Genetic markers for preeclampsia in Peruvian women / Marcadores genéticos de preeclampsia en mujeres peruanas

Abstract Background: Preeclampsia is a multiorgan disorder associated with maternal and perinatal morbi-mortality. In Peru, incidence is 10% and accounts for 22% of maternal deaths. Genome and genetic epidemiological studies have found an association between preeclampsia and genetic polymorphisms. Objective: To determine the association of the vascular endothelial growth factor (VEGF) +936 C/T and +405 G/C, interleukine-6 (IL-6) -174 G/C, IL-1β-511 C/T, Apo A-1-75 G/A, Apo B-100 2488 C/T (Xbal) polymorphisms with preeclampsia in pregnant Peruvian women. Methods: Were included preeclamptic and healthy (control) pregnant women. Maternal blood samples were subjected to DNA extraction, and molecular genetic analysis was conducted using the PCR-RFLP technique and following a specific protocol for each gene. Allele and genotypic frequencies in the cases and controls were compared. Results: No association was found between the VEGF+936C/T and VEGF+405 polymorphisms and preeclampsia. The frequencies of the GG genotypes and the G allele of the -174 G/C polymorphism in the IL6 gene in preeclamptic and controls showed significant differences, with higher frequencies in cases. For the -511 C/T polymorphism of the IL-1β gene, no significant differences were found in the frequencies of TT genotypes compared with CT+CC. The genotypes and alleles of the Apo-A1-75 G/A and Apo-B100 Xbal variants showed no significant differences between cases and controls. Conclusion: No association was found between the studied genetic markers and preeclampsia. However, in the -174G/C polymorphism of the IL-6 gene, significant differences were found mainly in the GG genotype and G allele.

Resumen Antecedentes: La preeclampsia es un trastorno multiorgánico asociado con la morbi-mortalidad materna y perinatal. En el Perú, su incidencia es del 10% y causa el 22% de las muertes maternas. Se encontró una asociación entre la preeclampsia y ciertos polimorfismos. Objetivo: Determinar asociación entre los polimorfismos genéticos del factor de crecimiento endotelial vascular (VEGF) +936 C/T y +405 G/C, interleucina-6 (IL-6) -174G/C, IL-1β -511 C/T, Apo A-1 -75 G/A, Apo B-100 2488 C/T (Xbal), y preeclampsia en gestantes peruanas. Métodos: Se incluyeron gestantes preeclámpticas y sanas (controles). Las muestras de sangre fueron procesadas para extracción del ADN, y el análisis se realizó con la técnica PCR-RFLP con protocolos específicos para cada gen y confirmación con secuenciamiento Sanger. Se compararon las frecuencias alélicas y genotípicas en los casos (preeclampsia) y los controles. Resultados: No se halló asociación entre los polimorfismos VEGF+936-C/T y VEGF+405 y la preeclampsia. Las frecuencias de los genotipos GG y el alelo G del polimorfismo -174-G/C en el gen IL6 en preeclámpticas y controles, mostraron diferencias significativas, con frecuencias más altas en los casos. Para el polimorfismo -511-C/T del gen IL-1β, no se encontraron diferencias significativas en las frecuencias de genotipos TT comparados con CT+CC. Los genotipos y alelos de las variantes Apo-A1-75-G/A y Apo-B100 Xbal no mostraron diferencias significativas entre los grupos Conclusión: No se encontró asociación entre los marcadores genéticos estudiados y la preeclampsia. Sin embargo, el polimorfismo -174-G/C en el gen IL6 mostró diferencias significativas principalmente en el genotipo GG y el alelo G.

Contribution of rs1799998 polymorphism in CYP11B2 gene in susceptibility to preeclampsia / Contribuição do polimorfismo rs1799998 no gene CYP11B2 na suscetibilidade à pré-eclampsia

Abstract Objectives: the present study aimed to evaluate the association between the rs1799998 polymorphism of the CYP11B2 gene and the susceptibility to preeclampsia (PE) in a Brazilian population. Methods: the study group comprised 61 women who were diagnosed with PE. The control group included 116 women who did not show changes in their blood pressure levels during their pregnancies. The rs1799998 polymorphism of the CYP11B2 gene was amplified by allele-specific polymerase chain reaction (PCR). A multiple logistic regression analysis was performed using the SNPStat program to evaluate the risk of the CYP11B2 gene rs1799998 polymorphism contributing to PE. Results: the PE group had the following genotypes: 1.64% CC, 91.80% CT, and 6.56% TT. In the control group, the observed genotypic frequencies were: 11% CC, 73% CT, and 16% TT. The genotypic frequency distribution did not fit the Hardy Weinberg Equilibrium (HWE) in either study group. The multiple logistic regression analysis showed a statistically significant difference for the rs1799998 polymorphism in the recessive model. Conclusion: the results suggest an association between the recessive model of C/C genotype of the rs1799998 polymorphism of the CYP11B2 gene and susceptibility to PE.

Resumo Objetivos: avaliar a associação entre o polimorfismo rs1799998 do gene CYP11B2 e a suscetibilidade à PE em uma população brasileira. Métodos: participaram desse estudo 61 mulheres com PE e 116 mulheres normotensas. O polimorfismo rs1799998 do gene CYP11B2 foi amplificado por PCR alelo-específica. O risco do polimorfismo rs1799998 do gene CYP11B2 contribuir com a PE foi avaliado pela análise de regressão logística múltipla. Resultados: as frequências genotípicas observadas foram 1.64% CC, 91.80% CT e 6.56% TT no grupo PE e 11%CC, 73%CT e 16%TT grupo controle. A distribuição da frequência genotípica não estava em Equilíbrio de Hardy Weinberg em nenhum dos grupos estudados. A análise de regressão logística múltipla demonstrou diferença estatisticamente significativa para o polimorfismo rs1799998 no modelo recessivo. Conclusão: o presente trabalho sugere associação do genótipo C/C no modelo recessivo, do polimorfismo rs1799998 do gene CYP11B2 com a suscetibilidade a PE.

Long non-coding RNA FAM99A modulated YAP1 to affect trophoblast cell behaviors in preeclampsia by sponging miR-134-5p

Preeclampsia (PE) is a complex pregnancy syndrome. Convincing evidence indicates that long non-coding RNAs (lncRNAs) are involved in the pathogenesis of PE. This research mainly investigated the mechanism of family with sequence similarity 99 member A (FAM99A) in PE. The expressions of FAM99A, miR-134-5p, and YAP1 were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell apoptosis, migration, and invasion were detected by flow cytometry or transwell assay. The interaction between miR-134-5p and FAM99A or YAP1 was confirmed by dual-luciferase reporter assay. The protein expression of YAP1 was determined by western blot assay. FAM99A and YAP1 were significantly up-regulated, and miR-134-5p was significantly down-regulated in PE tissues (n=30). miR-134-5p was verified as a candidate of FAM99A and YAP1. FAM99A promoted cell metastasis, but reduced apoptosis in HTR8/SVneo cells by regulating miR-134-5p. miR-134-5p down-regulated YAP1 expression to suppress cell metastasis, while it induced apoptosis in HTR8/SVneo cells. FAM99A positively modulated YAP1 expression by sponging miR-134-5p. FAM99A modulated YAP1 to accelerate cell migration and invasion, and inhibited cell apoptosis in PE cells by sponging miR-134-5p. The novel regulatory network may shed light on the pathogenesis of PE.

Interaction between NOS3 and HMOX1 on antihypertensive drug responsiveness in preeclampsia / Interação entre os genes NOS3 e HMOX1 na resposta à terapia antihipertensiva em pré-eclâmpsia

Abstract Objective We examined the interaction of polymorphisms in the genes heme oxygenase- 1 (HMOX1) and nitric oxide synthase (NOS3) in patients with preeclampsia (PE) as well as the responsiveness to methyldopa and to total antihypertensive therapy. Methods The genes HMOX1 (rs2071746, A/T) and NOS3 (rs1799983, G/T) were genotyped using TaqMan allele discrimination assays (Applied Biosystems, Foster City, CA, USA ), and the levels of enzyme heme oxygenase-1 (HO-1) were measured using enzyme-linked immunosorbent assay (ELISA). Results We found interactions between genotypes of the HMOX-1 and NOS3 genes and responsiveness tomethyldopa and that PE genotyped as AT presents lower levels of protein HO-1 compared with AA. Conclusion We found interactions between the HMOX-1 and NOS3 genes and responsiveness to methyldopa and that the HMOX1 polymorphism affects the levels of enzyme HO-1 in responsiveness to methyldopa and to total antihypertensive therapy. These data suggest impact of the combination of these two polymorphisms on antihypertensive responsiveness in PE.

Resumo Objetivo Examinamos a interação dos polimorfismos nos genes heme oxigenase-1 (HMOX1) eóxido nítrico sintase (NOS3) empacientes compré-eclâmpsia (PE)bem como as capacidades de resposta à metildopa e à terapia anti-hipertensiva. Métodos Os polimorfismos nos genes HMOX1 (rs2071746, A/T) e NOS3 (rs1799983, G/T) foram genotipados usando TaqMan allele discrimination assays (Applied Biosystems, Foster City, CA, EUA), e os níveis da enzima heme oxigenase-1 (HO-1) foram medidos por enzyme-linked immunosorbent assay (ELISA). Resultados Foram encontradas interações entre os genótipos da HMOX-1 e NOS3 e responsividade à metildopa, e que pacientes genotipados como AT apresentam níveis mais baixos de proteína HO-1 em comparação com o genótipo AA. Conclusão Foram encontradas interações entre os genes HMOX-1 e NOS3 e responsividade à metildopa e que o polimorfismo localizado no gene HMOX1 afeta os níveis de enzima HO-1 na resposta à metildopa e à terapia anti-hipertensiva. Esses dados sugerem o impacto da combinação desses dois polimorfismos na resposta antihipertensiva na PE.

Differential expression of microRNA-411 and 376c is associated with hypertension in pregnancy

Preeclampsia is a major reason of morbidity and mortality in pregnant women and perinatal fetus. Hence, it is of prime importance that diagnostic markers are defined to predict chances of preeclampsia in pregnant women. It has been previously shown that microRNA (miRNA)-376c expression is decreased in the placenta of preeclampsia patients at term. Even though this decrease was not mimicked in the placenta at the pre-term stage, miR-376c expression was decreased in the plasma of these patients as early as the second trimester. Plasma and placenta specimens were obtained from pregnant women having unifetal gestation undergoing perinatal care between January 2014 and December 2016 (n=49). Early trimester placentas were collected from patients undergoing terminated pregnancies through dilation and curettage procedure. Our results showed that in addition to miR-376c, miR-441 levels were decreased in the placenta of preeclampsia patients, and this decrease occurred both at pre-term and at term. This decrease is also mimicked in the plasma levels at both early and late weeks of pregnancy, highlighting that miR-441 levels can serve as a diagnostic marker of risk of preeclampsia in pregnant women. Overexpression of the miR-441, as well as miR-376c, promoted cell viability, migration, and invasion in the human immortalized cytotrophoblast cell line HTR8/SVneo, indicating that their decrease in pregnant women would result in anomalous apoptosis and functional imbalance resulting in premature abortion and other complications. MiR-441 level can thus potentially serve as diagnostic marker of preeclampsia in pregnant women.

Investigation of rs1800469 and rs1800468 Polymorphisms of the TGF-β 1 Gene in Women with Pre-eclampsia / Investigação dos Polimorfismos rs1800469 e rs1800468 do Gene TGF-β 1 em Mulheres com Pré-eclâmpsia

Abstract Objectives: to verify the contribution of polymorphisms rs1800469 and rs1800468 of the TGF-β1 gene and the risk factors for the pre-eclampsia development. Methods: this is a case-control study with 257 women from the Uberaba region of Minas Gerais were selected, 88 of them were in the pre-eclampsia group and 169 in the control group. Genotyping was performed by allelic discrimination using the real-time PCR technique. The odds ratio and the 95% confidence interval were used to evaluate the probability of the polymorphisms studied contributing for the pre-eclampsia development. The logistic regression analysis was performed to evaluate the relation among family recurrence, smoking, primiparity and the presence of polymorphic alleles and susceptibility of preeclampsia. Results: no association was found between polymorphisms rs1800469 and rs1800468 of the TGF-β1 gene and pre-eclampsia. The logistic regression analysis was statistically significant for family recurrence, showing that women with a family history of pre-eclampsia and primiparity are at an increased risk of developing the disease. Conclusions: no association was found between polymorphisms rs1800469 and rs1800468 of the TGF-β1 and pre-eclampsia gene. Factors such as family history and primiparity were associated to the risk of developing pre-eclampsia.

Resumo Objetivos: verificar a contribuição dos polimorfismos rs1800469 e rs1800468 do gene TGF-β1 e de fatores de risco para o desenvolvimento de PE. Métodos: trata-se de um estudo caso-controle, onde foram selecionadas 257 mulheres, da região de Uberaba, Minas Gerais, sendo 88 do grupo PE e 169 controles. A genotipagem foi realizada por discriminação alélica através da técnica de PCR em tempo real. Odds ratio e o intervalo de confiança de 95% foram usados para avaliar a probabilidade dos polimorfismos estudados contribuírem com o desenvolvimento de PE. A análise de regressão logística foi realizada para avaliar a relação entre recorrência familiar, tabagismo, primiparidade e presença dos alelos polimórficos e a suscetibilidade a PE. Resultados: não foi observada associação entre os polimorfismos rs1800469 e rs1800468 do gene TGF-β1 e PE. A análise de regressão logística foi estatisticamente significativa para recorrência familiar, mostrando que mulheres com histórico familiar de PE e mulheres primigestas possuem risco aumentado de desenvolver a doença. Conclusões: não foi encontrada associação entre os polimorfismos rs1800469 e rs1800468 do gene TGF-β1 e PE. Fatores como histórico familiar e primiparidade foram associados com o risco de desenvolvimento de PE.

Polymorphism in the lymphotoxin-alpha gene, position +252 (rs909253), is not associated with preeclampsia development in Brazilian women / Polimorfismo no gene da linfotoxina alfa, posição +252 (rs909253), não está associado com o desenvolvimento de pré-eclâmpsia em mulheres brasileiras

PURPOSE: To investigate the frequencies of polymorphic allele and genotypes for the LT-α gene, position +252 (rs909253), in Brazilian women with preeclampsia.METHODS: This is a case-control study, in which 30 women with preeclampsia, classified according to the criteria of the National High Blood Pressure Education Program, and 115 women in the control group, with at least two healthy pregnancies, were selected. Peripheral blood was collected, and DNA was extracted, followed by genotyping, using specific primers and restriction analysis. The genotypes obtained were AA, AG and GG. Statistical analysis was performed using the χ2association test. The Hardy-Weinberg Equilibrium was tested using the Haploview Program.RESULTS: The results showed no association between genotypes and preeclampsia development (χ2=2.0; p=0.4). When the AG and GG genotypes were grouped according to allele G presence or absence (genotype AA), the data showed that the presence of allele G was not significantly different between cases (women with preeclampsia) and controls (χ2=0.0; p=1.0). The LT-α gene polymorphism, position +252 (rs909253), seems not to be an important candidate for the development of preeclampsia. Other inflammatory genes should be researched, and studies involving gene-environment interactions should be performed, in order to reach a better understanding of the etiology of the preeclampsia.

OBJETIVO: Investigar as frequências do alelo polimórfico e genótipos para o gene da LT-α, posição +252 (rs909253), em mulheres brasileiras com pré-eclâmpsia.MÉTODOS: Trata-se de um estudo caso-controle, em que 30 mulheres com pré-eclâmpsia, classificadas de acordo com os critérios do National High Blood Pressure Education Program, e 115 mulheres do grupo controle, com pelo menos duas gestações saudáveis, foram selecionadas. Amostra de sangue periférico foi colhida, e o DNA foi extraído, seguido pela genotipagem, usando iniciadores específicos e análise de restrição. Os genótipos obtidos foram AA, AG e GG. A análise estatística foi realizada utilizando-se o teste de associação χ2. O Equilíbrio de Hardy-Weinberg foi testado com o auxílio do programa Haploview.RESULTADOS: Os resultados não mostraram associação entre os genótipos e o desenvolvimento de pré-eclâmpsia (χ2=2,0; p=0,4). Quando os genótipos AG e GG foram agrupados de acordo com a presença do alelo G ou ausência (genótipo AA), os dados mostraram que a presença do alelo G não foi significativamente diferente entre casos (mulheres com pré-eclâmpsia) e controles (χ2=0,0; p=1,0). O polimorfismo no gene LT-α, posição +252 (rs909253), parece não ser um importante candidato para o desenvolvimento de pré-eclâmpsia. Outros genes inflamatórios devem ser pesquisados, e estudos envolvendo interações gene-ambiente devem ser realizados para que se possa alcançar um melhor entendimento da etiologia da pré-eclâmpsia.

Papel protetor do alelo G do polimorfismo no gene Interleucina 10 (-1082G/A) contra o desenvolvimento de pré-eclâmpsia / Protective role of the G allele of the polymorphism in the Interleukin 10 gene (-1082G/A) against the development of preeclampsia

OBJETIVOS: Identificar a frequência do polimorfismo no gene IL-10, rs1800896 (-1082 A/G), em mulheres com pré-eclâmpsia (PE) e em mulheres do grupo controle e associar a presença deste polimorfismo com a proteção contra o desenvolvimento da PE. MÉTODOS: Estudo do tipo caso-controle, no qual foram selecionadas 54 mulheres com PE, classificadas de acordo com os critérios da National High Blood Pressure Education Program e 172 mulheres do grupo controle, com pelo menos duas gestações saudáveis. O polimorfismo proposto foi estudado utilizando-se a técnica de reação em cadeia da polimerase em tempo real (qPCR), com sondas de hidrólise. A análise estatística foi realizada utilizando-se o teste de associação do χ2. Odds ratio e seu intervalo de confiança de 95% foram usados para medir a força de associação entre o polimorfismo estudado e o desenvolvimento da PE. RESULTADOS: Foi observado aumento significativo da frequência do genótipo AG entre mulheres do grupo controle (85 versus 15% nas mulheres com PE). O alelo G é significativamente mais frequente entre as mulheres do grupo controle do que nas com PE (Teste χ2; p=0,01). O odds ratio para as portadoras do alelo G foi de 2, 13, indicando que apresentam menor risco de desenvolver PE do que as não portadoras. CONCLUSÕES: Sugere-se associação entre a presença do alelo G do polimorfismo no gene IL-10, rs1800896 (-1082 A/G), e a proteção contra o desenvolvimento da PE. Mais estudos sobre a contribuição dessas variações e os mecanismos pelos quais afetam o risco de desenvolver PE ainda necessitam de ser realizadas. .

PURPOSE: To identify the frequency of polymorphism in the IL-10 gene, rs1800896 (-1082 A/G), in women with preeclampsia (PE) and in women in a control group and to associate the presence of this polymorphism with protection against the development of PE. METHODS: This was a case-control study conducted on 54 women with PE, classified according to the criteria of the National High Blood Pressure Education Program, and on 172 control women with at least two healthy pregnancies. The proposed polymorphism was studied by the technique of real time polymerase chain reaction (qPCR), with hydrolysis probes. Statistical analysis was performed using the χ2 test. Odds ratio and confidence interval of 95% were used to measure the strength of association between the studied polymorphism and the development of PE. RESULTS: Statistically increased frequency of the AG genotype was observed among control women (85 versus 15% in women with PE). The G allele was significantly more frequent among control women than PE women (χ2 test, p = 0.01). The odds ratio for carriers of the G allele was 2.13, indicating a lower risk of developing PE compared to non-carriers. CONCLUSIONS: Thus, an association is suggested to occur between the presence of the G allele of the polymorphism in the IL-10 rs1800896 (-1082 A/G) gene and protection against the development of PE. More studies investigating the contribution of these variations and the mechanisms by which they affect the risk of developing PE still need to be undertaken. .

Evaluation of interleukin-10 [G-1082A] promoter polymorphism in preeclampsia

Preeclampsia is a pregnancy-specific syndrome that may be life-threatening, especially to the fetus. Several causes have been reported that may have a possible role in the development of the disorder. Interleukin-10 affect maternal intravascular inflammation, as well as endothelial dysfunction. The aim of this study was to investigate the association between IL-10 G-1082A polymorphism and pre-eclampsia. A total of eighty-eight pregnant women with preeclampsia and 100 women with normal pregnancy attending the Gynecological unit of Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the study. A standard amplification refractory mutation system [ARMS] PCR was carried out for genotyping IL-10 G-1082A promoter polymorphism in all the participants. Genotypic distribution of the control and patient groups were compared with values predicted by Hardy-Weinberg equilibrium using chi[2] test. Odd ratios [OR] and their respective 95% confidence intervals were used to measure the strength of association between IL-10 gene polymorphism and preeclampsia. The frequencies of IL-10 G-1082A genotypes, GG, GA and AA, were 17.8%, 41.09% and 41.09% in women with preeclampsia and 25%, 28% and 47% in the controls respectively. There was no significant difference in the distribution of genotypes and alleles of IL-10 G-1082A between the two groups [Test power=0.66]. The present study suggests that the IL-10 G-1082A gene promoter polymorphism is not a major genetic regulator in the etiology of preeclampsia

Preeclampsia: la evolución diagnóstica desde la genómica y la proteómica / Preeclampsia: diagnostic evolution from genomics and proteomics

La preeclampsia se define como la presencia de hipertensión arterial evidenciada con dos lecturas de presión arterial > 140/90 (presión arterial sistólica > 140 mmHg o diastólica > 90 mmHg) y proteinuria superior a 0,3 g/día después de la vigésima semana de embarazo en pacientes anteriormente normotensas. Aún se desconoce la verdadera causa, aunque existen algunas teorías que indican que la combinación de varios factores ambientales, genéticos e inmunológicos puede aumentar la susceptibilidad. La genómica y proteómica han venido proporcionando herramientas para la comprensión y diagnóstico de nuevos biomarcadores que apunten hacia novedosos avances en el diagnóstico, la prevención y el tratamiento de dicha patología.

Preeclampsia was defined as the presence of hypertension evidenced two blood pressure readings > 140/90 (systolic blood pressure > 140 mmHg or diastolic > 90 mmHg) and proteinuria greater than 0.3 g/day after the twentieth week pregnancy in previously normotensive patients. Still the real cause is unknown, although there are some theories that suggest that a combination of environmental factors, genetic and immunological may increase susceptibility. Genomics and proteomics have been providing necessary progress in the understanding and diagnosis of new biomarkers that point to novel advances in the diagnosis, prevention and treatment of this disease.

Polimorfismos genéticos do fator de crescimento do endotélio vascular na pré-eclâmpsia / Genetic polymorphisms of vascular endothelial growth factor in pre-eclampsia

OBJETIVO: Identificar polimorfismos genéticos do fator de crescimento do endotélio vascular (VEGF), posições +936C/T e -2578C/A, em mulheres com pré-eclâmpsia. MÉTODOS:Trata-se de um estudo transversal,constituído por 80 mulheres distribuídas em dois grupos: pré-eclâmpsia e grupo controle. A caracterização da amostra foi realizada mediante entrevista pré-estruturadae complementada por dados transcritos dos prontuários. Para identificação dos polimorfismos foi realizada extração de DNA, amplificação das sequências pela Reação em Cadeia da Polimerase (PCR) com primers específicos e análise por Polimorfismos de Comprimentos de Fragmentos de Restrição (RFLP). A análise estatística dos resultados foi realizada de forma descritiva e pelo teste do . O modelo de regressão logística múltipla foi utilizado para determinar o efeito dos polimorfismos na pré-eclampsia. RESULTADOS: Evidenciou-se uma maior frequência do alelo T do polimorfismo VEGF +936C/T nas pacientes com pré-eclâmpsia, embora com diferença não significativa.A presença do alelo A do VEGF -2578C/A foi maior no grupo controle, com diferença significativa. CONCLUSÕES: Não foi observada associação significativa do polimorfismo VEGF +936C/T com a pré-eclâmpsia. Para o polimorfismo VEGF -2578C/A observa-se diferença significativa entre os grupos, sendo o alelo A mais frequente no controle, sugerindo a possibilidade da portadora do alelo A apresentar menor suscetibilidade para o desenvolvimento de pré-eclâmpsia.

PURPOSE: To identify genetic polymorphisms of endothelial growth factor (VEGF), positions +936C/T and -2578C/A, in women with pre-eclampsia. METHODS: This was a cross-sectional study conducted on 80 women divided into two groups: pre-eclampsia and control. The sample was characterized using a pre-structured interview and data transcribed from the medical records. DNA extraction, amplification of sequences by the Polymerase Chain Reaction (PCR) with specific primers and polymorphism analysis of Restriction Fragment Length Polymorphism (RFLP) were performed to identify polymorphisms. The statistical analysis was performedin a descriptive manner and using the test. The multiple logistic regression model was used to determine the effect of polymorphisms on pre-eclampsia. RESULTS:Ahigher frequency of the T allele of theVEGF +936C/T polymorphism was observedin patients with pre-eclampsia, but with no significant difference. The presence of allele A of the VEGF -2578C/A was significantly higher in the control group. CONCLUSIONS:No significant association was observed between VEGF +936C/Tpolymorphism andpre-eclampsia. For the VEGF -2578C/A polymorphism a significant differencewas observed between thecontrol and pre-eclampsia group, with allele A being the most frequent in the control, suggesting the possibility that carriers of allele A have lower susceptibility to the development of pre-eclampsia.

Fisiopatologia da pré-eclâmpsia: aspectos atuais / Physiopathology of pre-eclampsia: new insights

A pré-eclâmpsia, principal causa de morte materna no mundo, é conhecida como a doença das teorias. Nos últimos anos, diversos avanços no área médica permitiram aprofundar nossos conhecimentos sobre a sua etiopatogenia. Sabemos, atualmente, que fatores genéticos, como a interação entre HLA paterno e linfócitos NK maternos, estão envolvidos na origem da placentação deficiente, um dos principais fatores de risco da pré-eclâmpsia. Fatores imunológicos, como a falha do estabelecimento da reação inflamatória tipo 2 na implantação do embrião, também poderiam dificultar a invasão trofoblástica. O conceito de que a pré-eclâmpsia não é uma doença única, mas um conjunto de doenças com manifestações clínicas comuns veio para ajudar na elucidação do problema. A pré-eclâmpsia é considerada, hoje em dia, um estado imflamatório com disfunção endotelial sistêmica. Nesta revisão, os autores compilam as teorias mais recentes sobre a fisiopatologia dessa doença tão intrigante.

Pre-eclampsia, the leading cause of maternal death around the world, is also known as the disease of theories. Several developments in the last years allowed us to improve our knowledge over its etiopathogeny. It is known that genetic factors, as the interaction between paternal HLA antigens and maternal natural killer lynfocytes, are involved in the origin of incomplete placentation, one of the most powerful risk factors for the development of pre-eclampsia. Imunological factors, as the failure in the establishment of inflammatory Reaction type 2, at implantation time, could also difficult the trophoblastic invasion. The conception of pre-eclampsia as a group of diseases with a common set of clinical manifestations help us to further understand the problem. Pre-eclampsia is considered to be an inflammatory state with systemic endothelial dysfunction. In this review paper, the authors gather the most recent theories about the physiopathology of such intriguing disease.

Polimorfismos de genes de citocinas na pré-eclâmpsia / Polymorphisms of genes of cytokines in preeclampsia

A pré-eclâmpsia é uma forma de hipertensão exclusiva da gravidez, sendo uma das principais causas de morbimortalidade materna e perinatal em todo o mundo. Diversas evidências mostram que mecanismos imunológicos estão envolvidos em sua fisiopatologia. Neste contexto, a participação das citocinas parece exercer papel importante na ativação do processo inflamatório verificado na doença. Estes fatores estão presentes em todo o processo reprodutivo exercendo papéis tanto de ativação como de inibição de respostas celulares. A identificação dos genes que codificam a produção de diferentes citocinas e a possibilidade de ocorrência de polimorfismo destes genes, modulando eventualmente expressão clínica com padrões diferenciados, trouxe novas perspectivas para avaliar a participação destes mediadores na pré-eclâmpsia. Essa atualização descreve as principais citocinas relacionadas com a gestação e as pesquisas relacionadas aos polimorfismos de genes que codificam IL-10, IL-6, IFN-y, TGF-b e TNF-a na pré-eclâmpsia.

The pre-eclampsia is an exclusive form of hypertension in pregnancy, one of the major causes of fetal and maternal morbidity and mortality throughout the world. Several evidences show that immune mechanisms are involved in its pathogenesis. In this context, the participation of the cytokines seems to play an important role in the activation of the inflammatory process observed in the disease. These factors are present throughout the reproductive process playing a role in the activation as well as in the inhibition of cell answers. The genes identification that codifies the production of different cytokines and the possibility of occurrence of polymorphisms of these genes, modulating eventually clinical expression with differentiated patterns, brought new perspectives to evaluate the participation of these mediators in the preeclampsia. This updating describes the main cytokines related to the gestation and the researches related to the polymorphisms of genes that codify IL-10, IL-6, IFN-y, TGF-b e TNF-a in the pre-eclampsia.

Genética de la preeclampsia / Genetics of preclampsia

La preeclampsia es un trastorno hipertensivo específico del embarazo y es una de las principales causas de morbilidad y mortalidad materna y neonatal en todo el mundo, afectando 5 a 7% de todos los embarazos. En Colombia es la primera causa de morbilidad y mortalidad materna, siendo un problema de salud pública. Muchas investigaciones coinciden en que su origen se relaciona con la interacción entre factores genéticos y ambientales. Múltiples estudios han explorado factores genéticos tratando de identificar regiones cromosómicas y genes candidatos cuyas variantes se relacionen con una mayor susceptibilidad a la enfermedad. La presente revisión ofrece una visión general de los factores genéticos asociados a la preeclampsia.

Preeclampsia is a hypertensive disorder that occurs only during pregnancy and is one of the main causes of maternal and neonatal morbidity and mortality, affecting 5-7% of pregnancies. In Colombia it is the primary cause of maternal morbidity and mortality, and an important public health issue. Many investigations agree that its origin is related to the interaction of genetic and environmental factors. Numerous studies have explored genetic factors in attempt to identify chromosomal regions and candidate genes, variants of which are related with increased susceptibility to the disease. This review offers a general vision of the genetic factors associated with preeclampsia.

Molecular analysis of the Von Hippel-Lindau (VHL) gene in a family with non-syndromic pheochromocytoma: the importance of genetic testing

The two index patients of the family analyzed in this study had undergone bilateral adrenalectomy for pheochromocytomas. This prompted genetic analyses of the probands and seven first-degree relatives. The two pheochromocytoma patients and two additional asymptomatic family members were found to harbor a mutation c496G>T in exon 3 of the VHL gene. The family was then lost to systematic follow-up. Three years after performing the initial genetic evaluation, the sister of the probands, who was known to carry the same VHL germline mutation, was referred to our service after a pregnancy that was complicated by preeclampsia. She reported paroxysms suggestive for pheochromocytoma, but her urinary metanephrines were negative. However, computerized tomography of the abdomen showed an adrenal mass that was also positive on metaiodobenzylguanidine (MIBG) scintigraphy. This study illustrates that molecular analysis of the index patient(s) can lead to the identification of presymptomatic relatives carrying the mutation. Moreover, despite negative urinary metanephrines, the identification of a specific mutation has led to an increased suspicion and detection of a pheochromocytoma in the sister of the probands.

Dois pacientes índices da família analisada neste estudo foram submetidos a adrenalectomia bilateral devido a feocromocitoma. Foi, então, realizado o estudo genético dos pacientes e de sete parentes de primeiro grau. Os dois pacientes com feocromocitoma e dois outros membros assintomáticos da família apresentaram a mutação c496G>T no exon 3 do gene VHL. A família perdeu seguimento médico. Três anos após a realização da avaliação genética, a irmã dos pacientes, portadora da mutação, foi encaminhada para o nosso serviço após uma gestação complicada por pré-eclampsia. Ela referia paroxismos sugestivos de feocromocitoma, mas as metanefrinas urinárias eram negativas. Entretanto, a tomografia computadorizada de abdômen evidenciou uma massa adrenal que também se contrastou na cintilografia com metaiodobenzilguanidina (MIBG). Esse estudo mostra que a análise molecular do paciente índice pode levar à identificação de parentes assintomáticos portadores da mutação. Além disso, mesmo com as metanefrinas urinárias negativas, a identificação de uma mutação específica levou a um aumento da suspeita e detecção de feocromocitoma na irmã dos afetados pela doença.

Genética de la preeclampsia: una aproximación a los estudios de ligamiento genético / Genetics of preeclampsia: an approach to genetic linkage studies

La preeclampsia es considerada un problema de salud pública debido a su alta prevalencia. Muchas investigaciones coinciden en que su origen se relaciona con la interacción entre factores genéticos y ambientales. Por esta razón, múltiples estudios han explorado tales factores genéticos tratando de identificar regiones cromosómicas y genes candidatos cuyas variantes se relacionen con una mayor susceptibilidad a la enfermedad. Diversos estudios de asociación han identificado algunos genes de susceptibilidad a la preeclampsia, pero los resultados no se han replicado consistentemente en todas las poblaciones, quizá por su complejidad clínica y genética. El levantamiento de mapas de genes y regiones cromosómicas basado en análisis de ligamiento ha mostrado resultados interesantes con algunos marcadores en los cromosomas 2 y 4. En este sentido, hay muchas expectativas con respecto a los genes localizados en tales regiones candidatas, debido a que la identificación de los factores de riesgo genético podría ayudar al entendimiento de esta condición y en proveer claves para su prevención y tratamiento.

Due to its high prevalence during pregnancies, preeclampsia is considered an important public health problem. Many investigators agree in that its expression is related to the interaction between genetic and environmental factors. Many studies have searched for genetic factors, attempting to identify chromosomal regions or candidate genes whose variants may be related to high preeclampsia susceptibility. Several studies have associated a number of susceptibility genes to preeclampsia, but the results have not been replicated consistently in all populations. Mapping of genes and chromosomal regions by linkage analysis has located potential markers on chromosomes 2 and 4. Identification of the genes located in these candidate regions will pinpoint the genetic risk factors, will lead to a better understanding of the syndrome, and will provide clues for its prevention and treatment.

Association of Angiotensin-Converting Enzyme and Angiotensinogen Gene Polymorphisms with Preeclampsia

We tested the hypothesis that angiotensin-converting enzyme (ACE) and angiotensinogen gene polymorphism influence the incidence, development and outcome of preeclampsia. Subjects were recruited from 90 Korean patients with preeclampsia during pregnancy and 98 age-matched controls. After isolation of DNA, polymerase chain reactions (PCR) were carried out to detect polymorphism of the ACE and angiotensinogen. M235T and T174M genotypes of angiotensinogen were determined by digestion with restriction enzyme endonuclease Tth 111-I and NCo I, respectively. The frequency of DD genotype was significantly greater in preeclampsia (0.36) than in controls (0.14) (p<0.05). The frequency of D allele was 0.55 in preeclampsia and 0.40 in controls (p<0.05). There were no differences in the onset of preeclampsia and pregnancy outcomes according to the ACE genotypes. There was no difference in the frequency of a allele of angiotensinogen M235T between the groups (0.79:0.78 in preeclampsia : controls). The frequency of T allele of angiotensinogen T174M gene was slightly increased, but not significantly, in preeclampsia (0.11) than in controls (0.07). In a multivariate analysis, only ACE genotype was associated with the development of preeclampsia (beta=0.27, p=0.05). In conclusion, a molecular variant of ACE, but not angiotensinogen, gene is associated with preeclampsia in Korean women.

Pre-eclampsia e a heranca mitocondrial / Preeclampsia and the mitochondrial inheritance

A ilucidacao da etiologia da pre-eclampsia se faz necessario para prevenir tao grave doenca que ainda hoje acarreta inumeras mortes maternas. A heranca mitocondrial tem sido...

Genetica e pre-eclampsia na gravidez: principios basicos / Genetic and preeclampsia in pregnancy: basic principles

A pre-eclampsia incide em 10 por cento das gestacoes em nosso meio, sendo uma das principais causas de obito materno quando na sua forma grave. O estudo genetico torna-se ferramenta cada vez mais importante no estudo da etiologia e fisiopatologia da pre-eclampsia. Os autores revisam as varias hipoteses de modelos de herancas geneticas dando enfase a hipotese do gene recessivo dividido e o modelo da heranca mitocondrial. Na verdade, um so modelo nao consegue explicar a...