Polymorphisms in endothelial nitric oxide synthase gene in early and late severe preeclampsia Patrícia Nessralla Alpoim a , Karina Braga Gomes a , Melina de Barros Pinheiro a , Lara Carvalho Godoi a , Letícia Lemos Jardim a , Ludmila Gomes Muniz b , Valéria C. Sandrim c , Ana Paula Fernandes a , Luci Maria S. Dusse a, * a Department of Clinical and Toxicological Analysis – Faculty of Pharmacy, Universidade Federal deMinas Gerais, Brazil b Graduate Studies and Research Group – Santa Casa de Belo Horizonte Santa Casa, Belo Horizonte, Minas Gerais, Brazil c Department of Pharmacology, Institute of Biosciences, Universidade Estadual Paulista (UNESP), Botucatu, São Paulo, Brazil ARTICLE INFO Article history: Received 11 June 2014 Revised 24 July 2014 Available online 11 August 2014 Keywords: Early/late preeclampsia Nitric oxide Polymorphisms Endothelial nitric oxide synthase gene A B ST R AC T Preeclampsia (PE) is characterized by hypertension and proteinuria, occurring after the 20th week of preg- nancy in women who have had no previous symptoms. The disease progresses with generalized vasoconstriction and endothelial dysfunction. Clinically, it is important to diagnose the severe form of the disease (sPE), in which blood pressure and proteinuria are much higher. Recently, the gestational age (GA) of the onset of PE has led to the classification of this disease as early (GA <34 weeks) and late (GA ≥34 weeks). Several genetic polymorphisms affecting endothelial nitric oxide synthase (eNOS) levels or function were described, including G894T (Glu298Asp), VNTR b/a (variable-number 27-bp tandem repeat) and T-786C (promoter) polymorphisms. Thus, the aim of this study was to compare the distribution of G894T, VNTR b/a and T-786C polymorphisms and their haplotypes in Brazilian early and late sPE, as well as in normotensive pregnant. A total of 201 women were evaluated, 53 with early sPE, 45 with late sPE and 103 as normotensive pregnant women. The frequency of 894T allele was higher in late sPE vs nor- motensive pregnant, and 894TT genotype was higher in late sPE vs early sPE and normotensive pregnant. For VNTR b/a polymorphism, higher frequencies of aa genotype and a allele were observed in early sPE vs late sPE and normotensive pregnant. Besides, the frequency of haplotype T-b-C was higher in late sPE vs early sPE and normotensive pregnant. Considering the results found for eNOS polymorphisms, it is possible to suggest that the functional alterations induced by these two polymorphisms may influence the time of severe PE onset, although both alterations are putatively associated with low NO bioavailability. However, other studies are necessary to validate these findings and clarify this issue. © 2014 Elsevier Inc. All rights reserved. 1. Introduction Preeclampsia (PE) is characterized by hypertension and protein- uria, occurring after the 20th week of pregnancy in women who have had no previous symptoms. Clinically, it is important to di- agnose the severe form of the disease (sPE), in which blood pressure and proteinuria are much higher [1]. The maternal cardiovascular system undergoes structural and functional changes to accommodate the increased circulatory re- quirements of the growing fetus. The mechanisms mediating uteroplacental changes during pregnancy are not fully under- stood. However, the l-arginine-NO pathway seems to play a central role in both normal pregnancy and PE [2]. Several genetic polymorphisms affecting endothelial nitric oxide synthase (eNOS) production levels or function were described. It has been suggested that the presence of G894T (Glu298Asp located in exon 7; rs1799983) polymorphism leads to proteolytic cleavage of eNOS in endothelial cells resulting in lower NO bioavailability [3]. The VNTR b/a (variable-number 27-bp tandem repeat located in intron 4) and T-786C (located in promoter; rs2070744) polymor- phisms have been associated with lower eNOS mRNA synthesis and consequently decreased NO levels [4,5]. These variants have already been associated with vascular disorders, including hypertension, cor- onary artery disease, diabetic complications and stroke [6–8]. The relationship between PE and eNOS gene polymorphisms has been investigated with inconsistent results [9–13]. PE is a complex disease and the forms, mild and severe, seem to have distinct eti- ology. Recently, the gestational age (GA) of the onset of PE were proposed to classify this disease in early (GA <34 weeks) and late (GA ≥34 weeks) PE. It has been admitted that early PE is associ- ated with ischemic placental lesions, while in late PE an adequate * Corresponding author. Fax: +55 31 3409 6985. E-mail address: lucidusse@gmail.com (L.M.S. Dusse) http://dx.doi.org/10.1016/j.niox.2014.07.006 1089-8603/© 2014 Elsevier Inc. All rights reserved. Nitric Oxide 42 (2014) 19–23 Contents lists available at ScienceDirect Nitric Oxide journal homepage: www.elsevier.com/locate/yniox