Association Of Nitric Oxide Synthase And Matrix Metalloprotease Single Nucleotide Polymorphisms With Preeclampsia And Its Complications.

Preeclampsia 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. To 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. This 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. We 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. Our data support that the NOS3 T-786C SNP is associated with preeclampsia and the severity of its complications.10e013669

Iron overload disorders

Abstract Iron overload disorders represent a variety of conditions that lead to increased total body iron stores and resultant end‐organ damage. An elevated ferritin and transferrin‐iron saturation can be commonly encountered in the evaluation of elevated liver enzymes. Confirmatory homeostatic iron regulator (HFE) genetic testing for C282Y and H63D, mutations most encountered in hereditary hemochromatosis, should be pursued in evaluation of hyperferritinemia. Magnetic resonance imaging with quantitative assessment of iron content or liver biopsy (especially if liver disease is a cause of iron overload) should be used as appropriate. A secondary cause for iron overload should be considered if HFE genetic testing is negative for the C282Y homozygous or C282Y/H63D compound heterozygous mutations. Differential diagnosis of secondary iron overload includes hematologic disorders, iatrogenic causes, or chronic liver diseases. More common hematologic disorders include thalassemia syndromes, myelodysplastic syndrome, myelofibrosis, sideroblastic anemias, sickle cell disease, or pyruvate kinase deficiency. If iron overload has been excluded, evaluation for causes of hyperferritinemia should be pursued. Causes of hyperferritinemia include chronic liver disease, malignancy, infections, kidney failure, and rheumatic conditions, such as adult‐onset Still's disease or hemophagocytic lymphohistiocytosis. In this review, we describe the diagnostic testing of patients with suspected hereditary hemochromatosis, the evaluation of patients with elevated serum ferritin levels, and signs of secondary overload and treatment options for those with secondary iron overload

Red blood cells microparticles are associated with hemolysis markers and may contribute to clinical events among sickle cell disease patients

Microparticles are sub-micron vesicles possessing protein and other materials derived from the plasma membrane of their parent cells, and literature suggests that they may have a role in the pathophysiology and downstream manifestations of sickle cell disease (SCD). The contributions of red blood cells microparticles (RMP) to the pathogenic mechanisms and clinical phenotypes of SCD are largely unknown. There is a controversy as to whether the proportions of intravascular hemolysis (approximately <= 30% of total hemolysis) would be enough to explain some complications seen in patients with SCD. We investigated RMP among 138 SCD patients and 39 HbAA individuals. Plasma RMPs were quantified by flow cytometry, plasma hemoglobin and heme by colorimetric assays, and haptoglobin and hemopexin by ELISA. The patients had higher RMP, plasma hemoglobin, and heme compared to the controls. On the contrary, haptoglobin and hemopexin were depleted in the patients. The RMP correlated positively with heme, lactate dehydrogenase, plasma hemoglobin, serum bilirubin, reticulocyte counts, and tricuspid regurgitant jet velocity of the patients. Contrarily, it correlated negatively with HbF, hemopexin, red blood cells counts, hemoglobin concentration, and haptoglobin. Although patients treated with hydroxyurea had lower RMP, this did not attain statistical significance. Patients with sickle leg ulcer and elevated tricuspid regurgitant jet velocity had higher levels of RMP. In conclusion, these data suggest that RMPs are associated with hemolysis and may have important roles in the pathophysiology and downstream complications of SCD981125072521CNPQ - Conselho Nacional de Desenvolvimento Científico e TecnológicoFAPESP – Fundação de Amparo à Pesquisa Do Estado De São Paulo2015/141693-02014/00984-

Thalassemia major phenotypes secondary to the association of beta 5 ' UTR +20(C -> T) allele with beta 39(C -> T)

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Different morphological and gene expression profile in placentas of the same sickle cell anemia patient in pregnancies of opposite outcomes

Environmentally induced changes in placental morphological and molecular phenotypes may provide relevant insight towards pathophysiology of diseases. Sickle cell disease (SCD) is a common inherited hemoglobin disorder characterized by chronic hemolytic anemia and vaso-occlusive crisis. SCD leads to higher morbidity and mortality, especially during pregnancy, with increased risk of preeclampsia (PE). To compare clinical findings, placental morphology, and gene expression in villous placental tissue using next generation sequencing. We included five cases. Two placentas from the same woman with homozygous SCD that had been pregnant twice and had different maternal and fetal outcomes (one early onset PE/eclampsia and a mostly non-complicated pregnancy); an early onset PE, a fetal growth restriction and a term, non-complicated pregnancy. Sixty-four differentially expressed genes were observed in the SCD+PE case, in comparison with the placenta from the SCD without PE, based on fold change. Among these genes, 59 were upregulated and 5 were downregulated. Enrichment analysis indicated two significant biological processes: response to copper ion (CYP1A1, AOC1, AQP1, and ATP5D) and triglyceride-rich lipoprotein particle clearance (GPIHBP1, APOC1, and APOE). The rare opportunity to evaluate the same patient in two different pregnancies, of opposing outcomes, and compare to other conditions of known placental and vascular/inflammatory involvement, may further the understanding of the pathophysiology of PE in SCD. Our results suggest that the clinical association between SCD and PE may be supported by common pathophysiological mechanisms, but that pathways involving response to copper and triglyceride metabolism could be important drivers of PE pathophysiology2445395403CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP409605/2016–62015/08330–5; 2014/00984–3This study was supported by S~ao Paulo Research Foundation (FAPESP) grant 2015/08330–5, grant 2014/00984–3 and the National Council for Scientific and Technological Development (CNPq) grant 409605/2016–

Major allele frequencies and Hardy-Weinberg tests for the study population.

<p>SNP, single nucleotide polymorphism; MAF, major allele frequency; HWE, Hardy-Weinberg equilibrium</p><p>Major allele frequencies and Hardy-Weinberg tests for the study population.</p

Genotype frequencies of NOS3 VNTR in intron 4 for the study population.

<p>VNTR, variable number of tandem repetitions; ND, not determined</p><p>Genotype frequencies of NOS3 VNTR in intron 4 for the study population.</p

<i>Odds ratios</i> for risk factors for preeclampsia.

<p>CI, confidence interval; values in bold were statistically significant.</p><p><i>Odds ratios</i> for risk factors for preeclampsia.</p

Number of preeclamptic patients according to severity score and genotype distributions for <i>NOS3</i> T-786C.

<p>Number of preeclamptic patients according to severity score and genotype distributions for <i>NOS3</i> T-786C.</p