Epistasis among eNOS, MMP-9 and VEGF maternal genotypes in hypertensive disorders of pregnancy

Abstract

Polymorphisms of the endothelial nitric oxide synthase (eNOS), matrix metalloproteinase-9 (MMP-9) and vascular endothelial growth factor (VEGF) genes were shown to be associated with hypertensive disorders of pregnancy. However, epistasis is suggested to be an important component of the genetic susceptibility to preeclampsia (PE). The aim of this study was to characterize the interactions among these genes in PE and gestational hypertension (GH). Seven clinically relevant polymorphisms of eNOS (T-786C, rs2070744, a variable number of tandem repeats in intron 4 and Glu298Asp, rs1799983), MMP-9 (C-1562T, rs3918242 and -90(CA) 13-25 , rs2234681) and VEGF (C-2578A, rs699947 and G-634C, rs2010963) were genotyped by TaqMan allelic discrimination assays or PCR and fragment separation by electrophoresis in 122 patients with PE, 107 patients with GH and a control group of 102 normotensive pregnant (NP) women. A robust multifactor dimensionality reduction analysis was used to characterize gene-gene interactions. Although no significant genotype combinations were observed for the comparison between the GH and NP groups (P40.05), the combination of MMP-9-1562CC with VEGF-634GG was more frequent in NP women than in women with PE (Po0.05). Moreover, the combination of MMP-9-1562CC with VEGF-634CC or MMP-9-1562CT with VEGF-634CC or-634GG was more frequent in women with PE than in NP women (Po0.05). These results are obscured when single polymorphisms in these genes are considered and suggest that specific genotype combinations of MMP-9 and VEGF contribute to PE susceptibility.

New Insights into the Role of Matrix Metalloproteinases in Preeclampsia

“…Contrary to this finding, the same variant of this MMP-9 polymorphism has been associated with a higher risk of gestational hypertension and preeclampsia in Kurdish and Chinese population [ 51 , 52 ]; also, some results suggest that this polymorphism may affect the therapeutic response to antihypertensive agents, concluding that this MMP-9 variant could help to identify those patients with a refractory response [ 37 ]. Additionally, Luizon et al reported that the combination of genotypes MMP-9-1562CC with VEGF-634CC or MMP-9-1562CT with VEGF-634CC or -634GG were significantly more frequent in women with preeclampsia than in normal pregnant women, and results suggest that these epistasis contribute to a higher susceptibility to developing preeclampsia [ 53 ]. Different results were reported in Brazilian and British women, where the MMP-9-1562 C/T polymorphism was not associated with the syndrome [ 54 , 55 ].…”

Effects of NAMPT polymorphisms and haplotypes on circulating visfatin/NAMPT levels in hypertensive disorders of pregnancy

“…These findings are relevant because the associated genetic markers may allow early detection of patients at increased risk of hypertensive disorders of pregnancy, which increase morbidity and mortality. 41 The present study has other limitations. First, we studied a relatively small number of patients and plasma visfatin/NAMPT levels were determined in a smaller number of patients.…”

Vascular endothelial growth factor (VEGF)‐634G/C polymorphism was associated with severe pre‐eclampsia and lower serum VEGF level

“…Although no significant association between VEGF +936 T allele and PE was observed in the study by Cunha et al ., the frequency of the VEGF ‐2578A allele was significantly higher in the control group . In another study, the combination of MMP ‐9 ‐1562CC with VEGF ‐634GG genotypes was more frequent in control women compared to PE women . Chedraui et al .…”