Tissue inhibitor of matrix metalloproteinase-1 polymorphism, plasma TIMP-1 levels, and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy.

Tissue inhibitor of metalloproteinase (TIMP)-1 is a major endogenous inhibitor of matrix metalloproteinase (MMP)-9, which may affect the responsiveness to therapy in hypertensive disorders of pregnancy. We examined whether TIMP-1 polymorphism (g.-9830T>G, rs2070584) modifies plasma MMP-9 and TIMP-1 levels and the response to antihypertensive therapy in 596 pregnant: 206 patients with preeclampsia (PE), 183 patients with gestational hypertension (GH) and 207 healthy pregnant controls. We also studied the TIMP-3 polymorphism (g.-1296T>C, rs9619311). Plasma MMP-9 and TIMP-1 levels were measured by ELISA. GH patients with the GG genotype for the TIMP-1 polymorphism had lower MMP-9 levels and MMP-9/TIMP-1 ratios than those with the TT genotype. PE patients with the TG genotype had higher TIMP-1 levels. The G allele and the GG genotype were associated with PE and responsiveness to antihypertensive therapy in PE, but not in GH. Our results suggest that the TIMP-1 g.-9830T>G polymorphism not only promotes PE but also decreases the responses to antihypertensive therapy.

Matrix metalloproteinase-9 polymorphisms affect plasma MMP-9 levels and antihypertensive therapy responsiveness in hypertensive disorders of pregnancy.

Abnormal matrix metalloproteinase (MMP)-9 levels may have a role in hypertensive disorders of pregnancy. We examined whether MMP-9 genetic polymorphisms (g.-1562C >T and g.-90(CA)13-25) modify plasma MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1 levels and the responses to antihypertensive therapy in 214 patients with preeclampsia (PE), 185 patients with gestational hypertension (GH) and a control group of 214 healthy pregnant (HP). Alleles for the g.-90(CA)13-25 polymorphism were grouped L (low) (< 21 CA repeats) or H (high) (≥ 21 CA repeats). Plasma MMP-9 and TIMP-1 concentrations were measured by enzyme-linked immunosorbent assay. Plasma MMP-9 concentrations were not affected by genotypes or haplotypes in HP and PE groups, except for the g.-90(CA)13-25 polymorphism: GH patients with the LH genotype for this polymorphism have higher MMP-9 levels than those with other genotypes. The T allele for the g.-1562C > T polymorphism and the H4 haplotype (combining T and H alleles) are associated with GH and lack of responsiveness to antihypertensive therapy in GH. The H2 haplotype (combining C and H alleles) was associated with lack of responsiveness to antihypertensive therapy in PE, but not in GH. In conclusion, our results show that MMP-9 genetic variants are associated with GH and suggest that MMP-9 haplotypes affect the responsiveness to antihypertensive therapy in hypertensive disorders of pregnancy.

Role of plasma PlGF, PDGF-AA, ANG-1, ANG-2, and the ANG-1/ANG-2 ratio as predictors of preeclampsia in a cohort of pregnant women.

INTRODUCTION: Preeclampsia affects 3-5% of pregnancies worldwide and is the primary cause of maternal-fetal and neonatal mortality. Previous studies show that alterations in maternal concentrations of angiogenic factors, such as PlGF, PDGF AA, ANG-1, and ANG-2, may play fundamental roles in the pathophysiology of the disease. OBJECTIVE: Determine whether the PlGF, PDGF AA, ANG-1, and ANG-2 are predictors of preeclampsia occurrence in a prenatal cohort study. PATIENTS AND METHODS: This is a case-control study associated with a prospective cohort of pregnant women, with gestational ages between 20 and 25 weeks, composed of 30 pregnant women with preeclampsia (PE) and 90 healthy pregnant women (HP). The plasma concentrations of the markers were determined using the ELISA method. The comparison between the case and control groups was performed using the t test on the SAS® 9.4 software. Also, ROC curves were constructed to evaluate the predictive potential of the biomarkers. RESULTS: Differences in the concentrations of PlGF, PDGF AA, ANG-1 and ANG-2, and the ANG-1/ANG-2 ratio were not observed between the PE and the HP groups. The predictive capacity of the biomarkers was assessed using ROC curves, in which the area under the curve for PlGF AUC = 0.55; PDGF AA AUC = 0.55; ANG-1 AUC = 0.47; ANG-2 AUC = 0.51, and the ANG-1/ANG-2 ratio AUC = 0.57. CONCLUSION: In pregnant women, with gestational ages between 20 and 25 weeks significant differences in biomarker concentrations between groups PE and HP were not observed. The ROC curves showed that the biomarkers were ineffective as preeclampsia predictors in the analyzed cohort.

Polymorphisms of the adiponectin gene in gestational hypertension and pre-eclampsia.

Adiponectin is a hormone involved in energy homeostasis by regulating glucose and lipid metabolism. In addition, the adiponectin gene (ADIPOQ) has polymorphisms that can modulate the circulating concentration of adiponectin. Abnormal adiponectin levels have been associated with pre-eclampsia (PE); however, the influence of genetic polymorphisms on the development of hypertensive disorders of pregnancy is unclear. The aim of this study was to examine whether ADIPOQ polymorphisms are associated with gestational hypertension (GH) and/or PE. We studied 401 pregnant women: 161 healthy pregnant (HP), 113 pregnant with GH and 127 pregnant with PE. ADIPOQ polymorphisms -11391G>A (rs17300539), -11377C>G (rs266729), 45T>G (rs2241766) and 276G>T (rs1501299) were genotyped by allelic discrimination assays using real-time PCR. Haplotypes were inferred using the PHASE 2.1 program. We observed that the genotypic frequencies of the -11377C>G polymorphism were different in PE compared with HP (P<0.0125), with the CT genotype being more commonly found in PE patients than in HP women (P<0.0125). However, allelic frequencies of this single-nucleotide polymorphism were similar between PE and HP (P>0.0125). No difference was observed when GH and HP groups were compared (both P>0.0125). In addition, we found no difference in genotype or allele distributions for the -11391G>A, 45T>G and 276G>T polymorphisms when we compared GH or PE with HP (all P>0.0125). In conclusion, we found a modest association between the CG genotype of the -11377C>G polymorphism and PE.

Assessment of oxidative status markers and NO bioavailability in hypertensive disorders of pregnancy.

The systemic oxidative status in hypertensives disorders of pregnancy (HDP) and its association with endothelial dysfunction is controversial. In the present study, we evaluated systemic plasma levels of oxidative stress markers (TBARS (thiobarbituric acid-reactive substances) and carbonyl) and total antioxidant status (FRAP (ferric reducing ability of plasma (ferric reducing/antioxidant power) and reduction of MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide))), as well as assessed the impact these markers have on nitric oxide (NO) status in healthy pregnant (HP, n=38), gestational hypertensive (GH, n=33) and preeclamptic pregnant women (PE, n=28). We found similar values of TBARS among all groups, and reduced carbonyl levels in HDP between the PE and GH. Conversely, significant increases in plasma activity of antioxidant status were observed in the GH and PE groups compared to the HP group (using both MTT or FRAP method). Importantly, HDP present significantly lower nitrite levels compared to HP women. In Conclusion, our findings show a compensatory antioxidant mechanism against reactive oxygen species (ROS) generation in HDP, which is not associated with nitrite levels restoration.

PP002. Study of polymorphisms of the adiponectin gene in women with gestational hypertension and preeclampsia.

INTRODUCTION: Adiponectin is involved in energy homeostasis by regulating glucose and lipid metabolism. Additionally, it presents anti-inflammatory and anti-atherosclerotic functions. Polymorphisms in adiponectin gene (ADIPOQ) can modulate the concentrations of adiponectin. The influence of these polymorphisms on the development of gestational hypertension (GH) and preeclampsia (PE) is unknown. OBJECTIVES: The aim of this work was to examine the influence of polymorphisms in the gene ADIPOQ on the development of gestational hypertension and preeclampsia. PATIENTS AND METHODS: We studied 401 pregnant women: 161 healthy pregnant (HP), 113 pregnant with gestational hypertension (GH) and 127 pregnant with preeclampsia (PE). Polymorphisms ADIPOQ -11391G>A (rs17300539), -11377C>G (rs266729), 45T>G (rs2241766) and 276G>T (rs1501299) were genotyped by allelic discrimination by PCR in real time. Haplotypes were inferred using the PHASE 2.1 program. RESULTS: There were no statistically significant differences in allele and genotype frequencies of the polymorphisms studied. In the analysis of haplotypes, we observed small differences in haplotype frequencies between groups, however, none of these differences was statistically significant (P>0.05). CONCLUSION: We found no association between the genotypic and allelic variants of the ADIPOQ gene polymorphisms with the development of gestational hypertension and preeclampsia.