Association of Nitric Oxide Synthase and Matrix Metalloprotease Single Nucleotide Polymorphisms with Preeclampsia and Its Complications

Abstract

BackgroundPreeclampsia is one of the leading causes of maternal and neonatal morbidity and mortality in the world, but its appearance is still unpredictable and its pathophysiology has not been entirely elucidated. Genetic studies have associated single nucleotide polymorphisms in genes encoding nitric oxide synthase and matrix metalloproteases with preeclampsia, but the results are largely inconclusive across different populations.ObjectivesTo investigate the association of single nucleotide polymorphisms (SNPs) in NOS3 (G894T, T-786C, and a variable number of tandem repetitions VNTR in intron 4), MMP2 (C-1306T), and MMP9 (C-1562T) genes with preeclampsia in patients from Southeastern Brazil.MethodsThis prospective case-control study enrolled 77 women with preeclampsia and 266 control pregnant women. Clinical data were collected to assess risk factors and the presence of severe complications, such as eclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome.ResultsWe found a significant association between the single nucleotide polymorphism NOS3 T-786C and preeclampsia, independently from age, height, weight, or the other SNPs studied, and no association was found with the other polymorphisms. Age and history of preeclampsia were also identified as risk factors. The presence of at least one polymorphic allele for NOS3 T-786C was also associated with the occurrence of eclampsia or HELLP syndrome among preeclamptic women.ConclusionsOur data support that the NOS3 T-786C SNP is associated with preeclampsia and the severity of its complications.

Mechanisms of Endothelial Dysfunction in Hypertensive Pregnancy and Preeclampsia

“…Also, the eNOS 894T allele is subject to selective proteolytic cleavage in ECs and vascular tissues, and this could account for the reduced vascular NO generation in homozygous subjects for this variant (Alpoim et al, 2014). The T−786C allele is also increased in PE compared with Norm-Preg women (Ben Ali Gannoun et al, 2015; Leonardo et al, 2015). Paternal genes may also play a role, and a paternal history of PE was associated with a 2.7% risk of PE when compared to men whose mothers had normal pregnancy (Esplin et al, 2001).…”

Matrix Metalloproteinases in Normal Pregnancy and Preeclampsia

“…268 The T786C allele is also increased in preeclamptic compared with normal pregnant women. 269,270 Genetic polymorphisms of eNOS could affect NO production. For instance, normal pregnant women with the TT phenotype for the T-786C allele have lower plasma nitrite levels than those with the CC phenotype 271 , and the TT phenotype has been proposed as a risk factor for preeclampsia in Tunisian women.…”

Polymorphisms in interleukin-6 and interleukin-10 may be associated with risk of preeclampsia

“…Many previous investigations have shown that several environmental factors play a key role in the pathogenesis of preeclampsia, such as preexisting hypertension, family history of the disease, lack of vitamin C, and vascular endothelial injury (Dekker et al, 2011). Previous studies have shown that polymorphisms in many genes are associated with preeclampsia risk, notably in those encoding nitric oxide synthase 3, dopamine receptor D1, DRD4, lymphotoxin-a, matrix metalloprotease, transforming growth factor-b1 (TGF-b1), cyclooxygenase 2, and plateletactivating factor acetylhydrolase (Deepthi et al, 2015;Leonardo et al, 2015;Pissetti et al, 2015;Ren et al, 2015;Su et al, 2015;Wolski et al, 2015;Zeng et al, 2016).…”