Blood DNA methylation marks discriminate Chagas cardiomyopathy disease clinical forms.

Chagas disease is a parasitic disease from South America, affecting around 7 million people worldwide. Decades after the infection, 30% of people develop chronic forms, including Chronic Chagas Cardiomyopathy (CCC), for which no treatment exists. Two stages characterized this form: the moderate form, characterized by a heart ejection fraction (EF) ≥ 0.4, and the severe form, associated to an EF < 0.4. We propose two sets of DNA methylation biomarkers which can predict in blood CCC occurrence, and CCC stage. This analysis, based on machine learning algorithms, makes predictions with more than 95% accuracy in a test cohort. Beyond their predictive capacity, these CpGs are located near genes involved in the immune response, the nervous system, ion transport or ATP synthesis, pathways known to be deregulated in CCCs. Among these genes, some are also differentially expressed in heart tissues. Interestingly, the CpGs of interest are tagged to genes mainly involved in nervous and ionic processes. Given the close link between methylation and gene expression, these lists of CpGs promise to be not only good biomarkers, but also good indicators of key elements in the development of this pathology.

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy.

Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

Blood DNA methylation marks discriminate Chagas cardiomyopathy disease clinical forms

Chagas disease is a parasitic disease from South America, affecting around 7 million people worldwide. Decades after the infection, 30% of people develop chronic forms, including Chronic Chagas Cardiomyopathy (CCC), for which no treatment exists. Two stages characterized this form: the moderate form, characterized by a heart ejection fraction (EF) ≥ 0.4, and the severe form, associated to an EF < 0.4. We propose two sets of DNA methylation biomarkers which can predict in blood CCC occurrence, and CCC stage. This analysis, based on machine learning algorithms, makes predictions with more than 95% accuracy in a test cohort. Beyond their predictive capacity, these CpGs are located near genes involved in the immune response, the nervous system, ion transport or ATP synthesis, pathways known to be deregulated in CCCs. Among these genes, some are also differentially expressed in heart tissues. Interestingly, the CpGs of interest are tagged to genes mainly involved in nervous and ionic processes. Given the close link between methylation and gene expression, these lists of CpGs promise to be not only good biomarkers, but also good indicators of key elements in the development of this pathology.

Epigenetic regulation of transcription factor binding motifs promotes Th1 response in Chagas disease cardiomyopathy

Abstract: Chagas disease, caused by the protozoan Trypanosoma cruzi, is an endemic parasitic disease of Latin America, affecting 7 million people. Although most patients are asymptomatic, 30% develop complications, including the often-fatal Chronic Chagasic Cardiomyopathy (CCC). Although previous studies have demonstrated some genetic deregulations associated with CCCs, the causes of their deregulations remain poorly described. Based on bulk RNA-seq and whole genome DNA methylation data, we investigated the genetic and epigenetic deregulations present in the moderate and severe stages of CCC. Analysis of heart tissue gene expression profile allowed us to identify 1407 differentially expressed transcripts (DEGs) specific from CCC patients. A tissue DNA methylation analysis done on the same tissue has permitted the identification of 92 regulatory Differentially Methylated Regions (DMR) localized in the promoter of DEGs. An in-depth study of the transcription factors binding sites (TFBS) in the DMRs corroborated the importance of TFBS's DNA methylation for gene expression in CCC myocardium. TBX21, RUNX3 and EBF1 are the transcription factors whose binding motif appears to be affected by DNA methylation in the largest number of genes. By combining both transcriptomic and methylomic analysis on heart tissue, and methylomic analysis on blood, 4 biological processes affected by severe CCC have been identified, including immune response, ion transport, cardiac muscle processes and nervous system. An additional study on blood methylation of moderate CCC samples put forward the importance of ion transport and nervous system in the development of the disease.

FAS gene polymorphisms (rs3740286 and rs4064) were not associated with pre-eclampsia risk.

Pre-eclampsia results in real risk and significant impact on indicators related to maternal and child health. The only known treatment is delivery of the fetus and placenta. Despite intensive research, the causes of PE remain to be elucidated. It is suggested that pre-eclampsia is caused by a global maternal inflammatory response to a damaged placenta. Besides inflammation, cytotoxic and apoptotic mechanisms are also implicated in the pathogenesis of pre-eclampsia. Considering the importance of apoptosis to pre-eclampsia genesis, the aim of this study was to determine the frequencies of the genotypes for FAS gene polymorphisms (rs3740286 and rs4064) and to associate these with pre-eclampsia development. Women with and without pre-eclampsia were investigated. Accordingly, peripheral blood was collected, and DNA extracted, followed by genotyping using Real-time PCR with hydrolysis probe. The results showed no association between genotypes and pre-eclampsia development for both polymorphisms studied (χ2=3.39; p=.177, for rs3740286 and χ2=0.119; p=.94 for rs4064). Women with familiar history of pre-eclampsia and primiparity showed more probability to develop the condition, by multiple logistic regression analysis (OR=8.61, CI=3.39-21.86, p<0.0001; OR=6.64. CI=2.94-14.99, p<0.0001, respectively). It seems that FAS gene polymorphisms (rs3740286 and rs4064) might not be important candidates for the development of pre-eclampsia.

Corrigendum: Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy.

[This corrects the article DOI: 10.3389/fimmu.2020.01386.].

Polymorphisms in Genes Affecting Interferon-γ Production and Th1 T Cell Differentiation Are Associated With Progression to Chagas Disease Cardiomyopathy.

Background: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is the most important clinical consequence of T. cruzi infection, while the others remain asymptomatic (ASY). IFN-γ and IFN-γ-producing Th1-type T cells are increased in peripheral blood and CCC myocardium as compared to ASY patients, while the Th1-antagonizing cytokine IL-10 is more expressed in ASY patients. Importantly IFN-γ-producing Th1-type T cells are the most frequent cytokine-producing T cell subset in CCC myocardium, while expression of Th1-antagonizing cytokines IL-10 and IL-4 is unaltered. The control of IFN-γ production by Th1-type T cells may be a key event for progression toward CCC. A genetic component to disease progression was suggested by the familial aggregation of cases and the association of gene polymorphisms with CCC development. We here investigate the role of gene polymorphisms (SNPs) in several genes involved in the control of IFN-γ production and Th1 T cell differentiation in CCC development. Methods: We studied a Brazilian population including 315 CCC cases and 118 ASY subjects. We assessed 35 Tag SNPs designed to represent all the genetic information contained in the IL12B, IL10, IFNG, and IL4 genes. Results: We found 2 IL12 SNPs (rs2546893, rs919766) and a trend of association for a IL10 SNP (rs3024496) to be significantly associated with the ASY group. these associations were confirmed by multivariate analysis and allele tests. The rs919766C, 12rs2546893G, and rs3024496C alleles were associated to an increase risk to CCC development. Conclusions: Our data show that novel polymorphisms affecting IL12B and IL10, but not IFNG or IL4 genes play a role in genetic susceptibility to CCC development. This might indicate that the increased Th1 differentiation and IFN-γ production associated with CCC is genetically controlled.

Polymorphisms in genes affecting interferon-γ production and Th1 T cell differentiation are associated with progression to Chagas Disease cardiomyopathy

BACKGROUND: Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America. Thirty percent of infected individuals develop chronic Chagas cardiomyopathy (CCC), an inflammatory dilated cardiomyopathy that is the most important clinical consequence of T. cruzi infection, while the others remain asymptomatic (ASY). IFN-γ and IFN-γ-producing Th1-type T cells are increased in peripheral blood and CCC myocardium as compared to ASY patients, while the Th1-antagonizing cytokine IL-10 is more expressed in ASY patients. Importantly IFN-γ-producing Th1-type T cells are the most frequent cytokine-producing T cell subset in CCC myocardium, while expression of Th1-antagonizing cytokines IL-10 and IL-4 is unaltered. The control of IFN-γ production by Th1-type T cells may be a key event for progression toward CCC. A genetic component to disease progression was suggested by the familial aggregation of cases and the association of gene polymorphisms with CCC development. We here investigate the role of gene polymorphisms (SNPs) in several genes involved in the control of IFN-γ production and Th1 T cell differentiation in CCC development. METHODS: We studied a Brazilian population including 315 CCC cases and 118 ASY subjects. We assessed 35 Tag SNPs designed to represent all the genetic information contained in the IL12B, IL10, IFNG, and IL4 genes. RESULTS: We found 2 IL12 SNPs (rs2546893, rs919766) and a trend of association for a IL10 SNP (rs3024496) to be significantly associated with the ASY group. these associations were confirmed by multivariate analysis and allele tests. The rs919766C 12rs2546893G, and rs3024496C alleles were associated to an increase risk to CCC development. CONCLUSIONS: Our data show that novel polymorphisms affecting IL12B and IL10, but not IFNG or IL4 genes play a role in genetic susceptibility to CCC development. This might indicate that the increased Th1 differentiation and IFN-γ production associated with CCC is genetically controlled.

Polymorphisms in the IL17A gene are not involved in the development of preeclampsia in the Brazilian population / Polimorfismos no gene IL17A não estão envolvidos no desenvolvimento de pré-eclâmpsia na população brasileira

ABSTRACT Introduction: Preeclampsia is defined by the development of hypertension associated with proteinuria after the 20th week of gestation in previously normotensive women. IL17A is a potent inducer of tissue inflammation and polymorphisms in the IL17A gene can modulate gene expression and affect the functioning of Th17 cells, strengthening susceptibility to preeclampsia. Objective: To investigate the polymorphisms rs4711998 A>G, rs8193036 C>T and rs2275913 A>G in the IL17A gene in women with preeclampsia. Methods: This is a control case study, composed of 263 women, 89 with preeclampsia and 174 of the control group. The polymorphisms investigated by real time polymerase chain reaction (PCR) allele discrimination technique. The risk of IL17A polymorphisms contributing to preeclampsia was assessed by the inheritance model through logistic regression. Statistical power presented 99.5% for association detection. Statistical significance was defined as p < 0.05. Results: Genotype frequencies as well as multiple logistic regression analysis were not statistically significant for the rs4711998 A>G, rs8193036 C>T and rs2275913 A>G polymorphisms of the IL17A gene. No association was found between any haplotypes of the polymorphisms investigated and the risk of developing PE. Conclusion: There is no association between the allele frequencies, genotype, inheritance models and haplotypes of the rs4711998 A>G, rs8193036 C>T and rs2275913 A>G polymorphisms of the IL17A gene and PE.

RESUMEN Introducción: La preeclampsia (PE) se define como hipertensión arterial asociada a proteinuria después de la semana 20 de gestación en mujeres anteriormente normotensas. La interleucina 17ª (IL17A) es un inductor potente de inflamación tisular y polimorfismos del gen IL17A pueden modular la expresión génica y afectar las funciones de las células Th17, aumentando la susceptibilidad a la PE. Objetivo: Investigar los polimorfismos rs4711998 A>G, rs8193036 C>T y rs2275913 A>G del gen IL17A en pacientes con PE. Métodos: Se realizó un estudio de casos y controles, compuesto por 263 mujeres: 89 diagnosticadas con PE y 174 del grupo de control. Se evaluaron los polimorfismos investigados a partir del ácido desoxirribonucleico (ADN) genómico aislado de la sangre periférica por reacción en cadena de la polimerasa (PCR) en tiempo real para discriminación alélica. El riesgo de los polimorfismos del gen IL17A para la PE fue evaluado según el modelo de herencia empleando regresión logística. El poder estadístico presentó 99,5% para la detección de asociación. Resultados: Las frecuencias genotípicas, así como el análisis de regresión logística múltiple, no fueron estadísticamente significativas para los polimorfismos rs3761549 C>T, rs3761548 A>C y rs2232365 A>G del gen IL17A. Ningún haplotipo de los polimorfismos investigados mostró asociación con el riesgo de desarrollo de PE. Conclusión: No hay asociación entre las frecuencias alélicas y genotípicas, los modelos de herencia y los haplotipos de los polimorfismos rs4711998 A>G, rs8193036 C>T y rs2275913 A>G del gen IL17A y la PE.

RESUMO Introdução: A pré-eclâmpsia (PE) é definida pelo desenvolvimento de hipertensão arterial associada à proteinúria após a semana de gestação em mulheres previamente normotensas. A interleucina 17A (IL17A) é um potente indutor de inflamação tecidual, e polimorfismos no gene IL17A podem modular a expressão gênica e afetar o funcionamento das células Th17, contribuindo para a suscetibilidade à PE. Objetivo: Investigar os polimorfismos rs4711998 A>G, rs8193036 C>T e rs2275913 A>G no gene IL17A em mulheres com PE. Métodos: Trata-se de um estudo do tipo caso-controle, composto por 263 mulheres, sendo 89 diagnosticadas com PE e 174 do grupo-controle. Os polimorfismos investigados foram avaliados a partir do ácido desoxirribonucleico (DNA) genômico extraído do sangue periférico pela técnica de discriminação alélica por reação em cadeia da polimerase (PCR) em tempo real. O risco de os polimorfismos do gene IL17A contribuírem com a PE foi avaliado pelo modelo de herança através da regressão logística. O poder estatístico apresentou 99,5% para a detecção de associação. A significância estatística foi definida como p < 0,05. Resultados: As frequências genotípicas, assim como a análise de regressão logística múltipla, não foram estatisticamente significativas para os polimorfismos rs3761549 C>T, rs3761548 A>C e rs2232365 A>G do gene IL17A. Não foi observada associação entre nenhum dos haplótipos dos polimorfismos investigados e o risco de desenvolvimento de PE. Conclusão: Não há associação entre as frequências alélicas e genotípicas, os modelos de herança e os haplótipos dos polimorfismos rs4711998 A>G, rs8193036 C>T e rs2275913 A>G do gene IL17A e a PE.

Ansiedade, depressão e qualidade de vida de pacientes com câncer mamário e ginecológico sob quimioterapia / Ansiedad, depresión y calidad de vida de pacientes con cáncer mamario y ginecológico en quimioterapia / Anxiety, depression and quality of life of patients with breast or gynecological cancer undergoing chemotherapy1

RESUMO Tristeza e pesar são reações comuns entre pessoas que enfrentam o câncer, e estas reações podem influenciar sua qualidade de vida. Este estudo teve por objetivo verificar a existência de correlações entre os escores de ansiedade e depressão e domínios de qualidade de vida, nos momentos pré e pós-quimioterapia. Tratou-se de estudo observacional quantitativo, descritivo e de delineamento longitudinal-prospectivo. Participaram do estudo 14 mulheres, diagnosticadas com câncer de mama ou ginecológico, submetidas à quimioterapia, entre dezembro/2012 e abril/2013. Foram utilizados o WHOQOL-bref e Escala Hospitalar de Ansiedade e Depressão. A coleta de dados deu-se a partir da resposta individual das mulheres aos instrumentos. Para correlacionar os escores de ansiedade e depressão com os domínios de qualidade de vida, utilizou-se o coeficiente de correlação linear de Pearson. O domínio físico da qualidade de vida correlacionou-se negativamente com depressão, nos momentos pré e pós-quimioterapia. Houve também correlação negativa entre domínio psicológico e ambiental com ansiedade e depressão nos momentos pré e pós-quimioterapia. Em relação ao domínio social, não houve correlação. Concluiu-se que ansiedade e depressão influenciaram negativamente a qualidade de vida das mulheres estudadas nos domínios físico, psicológico e ambiental.

RESUMEN Tristeza y pesar son reacciones comunes entre personas que enfrentan el cáncer, y estas reacciones pueden afectar su calidad de vida. Este estudio tuvo el objetivo de verificar la existencia de correlaciones entre las puntuaciones de ansiedad y depresión y dominios de calidad de vida, en los momentos pre y post quimioterapia. Se trató de un estudio observacional cuantitativo, descriptivo y de delineamiento longitudinal-prospectivo. Participaron del estudio 14 mujeres, diagnosticadas con cáncer de mama o ginecológico, sometidas a quimioterapia, entre diciembre/2012 y abril/2013. Fueron utilizados el WHOQOL-bref y Escala Hospitalaria de Ansiedad y Depresión. La recolección de datos ocurrió a partir de la respuesta individual de las mujeres a los instrumentos. Para correlacionar las puntuaciones de ansiedad y depresión con los dominios de calidad de vida, se utilizó el coeficiente de correlación lineal de Pearson. El dominio físico de la calidad de vida se correlacionó negativamente con depresión, en los momentos pre y post quimioterapia. Hubo también correlación negativa entre dominio psicológico y ambiental con ansiedad y depresión en los momentos pre y post quimioterapia. Con relación al dominio social, no hubo correlación. Se concluyó que ansiedad y depresión influyen negativamente la calidad de vida de las mujeres estudiadas en los dominios físico, psicológico y ambiental.

ABSTRACT Sadness and grief are common reactions among people facing cancer, and these reactions can have an impact on their quality of life. The objective of this study was to determine the existence of correlations between depression and anxiety scores and quality of life domains, during pre- and post-chemotherapy. This was an observational, quantitative, descriptive study, with a longitudinal-prospective design. The 14 women who participated in the study had been diagnosed with breast or gynecological cancer and underwent chemotherapy between December 2012 and April 2013. The WHOQOL-BREF and Hospital Anxiety and Depression Scale were used. The data was collected through the individual responses of the women to the instruments. To correlate the anxiety and depression scores with the quality of life domains, the Pearson correlation coefficient was used. The physical health domain of quality of life had a negative correlation with depression during pre- and post-chemotherapy. There was also a negative correlation between the psychological and environment domains and anxiety and depression during pre- and post-chemotherapy. As for the social relationships domain, there was no correlation. It was concluded that anxiety and depression did not negatively influence the quality of life of the women in the physical health, psychological and environment domains.

Gene Polymorphisms in FAS (Rs3740286 and Rs4064) Are Involved in Endometriosis Development in Brazilian Women, but not those in CASP8 (rs13416436 and rs2037815) / Polimorfismos do gene FAS (rs3740286 e rs4064) estão envolvidos no desenvolvimento de endometriose em mulheres brasileiras, mas não os no CASP8 (rs13416436 e rs2037815)

Abstract Objective The present study aims to investigate the association between caspase-8 (CASP8) (rs13416436 and rs2037815) and Fas cell surface death receptor (FAS) (rs3740286 and rs4064) polymorphisms with endometriosis in Brazilian women. Methods In the present case-control study, 45 women with a diagnosis of endometriosis and 78 normal healthy women as a control group were included. The genotyping was determined by real-time polymerase chain reaction (PCR) with Taqman hydrolysis probes (Thermo Fisher Scientific, Darmstadt, Germany). Genotypic and allelic frequencies were analyzed using Chi-squared (χ2) test. In order to determine the inheritance models and haplotypes ,SNPStats (Institut Català d'Oncologia, Barcelona, Spain) was used. Levels of 5% (p = 0.05) were considered statistically significant. Results No significant difference was observed in genotypic or allelic frequencies between control and endometriosis groups for rs13416436 and rs2037815 (CASP8 gene). On the other hand, a significant difference between rs3740286 and rs4064 (FAS gene) was found. Regarding polymorphisms in the FAS gene, a statistically significant differencewas found in co-dominant and dominantmodels. Only the haplotype containing the rs3740286A and rs4064G alleles in the FAS gene were statistically significant. Conclusion The polymorphisms in the CASP8 gene were not associated with endometriosis. The results indicate an association between FAS gene polymorphisms and the risk of developing endometriosis.

Resumo Objetivo Investigar a associação entre os polimorfismos dos genes caspase-8 (CASP8) (rs13416436 e rs2037815) e FAS (rs3740286 e rs4064) em mulheres brasileiras com endometriose. Métodos Trata-se de um estudo do tipo caso-controle, no qual foram incluídas 45 mulheres com diagnóstico de endometriose e 78 controles. A genotipagem das amostras foi determinada usando a reação em cadeia de polimerase em tempo real com sondas de hidrólise TaqMan (Thermo Fisher Scientific, Darmstadt, Germany). As frequências genotípicas e alélicas foram analisadas usando o teste do qui-quadrado. O SNPStats (Institut Català d'Oncologia, Barcelona, Espanha) foi usado para determinar os modelos de herança e os haplótipos. Os níveis de significância estatística considerados foram de 5% (p = 0,05). Resultados Não foi observada diferença significativa nas frequências genotípicas ou alélicas entre os grupos de controle e de endometriose para os polimorfismos rs13416436 e rs2037815 (gene CASP8). Por outro lado, foi encontrada uma diferença significativa entre os polimorfismos rs3740286 e rs4064 (gene FAS). Em relação aos polimorfismos do gene FAS, foi encontrada uma diferença estatisticamente significativa nos modelos codominante e dominante. Apenas o haplótipo contendo os alelos rs3740286A e rs4064G no gene FAS foi estatisticamente significativo. Conclusão Não há associação entre os polimorfismos do gene CASP8 e endometriose. Entretanto, há associação entre os polimorfismos do gene FAS e o risco de desenvolver endometriose.

α-Tocopherol influences glycaemic control and miR-9-3 DNA methylation in overweight and obese women under an energy-restricted diet: a randomized, double-blind, exploratory, controlled clinical trial.

BACKGROUND: Excess weight is a strong risk factor for the development of dysglycaemia. It has been suggested that changes in the metabolism microRNAs, small non-coding RNAs that regulate gene expression, could precede late glycaemic changes. Vitamin E in turn may exert important functions in methylation and gene expression processes. This study aimed to determine the effect of α-tocopherol on glycaemic variables and miR-9-1 and miR-9-3 promoter DNA methylation in overweight women. METHODS: A randomized, double-blind, exploratory, placebo-controlled study was conducted in overweight and obese adult women (n = 44) who ingested synthetic vitamin E (all-rac-α-tocopherol), natural source vitamin E (RRR-rac-α-tocopherol) or placebo capsules and were followed up for a period of 8 weeks. Supplemented groups also received dietary guidance for an energy-restricted diet. An additional group that received no supplementation and did not follow an energy-restricted diet was also followed up. The intervention effect was evaluated by DNA methylation levels (quantitative real-time PCR assay) and anthropometric and biochemical variables (fasting plasma glucose, haemoglobin A1C, insulin, and vitamin E). RESULTS: Increased methylation levels of the miR-9-3 promoter region (P < 0.001) and reduced haemoglobin A1C (P < 0.05) were observed in the natural source vitamin E group after intervention. Increased fasting plasma glucose was observed in the synthetic vitamin E group, despite the significant reduction of anthropometric variables compared to the other groups. CONCLUSIONS: α-Tocopherol from natural sources increased methylation levels of the miR-9-3 promoter region and reduced haemoglobin A1C in overweight women following an energy-restricted diet. These results provide novel information about the influence of vitamin E on DNA methylation. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02922491. Registered 4 October, 2016.

Gene Polymorphisms in FAS (Rs3740286 and Rs4064) Are Involved in Endometriosis Development in Brazilian Women, but not those in CASP8 (rs13416436 and rs2037815).

OBJECTIVE: The present study aims to investigate the association between caspase-8 (CASP8) (rs13416436 and rs2037815) and Fas cell surface death receptor (FAS) (rs3740286 and rs4064) polymorphisms with endometriosis in Brazilian women. METHODS: In the present case-control study, 45 women with a diagnosis of endometriosis and 78 normal healthy women as a control group were included. The genotyping was determined by real-time polymerase chain reaction (PCR) with Taqman hydrolysis probes (Thermo Fisher Scientific, Darmstadt, Germany). Genotypic and allelic frequencies were analyzed using Chi-squared (χ2) test. In order to determine the inheritance models and haplotypes ,SNPStats (Institut Català d'Oncologia, Barcelona, Spain) was used. Levels of 5% (p = 0.05) were considered statistically significant. RESULTS: No significant difference was observed in genotypic or allelic frequencies between control and endometriosis groups for rs13416436 and rs2037815 (CASP8 gene). On the other hand, a significant difference between rs3740286 and rs4064 (FAS gene) was found. Regarding polymorphisms in the FAS gene, a statistically significant difference was found in co-dominant and dominant models. Only the haplotype containing the rs3740286A and rs4064G alleles in the FAS gene were statistically significant. CONCLUSION: The polymorphisms in the CASP8 gene were not associated with endometriosis. The results indicate an association between FAS gene polymorphisms and the risk of developing endometriosis.

OBJETIVO: Investigar a associação entre os polimorfismos dos genes caspase-8 (CASP8) (rs13416436 e rs2037815) e FAS (rs3740286 e rs4064) em mulheres brasileiras com endometriose. MéTODOS: Trata-se de um estudo do tipo caso-controle, no qual foram incluídas 45 mulheres com diagnóstico de endometriose e 78 controles. A genotipagem das amostras foi determinada usando a reação em cadeia de polimerase em tempo real com sondas de hidrólise TaqMan (Thermo Fisher Scientific, Darmstadt, Germany). As frequências genotípicas e alélicas foram analisadas usando o teste do qui-quadrado. O SNPStats (Institut Català d'Oncologia, Barcelona, Espanha) foi usado para determinar os modelos de herança e os haplótipos. Os níveis de significância estatística considerados foram de 5% (p = 0,05). RESULTADOS: Não foi observada diferença significativa nas frequências genotípicas ou alélicas entre os grupos de controle e de endometriose para os polimorfismos rs13416436 e rs2037815 (gene CASP8). Por outro lado, foi encontrada uma diferença significativa entre os polimorfismos rs3740286 e rs4064 (gene FAS). Em relação aos polimorfismos do gene FAS, foi encontrada uma diferença estatisticamente significativa nos modelos codominante e dominante. Apenas o haplótipo contendo os alelos rs3740286A e rs4064G no gene FAS foi estatisticamente significativo. CONCLUSãO: Não há associação entre os polimorfismos do gene CASP8 e endometriose. Entretanto, há associação entre os polimorfismos do gene FAS e o risco de desenvolver endometriose.

Perfil epidemiológico dos nascidos vivos em Belo Horizonte, MG, Brasil / Perfil epidemiológico de los nacidos vivos en Belo Horizonte, MG, Brasil / Epidemiological profile of live births in Belo Horizonte, MG, Brazil

OBJETIVO: este estudo teve por objetivo descrever o perfil epidemiológico dos nascidos vivos residentes no município de Belo Horizonte/MG, no período de 1994 a 2014. MÉTODO: trata-se de uma pesquisa transversal, retrospectiva, de abordagem quantitativa, realizada com base nos dados secundários disponíveis no Sistema de Informações sobre Nascidos Vivos. RESULTADOS: os resultados evidenciaram 738.314 nascimentos no município de Belo Horizonte/MG nesse período, sendo a maioria do sexo masculino (51,1%); a termo (90,2%); com índice de Apgar entre 08 e 10 no primeiro minuto de vida (85%); com peso ao nascer entre 2500g e 3999g (86,4%); e sem a presença de anomalias congênitas (58,2%). CONCLUSÃO: o Sistema de Informações sobre Nascidos Vivos representa um avanço no registro de dados e serve de subsídio para o planejamento e a implantação de políticas públicas voltadas para a saúde materno-infantil.

OBJECTIVE: this study aimed to describe the epidemiological profile of live births living in the city of Belo Horizonte, MG, from 1994 to 2014. METHOD: this is a cross-sectional, retrospective, quantitative approach based on the secondary data available in the Live Births Information System. RESULTS: the results showed 738,314 births in the city of Belo Horizonte / MG in this period, being the majority male ones (51.1%); at term (90.2%); with an Apgar score between 8 and 10 in the first minute of life (85%); with birth weight between 2500g and 3999g (86.4%); and without the presence of congenital anomalies (58.2%). CONCLUSION: the Live Births Information System represents an advance in the data registry and works as a subsidy for the planning and implementation of public policies focused on maternal and child health.

OBJETIVO: este estudio tuvo por objetivo describir el perfil epidemiológico de los nacidos vivos residentes en el municipio de Belo Horizonte/MG, en el período de 1994 a 2014. MÉTODO: se trata de una pesquisa transversal, retrospectiva, de abordaje cuantitativa, realizada con base en los datos secundarios disponibles en el Sistema de Informaciones sobre Nacidos Vivos. RESULTADOS: los resultados evidenciaron 738.314 nacimientos en el municipio de Belo Horizonte/MG en ese período, siendo la mayoría del sexo masculino (51,1%); a término (90,2%); con índice de Apgar entre 08 y 10 en el primero minuto de vida (85%); con peso al nacer entre 2500g y 3999g (86,4%); y sin la presencia de anomalías congénitas (58,2%). CONCLUSIÓN: el Sistema de Informaciones sobre Nacidos Vivos representa un avanzo en el registro de datos y sirve de subsidio para el planeamiento y la implantación de políticas públicas volteadas para la salud materno-infantil.

CASPASE-8 gene polymorphisms (rs13416436 and rs2037815) are not associated with preeclampsia development in Brazilian women.

BACKGROUND: Preeclampsia is responsible for considerable mortality and morbidity of mother and sibling. The etiology of preeclampsia is still unknown. Family studies indicate the involvement of genes located on chromosome 2 in preeclampsia development. Considering the importance of apoptosis and chromosome 2, one promising candidate for the study of the genetic cause of this syndrome is the CASPASE-8 gene, which was chosen as the subject of this study. OBJECTIVE: The aim of this study was to determine the frequencies of the genotypes for CASP8 gene polymorphisms (rs13416436 and rs2037815) and to associate these with preeclampsia development in Brazilian women. METHODS: Women with and without preeclampsia were investigated. Accordingly, peripheral blood was collected and DNA extracted, followed by genotyping using Real-time PCR with hydrolysis probe (Taqman® Life Technologies). RESULTS: The results showed no association between genotypes and preeclampsia development for both polymorphisms studied (χ2 = 1.03; p = 0.59, for rs13416436 and χ2 = 1.06; p = 0.58 for rs2037815). CONCLUSIONS: It seems that CASP8 gene polymorphisms (rs13416436 and rs2037815) are not important candidates for the development of preeclampsia. Other genes related to the apoptosis process or other polymorphisms in this gene should be studied in order to understand better the etiology of preeclampsia.

Polymorphism in the lymphotoxin-alpha gene, position +252 (rs909253), is not associated with preeclampsia development in Brazilian women.

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 χ2 association 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.

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.

Functional IL18 polymorphism and susceptibility to Chronic Chagas Disease.

BACKGROUND: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy, affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the rest of the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotal role in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described. IL-18 could potentially amplify the process by inducing increased expression of IFN-γ which in turn can increase the production of IL-18, thereby creating a positive feedback mechanism. In order to assess the contribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the association between a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developing Chagas cardiomyopathy. METHODS AND RESULTS: We analyzed the rs2043055 marker in the IL18 gene in a cohort of Chagas disease cardiomyopathy patients (n=849) and asymptomatic subjects (n=202). We found a significant difference in genotype frequencies among moderate and severe CCC patients with ventricular dysfunction. CONCLUSIONS: Our analysis suggests that the IL18 rs2043055 polymorphism- or a SNP in tight linkage disequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome.

Functional IL18 polymorphism and susceptibility to Chronic ChagasDisease

Background: Chronic Chagas Disease cardiomyopathy (CCC), a life-threatening inflammatory dilated cardiomyopathy,affects 30% of the approximately 8 million patients infected by Trypanosoma cruzi, the restof the infected subjects remaining asymptomatic (ASY). The Th1 T cell-rich myocarditis plays a pivotalrole in CCC pathogenesis. Local expression of IL-18 in CCC myocardial tissue has recently been described.IL-18 could potentially amplify the process by inducing increased expression of IFN-c which in turn canincrease the production of IL-18, thereby creating a positive feedback mechanism. In order to assess thecontribution of the IL-18 to susceptibility to Chronic Chagas Disease, we investigated the associationbetween a single nucleotide polymorphism (SNP) located in the IL-18 gene with the risk of developingChagas cardiomyopathy.Methods and results: We analyzed the rs2043055 marker in the IL18 gene in a cohort of Chagas diseasecardiomyopathy patients (n = 849) and asymptomatic subjects (n = 202). We found a significant differencein genotype frequencies among moderate and severe CCC patients with ventricular dysfunction.Conclusions: Our analysis suggests that the IL18 rs2043055 polymorphism- or a SNP in tight linkagedisequilibrium with it- may contribute to modulating the Chagas cardiomyopathy outcome.

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

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.