 among patients and 0.05 among controls (CI = 95%, OR = 0.7-0.9, p < 0.001). Significant negative correlation was seen between NO and cytokines levels (tumor necrosis factor-α and interferon-γ) in eclamptic women (p = 0.001)., Conclusion: This study concluded that eclampsia is associated with decreased levels of NO and increased levels of circulating inflammatory cytokines, which might be contributed due to single-nucleotide polymorphism, pointing toward the role of endothelial and inflammatory components.

Aim: To evaluate endothelial nitric oxide synthase (eNOS) gene polymorphisms in preeclampsia with or without eclampsia in a Turkish population., Material and Methods: Fifty-seven preeclamptic and 60 normotensive women were enrolled in the present study. The study focused on two functional variants: a variant in exon 7-G to T conversion at nucleotide position 894 resulting in the replacement of glutamic acid with aspartic acid at codon 298 (Glu298Asp) and a variant variable number of 27 bp tandem repeats in intron 4 (VNTR intron 4). Two polymorphisms in the maternal eNOS gene were characterized by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Preeclamptic pregnant women were evaluated into two subgroups according to the presence of eclampsia., Results: We demonstrated a significant difference in patients with preeclampsia in terms of Glu298Asp/eNOS genotype frequency. G/G homozygotes of Glu298Asp among healthy pregnancies were significantly frequent when T/T homozygotes were significantly frequent among preeclamptic pregnancies. We showed that G/T heterozygotes of Glu298Asp/eNOS gene were significantly frequent among preeclamptic pregnant women who did not develop eclampsia than in preeclamptic pregnant women with eclampsia., Conclusion: Glu298Asp polymorphism in the eNOS gene could be an individual's risk factor and may modulate progression to an eclampsia complication of preeclampsia in the Turkish population., (© 2011 The Authors. Journal of Obstetrics and Gynaecology Research © 2011 Japan Society of Obstetrics and Gynecology.)

Immune maladaption between mother and infant has been suggested to induce preeclampsia/eclampsia. When fetuses share more human leukocyte antigen (HLA) types with their mother, immune differences would be limited and thereby could affect this risk. Data from Danish women (1996-2002) with single live-birth pregnancies complicated by severe preeclampsia/eclampsia were compared to women with term pregnancies uncomplicated by hypertension. HLA A, B, and DR types were resolved at the intermediate-level typing (antigen). A total of 201 cases and 195 control mother-infant pairs had complete HLA types. The odds ratios of preeclampsia/eclampsia in mothers sharing both HLA antigens with their infants were 1.19 (95% confidence interval: 0.81-1.76) for HLA A, 0.91 (0.59-1.42) for HLA B, and 1.05 (0.5-1.59) for HLA DR antigens. No specific HLA antigens in either mother or infant appeared important after Bonferroni correction, except possibly DR01 in mothers (protective). Thus, maladaption mediated by adaptive immunity between mother and infant is not the basis for the mother developing preeclampsia/eclampsia., ((c) 2010 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

The clinical spectrum of preeclampsia (PE) ranges from mild hypertension to severe vasospasm associated with convulsions and multiple organ damage. The biological factors that determine the progression of PE to eclampsia (E) are unknown. Endothelial cell activation seems related to an impaired maternal immune response. The production of cytokines, IL-10 and TGF-beta1, is apparently suppressed, and altered IL-2/IL-10 and TNF-alpha/IL-10 ratios have been reported in preeclamptic cases. The relationship between PE and cytokine gene polymorphism has been studied, but there are few studies that include eclamptic patients. This study aimed at investigating whether polymorphisms in genes, TNF-alpha promoter (-308 G>A), IL6 promoter (-174 G>C), IFN-gamma intron 1 (+874 A>T), IL10 promoters (-1082 A>G), (-819 C>T) and (-592 C>A) and TGF-beta1 codon 10 (+869 T>C) and codon 25 (+915 G>C) are associated with E and/or PE. Genotyping was carried out in 266 Mulatto women from the northeastern region of Brazil who were referred to a single maternity hospital: 92 with PE, 73 with E and 101 normotensive controls. The chi(2) or Fisher's exact tests were used to compare genotype frequencies. Among the six single-nucleotide polymorphisms (SNPs) studied, we found no difference in genotype frequencies between the groups. There was a higher frequency of IFN-gamma (+874 A) in eclamptic patients in comparison with that in controls. (70.3 vs. 57.8%, respectively; P=0.02). There were no other significant differences in allelic frequencies between eclamptic, preeclamptic and control groups We found no independent association between any single SNP and PE or E risk in this population of Mulatto women from the northeastern region of Brazil.

Objective: The angiotensinogen gene M235T polymorphism is related to an increased risk of hypertension. Hypertension and pregnancy-induced hypertension have been suggested to share common etiologic factors. We examined whether this mutation also increases the risk of preeclampsia/eclampsia., Methods: Pubmed/Medline, Web of Science and EMBASE were searched and a hand search of bibliographies was conducted. In all, 17 studies (including 1446 cases and 3829 controls) published in English between 1993 and October 2006 on the association of angiotensinogen gene M235T polymorphism with preeclampsia/eclampsia were selected., Results: The overall odds ratio (OR) under a random effects model revealed that individuals homozygous for the T allele were 1.62 times more likely to develop preeclampsia/eclampsia [95% confidence interval (CI), 1.12 to 2.33; P = 0.01) compared to individuals homozygous for the M allele. The relation in Caucasians (OR = 1.99; 95% CI, 1.18-3.36; P = 0.01) was similar to that in East Asian populations (OR = 1.74; 95% CI, 0.92-3.28; P = 0.09), although the latter was not statistically significant due to lower numbers of studies. Under additive, recessive and dominant genetic models positive associations were also found. A meta-regression analysis showed that ethnic background was a significant source of between-study heterogeneity (P = 0.04) but design of the study, study size and Hardy-Weinberg equilibrium deviation were not. There was a low probability of publication bias., Conclusion: Our meta-analysis expands the findings on hypertension by showing that the presence of the T allele of the angiotensinogen gene is associated with an increased risk to develop preeclampsia/eclampsia.

The genetic background predisposing pregnant women to pre-eclampsia/eclampsia (PE/E) is still unknown. The aim of the current study was to investigate whether there is an association between the TNF-alpha-308 and 850 polymorphisms and PE or eclampsia. In this study, 40 cases of eclampsia, 113 cases of PE and 80 normotensive control cases were genotyped for the TNF-alpha-G-308A and C-850 polymorphisms. At position 308, the replacement of Guanine with Adenosine was denoted as TNF2. We found a significant difference between the TNF2 allele frequencies of the eclamptic, pre-eclamptic and normotensive controls. TNF2 (AA) polymorphism frequency was significantly higher among the eclamptics and pre-eclamptics (control : 5%, PE : 13.3%, E : 12.9%). A significantly different genotype distribution of C-850T polymorphism was observed between the PE/E and control groups, with the frequency of the variant TT genotype being significantly reduced in the preeclamptics (PE : 17% ; E : 17.5%) when compared with the control group (24.3%). We have demonstrated an association between TNF-alpha polymorphisms and pre-eclampsia susceptibility. However, it is not known whether C-850T polymorphism has a functional effect on the TNF-alpha gene. In addition, it was not possible to determine whether this polymorphism promotes the progression from PE to eclampsia because of no statistically significant difference between eclampsia and the controls.

Objectives: To investigate the hypothesis that women who are genetically programmed to produce higher levels of transforming growth factor-beta 1 are more likely to develop severe eclampsia/pre-eclampsia., Design: Case-control study., Methods: Blood samples from women whose pregnancy was complicated by eclampsia (n=37) or pre-eclampsia (n=49) and healthy controls (n=86) were analyzed for the presence of polymorphisms at codons 10 and 25 of the transforming growth factor-beta 1 gene. The polymorphisms are thought to determine whether an individual produces low, medium, or high levels of the cytokine. The analysis was carried out using the ARMS-PCR technique., Results: Women who developed eclampsia/pre-eclampsia with severe renal and neurological complications or had neonatal deaths/still births were more likely to have the high-producer allele T in codon 10 of the transforming growth factor-beta 1 gene than healthy controls. By contrast, the transforming growth factor-beta 1 producer genotype and allele frequency as determined by gene polymorphisms at codon 25 were comparable in cases and controls. The cytokine producer status per se appears to had no bearing on whether a patient developed eclampsia/pre-eclampsia., Conclusions: Our findings suggest that women who experience eclampsia/pre-eclampsia with severe maternal and/or fetal complications are more likely to have a genetic predisposition to produce high levels of transforming growth factor-beta 1 as defined by polymorphisms at codon 10. While it is recognized that eclampsia/pre-eclampsia has heterogenous pathomechanisms, we have demonstrated a strong relationship between poor maternal and pregnancy outcomes and codon 10 polymorphisms. The characterization of the immunogenetic make-up of the women may be an additional tool in the differentiation of component pathologies and/or prediction of severity of the syndrome.

Objectives: It is possible that altered control of aldosterone synthase gene (CYP11B2) expression or translation may be responsible for hypertension. Hypertension is one of the major components of preeclampsia. We present here a study investigating the association between the CYP11B2 gene polymorphism in the promoter region at the position of -344 and preeclampsia., Study Design: We analyzed a group of Turkish women for preeclampsia (n=143), eclampsia (n=36), and the HELLP syndrome (n=55) and compared them with controls (n=147). Genotypes for CYP11B2 were determined by polymerase chain reaction followed by digestion with BsuRI restriction enzyme., Results: The -344T/T, -344C/T, and -344C/C genotypes were found at comparable frequencies among the study groups, between the study and control groups, and between the study groups combined and the control group (p>0.05). We combined the genotypes of TC and CC (polymorphic) and compared them with the TT (wild-type) genotype. There was no significant difference in the frequency of the TC plus CC genotypes among the study groups, between the study and control groups, and between the study groups combined and the control group (p>0.05). There was no association of the CYP11B2 polymorphism among the preeclampsia, eclampsia, and HELLP groups and controls., Conclusions: The CYP11B2 gene polymorphism is not directly associated with preeclampsia, eclampsia, and the HELLP syndrome in women with these conditions. Therefore, this polymorphism may not be a risk factor for these disorders, at least not in the Turkish population.

Objective: To study the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in preeclampsia placenta and the relation with preeclampsia attacks., Methods: Forty-four samples from pregnant women with preeclampsia (preeclampsia group), 38 samples from pregnant women with eclampsia, and 49 samples from normal pregnancies (control group) were obtained. We detected the expression of EMMPRIN in placenta by immunohistochemistry and the expression of EMMPRIN mRNA by RT-PCR., Results: (1) EMMPRIN positive expression: in preeclampsia group, the moderate expression rate was 18% (8/44) and the strong positive rate was 9% (4/44); in eclampsia group moderate positive rate was 21% (8/38) and strong positive rate 13% (5/38). The difference of the two groups was insignificant (P > 0.05). In control group the moderate positive rate was 12% (6/49) and strong positive rate 82% (40/49), the difference from the preeclampsia and the eclampsia groups was significant (P < 0.001). (2) EMMPRIN mRNA expression: in preeclampsia group EMMPRIN mRNA expression in term placenta (37 - 40 gestational weeks) was 0.342 +/- 0.002, and in eclampsia group 0.344 +/- 0.023; the difference between the two groups was insignificant (P > 0.05). In control group EMMPRIN mRNA expression in term placenta (37 - 40 gestational weeks) was 0.872 +/- 0.094, the differences between the control group and preeclampsia and eclampsia groups were both significant (P < 0.001)., Conclusion: The decrease in the expression of EMMPRIN in placenta is an important cause of preeclampsia onset; expression rate of EMMPRIN may serve as an indicator in predicting preeclampsia.

Objective: To investigate the association between the single nucleotide polymorphism (SNP) at locus 589 of dopamine-beta-hydroxylase (DbetaH) gene and hypertensive disorder complicating pregnancy (HDCP)., Methods: One hundred and seven pregnant women with hypertensive disorder complicating pregnancy (HDCP group) and 95 normal pregnant women (control group) matched for age and gestation were selected. Genotypes of the SNP at locus 589 were typed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP)., Results: (1) The frequencies of DbetaH GG, GA and AA genotypes of the SNP at locus 589 were 75.7%, 21.5% and 2.8% in HDCP group, respectively. They were 72.6%, 24.2% and 3.2% in normal control group, respectively (P > 0.05). The frequencies of the two alleles G and A were 86.4% and 13.6% in HDCP group, and 84.7% and 15.3% in normal control group, respectively (P > 0.05). (2) No evident differences existed in distribution of genotypes of the SNP at locus 589 between mild preeclampsia, severe preeclampsia and eclampsia groups (P > 0.05)., Conclusion: The SNP at locus 589 of DbetaH gene is not associated with hypertensive disorder complicating pregnancy, nor is it associated with the severity of hypertensive disorder complicating pregnancy.

Background: Preeclampsia and its association with thrombophilia remain controversial, due to inconsistent results in different studies, which include different ethnic groups, selection criteria, and patient numbers. The aim of this study was to determine the relationship between thrombophilia and preeclamptic patients in our region., Methods: In a prospective case-control study, we compared 100 consecutive women with preeclampsia and eclampsia (group 1) with 100 normal pregnant women (group 2). All women were tested two months after delivery for mutations of factor V Leiden, methylenetetrahydrofolate reductase (MTHFR), and prothrombin gene mutation as well as for deficiencies of protein C, protein S, and antithrombin III., Results: A thrombophilic mutation was found in 42 (42%) and 28 (28%) women in group 1 and group 2, respectively (P=0.27, OR 1.5, 95%CI 1.0-2.2). The incidence of Factor V Leiden mutation (heterozygous), prothrombin mutation (heterozygous), prothrombin mutation (homozygous), MTHFR mutation (homozygous) was not statistically significant in group 1 compared with group 2 (P>0.05). Also, deficiencies of protein S, protein C, and antithrombin III were not statistically significant in group 1 compared with group 2 (P>0.05)., Conclusion: There was no difference in thrombophilic mutations between preeclamptic patients and normal pregnant women in our region. Therefore, we suggest that preeclamptic patients should not be tested for thrombophilia.

Objective: Decreased HLA-G expression has been linked to a number of pregnancy disorders, including preeclampsia, and a genetic basis for HLA-G regulation has yet to be found. The aim of this study was to determine whether a C-to-T base substitution 56 base pairs (bp) upstream from the HLA-G transcription start site is associated with preeclampsia., Methods: 277 nulliparous women consisting of 113 normotensive, 118 preeclamptic, and 46 eclamptic patients were typed for the -56T polymorphism using restriction fragment length polymorphism and allelic discrimination analysis., Results: -56T allele frequencies for eclamptic, preeclamptic, and normotensive women were 0.053, 0.030, and 0.035, respectively. A chi2 test indicated that there was no significant association with the polymorphism in preeclamptic or eclamptic women with p > 0.05., Conclusion: The -56T HLA-G polymorphism is not associated with preeclampsia or eclampsia in our population.

Pre-eclampsia/eclampsia is a serious disorder of human pregnancy that has a worldwide incidence of 2-10% and carries a severe morbidity and mortality risk for both mother and child. Its precise cause remains unknown. However, there is increasing evidence of an underlying complex maternal genetic susceptibility. Its high population incidence in the face of strong negative selection pressure suggests that the gene(s) involved have a selective advantage and/or a high mutation rate. One class of genetic diseases that involve a high mutation rate are the trinucleotide repeat expansion diseases. Thus, the aim of this study was to determine whether there is an association between a trinucleotide (CAG) repeat expansion and pre-eclampsia/eclampsia. We have used the repeat expansion detection (RED) method, which was developed to directly identify clinically significant repeat expansions, to analyse genomic DNA from an Australian and New Zealand population. The maximal CAG repeat length for each individual was recorded and the Mann-Whitney U and Wilcoxon rank sum test for independent samples were used to compare distributions for CAG/CTG repeats between two populations. There were no statistically significant differences between the distribution of CAG repeats in normotensive (n = 59) and severe pre-eclampsia (n = 69) (Mann-Whitney U = 1732; P = 0.14), and normotensive (n = 59) and eclamptic (n = 15) populations (Mann-Whitney U = 417, P = 0.726). Therefore, these RED results do not support a role for a large CAG expansion in pre-eclampsia/eclampsia. However, these data do not preclude the possibility that a small CAG expansion is associated with the disorder nor do they negate the hypothesis that a highly mutable gene contributes to the genetic component of pre-eclampsia/eclampsia.

Aim: There is substantial evidence that genetic factors play a role in pre-eclampsia. The aim of this study was to determine whether genetic variability in the encoding of genes for glutathione S-transferase M1 (GSTM1) and glutathione S-transferase T1 (GSTT1) contributes to individual differences in susceptibility to pre-eclampsia, eclampsia, or hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome)., Methods: A total of 221 women with pre-eclampsia, eclampsia and HELLP syndrome and 147 healthy female controls were genotyped for GSTM1 and GSTT1 polymorphisms by polymerase chain reaction (PCR). Statistical evaluation of differences in polymorphic rates was carried out using chi(2) analysis., Results: This study included 140 pre-eclamptic, 33 eclamptic and 48 HELLP syndrome cases and 147 healthy controls. The frequencies for the GSTM1 null genotype were 58%, 45%, and 60% for pre-eclampsia, eclampsia, and HELLP syndrome, respectively, and in controls it was 55%. The distribution of the GSTT1 null genotype was 22%, 21%, and 27% for pre-eclampsia, eclampsia, and HELLP syndrome, respectively, and in controls it was 22%. There was no significant association between GSTM1 and GSTT1 polymorphisms and pre-eclampsia, eclampsia, and HELLP syndrome., Conclusion: Our data do not support a role for polymorphisms of the GSTM1 and GSTT1 genes in the pathogenesis of pre-eclampsia, eclampsia and HELLP syndrome.

The possible role of the beta-subunit of the epithelial sodium channel T594M polymorphism in hypertensive disorders of pregnancy has not been examined. This study compared Black South African women with pre-eclampsia (n= 204), early onset pre-eclampsia (n= 67), eclampsia (n= 120) and gestational hypertension (n= 78) with 338 women from the same ethnic group who had full-term normotensive pregnancies, for the presence of the T594M polymorphism. The variant allele was detected in 1.7% to 3.8% of the various patient groups and in 3.6% of the control group reflecting no significant difference. These results suggest that the T594M polymorphism in the sodium channel beta-subunit is not associated with the pathogenesis of pre-eclampsia or gestational hypertension.

The genetic background predisposing pregnant women to the disorder pre-eclampsia/eclampsia (PE/E) is still unknown. There is compelling evidence to suspect involvement of the immune system in the development of PE/E. The aim of this current study was to investigate whether there is an association between the tumor necrosis factor (TNF)-alpha -307 polymorphism and PE or eclampsia. In this study, 51 cases of eclampsia, 122 cases of PE and 100 normotensive control cases were genotyped for the TNF-alpha -307 polymorphism. We found a significant difference between the TNF2 allele frequencies of eclamptic and normotensive controls (chi(2) = 6.3 and p = 0.025), but not of pre-eclamptic and normotensive controls (chi(2) = 0.5 and p = 1.0). We conclude from this study that the TNF2 allele contributes to the occurrence of eclampsia in our population., (Copyright 2004 S. Karger AG, Basel)

To determine whether consanguinity is more likely to be associated with severe forms of pre-eclampsia/eclampsia. Presuming a pure genetic contribution, we speculated that consanguineous marriages would increase the occurrence of severe forms of pre-eclampsia/eclampsia, through an expected increased chance for homozygosity to the putative gene. The study is a clinical case series on pre-eclamptic/eclamptic primiparae delivered at Princess Badea Teaching Hospital, which is a tertiary referral center. The internationally accepted definitions for hypertension, proteinuria, mild and severe pre-eclampsia were adopted. The study included 77 primiparae. The incidence of consanguinity in the studied sample was 38%. Of them, 28 (36.4%) had mild pre-eclampsia, 45 (58.4%) had severe pre-eclampsia and four (5.2%) had eclampsia. There was no statistically significant difference in the occurrence of severe pre-eclampsia/eclampsia between primiparae married to a first cousin or a relative other than a first cousin and primiparae married to a non-relative, odds ratio 1.1 (95% CI 0.33-3.87), P value 0.94, odds ratio 2.6 (95% CI 0.45-27.6), P value 0.30, respectively. Also, there was no statistically significant difference in occurrence of severe pre-eclampsia/eclampsia between primiparae whose parents are first cousins or relatives other than a first cousin and primiparae whose parents are non-relatives, odds ratio 1.3 (95% CI 0.36-4.72), P value 0.81, odds ratio 1.61 (95% CI 0.23-18.4), P value 0.70, respectively. Our study did not support a causal relationship between consanguinity and the occurrence of severe pre-eclampsia/eclampsia. The role of more complex genetic, immunologic, metabolic, hemostatic or, possibly yet, other unknown factors have to be explored.

It has been suggested that gene aberrations may contribute to vascular endothelial dysfunction of pre-eclampsia in Caucasian and Japanese women. This study was undertaken to examine the association between pre-eclampsia in Black Zulu speaking South African women and the Factor 5 Leiden mutation. 100 patients with pre-eclampsia comprised the study group. The control group comprised 110 normotensive pregnant women of the same population group. Genotyping was performed to detect the G or A allele at residue 506 of the Factor V gene, and the C or T allele at residue 455 of the thrombomodulin gene. Our findings demonstrate that these particularly genetic loci are of little use in disease association studies for pre-eclampsia in homogenous Zulu speaking Africans.

Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.

Objective: To investigate potential association or linkage among nine polymorphisms in the genes encoding tumor necrosis factor (TNF) alpha or lymphotoxin (LT) alpha and preeclampsia., Methods: Four di-allelic polymorphisms and five microsatellite markers in the genes encoding TNF-alpha (TNF) and LTalpha (LTA) and their haplotypes were studied in 150 Dutch families. These families contained sib-pairs of women affected with preeclampsia; eclampsia; the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (strict criteria); or pregnancy-induced hypertension (mild criteria). Frequencies were compared with 98 healthy controls. Nonparametric affected sib-pair analyses for allele sharing among siblings were carried out for all nine markers. Each sibship was composed of an affected index woman and one or more affected sisters., Results: Although we found a striking association with the TNF-I haplotype in 30 index women with (pre-)eclampsia or HELLP syndrome compared with controls (odds ratio [OR] 3.8; 95% confidence interval [CI] 1.6, 8.9), this association was not found in their 30 sisters meeting similar disease criteria. Analyses in all 150 families showed a similar TNF-I association in 122 index women meeting the strict criteria compared with controls (OR 1.9; 95% CI 1.1, 3.3), but, again, not in their 91 sisters meeting similar disease criteria. This association was stronger in a subgroup of 75 index women with preeclampsia only (OR 2.3; 95% CI 1.2, 4.2). No excess allele sharing for any marker was seen between the siblings., Conclusion: The nine polymorphisms studied in the TNF-LTA region did not show evidence for association or linkage with familial preeclampsia.

Objective: To examine the role of preeclampsia and eclampsia in pregnancy-related mortality., Methods: We used data from the Centers for Disease Control and Prevention's Pregnancy Mortality Surveillance System to examine pregnancy-related deaths from preeclampsia and eclampsia from 1979 to 1992. The pregnancy-related mortality ratio for preeclampsia-eclampsia was defined as the number of deaths from preeclampsia and eclampsia per 100,000 live births. Case-fatality rates for 1988-1992 were calculated for preeclampsia and eclampsia deaths per 10,000 cases during the delivery hospitalization, using the National Hospital Discharge Survey., Results: Of 4024 pregnancy-related deaths at 20 weeks' or more gestation in 1979-1992, 790 were due to preeclampsia or eclampsia (1.5 deaths/100,000 live births). Mortality from preeclampsia and eclampsia increased with increasing maternal age. The highest risk of death was at gestational age 20-28 weeks and after the first live birth. Black women were 3.1 times more likely to die from preeclampsia or eclampsia as white women. Women who had received no prenatal care had a higher risk of death from preeclampsia or eclampsia than women who had received any level of prenatal care. The overall preeclampsia-eclampsia case-fatality rate was 6.4 per 10,000 cases at delivery, and was twice as high for black women as for white women., Conclusion: The continuing racial disparity in mortality from preeclampsia and eclampsia emphasizes the need to identify those differences that contribute to excess mortality among black women, and to develop specific interventions to reduce mortality from preeclampsia and eclampsia among all women.

Objective: We investigated maternal versus fetal genetic causes of preeclampsia and eclampsia by assessing concordance between monozygotic and dizygotic female co-twins, between female partners of male monozygotic and dizygotic twin pairs, and between female twins and partners of their male co-twins in dizygotic opposite-sex pairs., Study Design: Two large birth cohorts of volunteer Australian female twin pairs (N = 1504 pairs and N = 858 pairs) were screened and interviewed, and available medical and hospital records were obtained and reviewed where indicated, with diagnoses assigned according to predetermined criteria., Results: With strict diagnostic criteria used for preeclampsia and eclampsia, no concordant female twin pairs were found. Collapsing diagnoses of definite, probable, or possible preeclampsia or eclampsia resulted in very low genetic recurrence risk estimates., Conclusion: Results from these two cohorts of female twin pairs do not support clear, solely maternal genetic influences on preeclampsia and eclampsia. Numbers of parous female partners of male twins were too low for conclusions to be drawn regarding paternal transmission.

The C677T methylenetetrahydrofolate reductase (MTHFR) gene polymorphism results in reduced MTHFR enzymatic activity. This in turn results in increased levels of homocysteine. It has been suggested that increased levels of homocysteine cause vascular disease, which is known to increase the risk of developing pre-eclampsia (PE) during pregnancy. However, recent studies on Japanese, Italian and American populations have failed to reach agreement on an association between the C677T polymorphism and PE. In this study, 156 cases of eclampsia (E)/PE and 79 normal pregnant control cases from an Australian population were genotyped for this mutation. No significant difference could be found in the incidence of the homozygote mutation or in the allele frequency. We conclude from this study that the C677T mutation in our population is not associated with the development of PE/E., (Copyright 2000 S. Karger AG, Basel.)

In European and Japanese but not in Australian, American, and South African women, the C677T methylenetetrahydrofolate reductase (MTHFR) polymorphism has been reported to be a genetic risk factor pre-eclampsia/eclampsia (PE/E). The recently described A1298C MTHFR gene polymorphism also results in reduced MTHFR enzyme activity, although to a lesser extent than the previously described C677T polymorphism. Heterozygotes for both polymorphisms are reported to have an even lower MTHFR enzymatic activity than seen in homozygotes for the C677T genotype. In this current study we determined the allele frequency of the A1298C MTHFR gene polymorphism in an Australian population and examined this polymorphism alone and in combination with the C677T MTHFR polymorphism for an association with PE/E. Neither the A1298C polymorphism alone nor a combination of both polymorphisms showed an association with PE/E in our population of Australian women., (Copyright 2000 S. Karger AG, Basel.)

Objective: A strong independent association between the prothrombin G20210A gene mutation and pre-eclampsia has been reported in an Italian population. This result was not confirmed in a subsequent study in a Dutch population. The objective of this study was to further test the hypothesis that the prothrombin G20210A mutation is associated with pre-eclampsia/eclampsia., Methods: Seventeen eclamptics and 67 pre-eclamptics were recruited from 34 multicase Australian/New Zealand families. An additional 105 unrelated pre-eclamptic/eclamptic women and 119 parous women were recruited as controls., Results: The overall incidence for the prothrombin G20210A gene mutation in the pre-eclamptic group was 3.6% (95% CI 1.2-8.2%) which was not significantly different from the control group 2.5% (95% CI 0.5-7.2%) (p = 0.73, OR 1.44, 95% CI 0.34-6.17)., Conclusion: This study provides little evidence of a significant relationship between the prothrombin G20210A gene mutation and pre-eclampsia. Based on our results, we do not recommend testing for the prothrombin G20210A mutation in the routine investigation of women with pre-eclampsia., (Copyright 2000 S. Karger AG, Basel.)