Abstract
BackgroundPreeclampsia (PE) is a complex pregnancy hypertensive disorder with multifaceted etiology. The endothelial nitric oxide synthase (eNOS) gene and nitric oxide (NO) levels has been reported to be associated with PE predisposition in various populations. Therefore, present study was designed to investigate the role of NO levels and eNOS gene variants in preeclamptic women in Pakistan.MethodsA total of 600 women were evaluated, 188 of PE with mild features, 112 of PE with severe features and 300 normotensive pregnant women. NO levels were detected by Greiss reaction method and genotyping following sequencing was conducted for eNOS gene variants. Further insilico studies were performed to get insights into the structural and functional impact of identifies mutation on eNOS protein as well as on protein regulation.ResultsReduced concentrations of NO were reported in all PE groups (p < 0.05) as compared to controls. The frequency of c.894 T (p.298Asp) and g.-786C alleles were significantly associated with PE. In addition, novel homozygous variant g.2051G > A was also significantly associated with PE when compared to normotensive women. Dynamic simulation studies revealed that Glu298Asp mutation destabilize the protein molecule and decrease the overall stability of eNOS protein. Molecular docking analysis of mutant promoter with transcription factors STAT3 and STAT6 proposed changes in protein regulation upon these reported mutations in upstream region of the gene.ConclusionConsidering the results of current study, the functional alterations induced by these variants may influence the bioavailability of NO and represents a genetic risk factor for increased susceptibility to PE. However, large studies or meta-analysis are necessary to validate these findings.
Highlights
IntroductionPreeclampsia (PE) is a complex pregnancy hypertensive disorder with multifaceted etiology characterized by de novo hypertension, with or without proteinuria, accompanied with the signs of maternal acute kidney injury (AKI), neurological features, liver dysfunction, hemolysis or thrombocytopenia, or fetal growth restriction after 20 weeks of gestation [1,2,3]
Preeclampsia (PE) is a complex pregnancy hypertensive disorder with multifaceted etiology characterized by increased hypertension and proteinuria after 20 weeks of gestation
The present study was directed to determine the role of endothelial nitric oxide synthase (eNOS) in susceptibility to PE and the association of c.894G > T (p.(Glu298Asp), intron 4b/4a, g.-786 T > C and other possible variants of eNOS gene with preeclampsia in Pakistani population
Summary
Preeclampsia (PE) is a complex pregnancy hypertensive disorder with multifaceted etiology characterized by de novo hypertension, with or without proteinuria, accompanied with the signs of maternal acute kidney injury (AKI), neurological features, liver dysfunction, hemolysis or thrombocytopenia, or fetal growth restriction after 20 weeks of gestation [1,2,3]. It is the leading cause of maternal and prenatal morbidity and mortality in developing countries [4]. Disturbed trophoblastic invasion and spiral arteries remodeling results in endothelial dysfunction which leads to vasoconstriction [11]
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