Georgina Severo Ribeiro

Genetic polymorphisms and cerebrovascular disease in children with sickle cell anemia from Rio de Janeiro, Brazil

The aim of the present work was to examine possible genetic risk factors related to the occurrence of cerebrovascular disease (CVD) in Brazilian population, the frequency of β(S)-globin gene haplotypes and co-inheritance with α-thalassemia (-α(3.7kb)) and single nucleotide polymorphism of methylenetetrahydrofolate reductase (MTHFR-C677T), Factor V Leiden (FV-G1691A) and prothrombin (PT-G20210A) genes in children from Rio de Janeiro. Ninety four children with sickle cell anemia (SCA) were included, 24 patients with cerebrovascular involvement and 70 patients without CVD as control group. The mean age of children at the time of the cerebrovascular event was similar to the control group. The frequency of -α(3.7kb) thalassemia was similar in both groups (p=0.751). Children with Bantu/Atypical β(S)-globin gene haplotype presented 15 times more chance (OR=15.4 CI 95% 2.9-81.6) of CVD than the other β(S)-globin gene haplotypes. The C677T polymorphism of MTHFR gene was similar in both groups (p=0.085). No mutation in the FV Leiden or PT genes was found. A large study seems necessary to establish the role of these genetic polymorphisms in Brazilian miscegenated population.

Endothelial nitric oxide synthase Glu298Asp gene polymorphism in a multi-ethnical population with heart failure and controls.

Brazilian population has a multi-ethnical profile and the prevalence of endothelial nitric oxide synthase enzyme (eNOS) polymorphism in heart failure (HF) has not been previously studied. Therefore the present study assessed the association of eNOS Glu298Asp polymorphism in patients with HF and controls. In a crossover study, was analysed the distribution of the Glu298Asp in 100 outpatients with HF, and 103 healthy controls. Self-reported race were analyzed. Left atria and left ventricle diameters and ejection fraction were evaluated in patients group. Glu298Asp was analysed by polymerase chain reaction and restriction fragment length polymorphism. The patients average age was 59 years, 66% males, 49% Afro-descendants. The allelic frequency in patient group was Glu298=72%/Asp298=28% and the genotype frequency (GF) was Glu298Glu:49%; Glu298Asp:47%; Asp298Asp:4%. In control group, 60% Glu298 and 40% Asp298; 35% Glu298Glu, 49.5% Glu298Asp and 15.5% Asp298Asp. The prevalence of allele Glu298 was significantly higher in patients (p=0.009) as genotype Glu298Glu (p=0.03). The Glu298 in Afro-Brazilians (79%) and white patients (67%) were similar, although there was significant difference (p=0.03) in GF Glu298Glu between Afro-Brazilians and whites. There was an increased prevalence of hypertension and increased atria in Glu298Glu patients comparing with combined genotype Glu298Asp and Asp298Asp. This study suggests a regional variation in the distribution of Glu298Asp. The comparison of this distribution in African-Brazilian suggests a synergistic effect of African-descendent, Glu298Glu genotype and HF. Also demonstrated an increased frequency of Glu298 and Glu298Glu, suggesting interaction of them with HF. In HF patients, the clinical, echocardiograph and genotype analysis suggests an association of Glu298 allele and hypertension.

Sickle cell disease: acute clinical manifestations in early childhood and molecular characteristics in a group of children in Rio de Janeiro

Objectives To describe clinical events of sickle cell disease and the correlation with β-globin haplotypes and α-thalassemia in under 6-year-old children. Methods A retrospective study was conducted of under 6-year-old children from the neonatal screening program in Rio de Janeiro. Forty-eight male and 48 female children were enrolled in this study, 79 with sickle cell anemia and 17 with hemoglobin SC. The mean age was 29.9 (standard deviation = 20.9) months, 62 (16.2 ± 8.6) were aged between 0-3 years old and 34 (54.9 ± 11.3) were from 3-6 years old. Painful events, acute splenic sequestration, hemolytic crises, hand-foot and acute chest syndromes and infections were evaluated. Results The events were more frequent in under 3-year-old children, 94% of children had at least one episode. Infection was the most common event affecting 88.5% of children. Acute splenic sequestration took place earlier, while painful crises and acute chest syndromes in under 6-year-old children. Thal-α 3.7 was observed in 20.9% of cases. Bantu was the most frequent haplotype found, followed by Benin. No correlation was observed between clinical events and β-globin haplotypes. Children with sickle cell anemia and α-thalassemia have less infectious events. No correlation was found among these polymorphisms and clinical events, however, the majority of children with Bantu/Bantu and without α-thalassemia had more clinical events.

β-adrenergic receptor polymorphisms in susceptibility, response to treatment and prognosis in heart failure: Implication of ethnicity

Common functional polymorphisms in β-adrenergic receptor (βAR) genes have been associated with heart failure (HF) phenotypes and pharmacogenetic interactions with βAR blockers. This study evaluated the association between βAR polymorphisms and carvedilol drug response and prognosis in patients with HF. In this prospective cohort controlled study, 326 volunteers were enrolled [146 HF patients (ejection fraction (EF)<50% by Simpson) and 180 healthy controls]. Drug response was evaluated by echocardiography and outcomes were mortality and hospitalization. DNA was extracted from peripheral blood leukocytes, fragments were amplified by the polymerase reaction and genotyped by restriction fragment length polymorphism (RFLP) for Ser49Gly and Arg389Gly βAR-1 polymorphisms and Gln27Glu and Arg16Gly βAR-2 polymorphisms. The study population was in Hardy‑Weinberg equilibrium. The survival rate was adjusted using the Kaplan-Meier method. HF patients showed the following characteristics: EF 35±9%, 69.9% male, age 59±13 years, 50.7% self-identified as black, 46% had ischemic etiology. The mean follow-up of 23 months showed 18 mortalities and 46 hospitalizations. The genotypes Glu27Glu (24.7 vs. 6.1%, p=0.0004) and Arg16Arg (72.6 vs. 22.8, p<0.0001) of βAR2 polymorphisms and Gly49Gly (33.6 vs. 4.3%, p<0.0001) of the βAR1 polymorphism were higher in HF patients compared with controls. Patients with hospital admission showed a significantly higher Gly389 allelic frequency (54.9 vs. 42.1%, p=0.039), and the trend prevailed among patients who succumbed to the disease (61.1%, p=0.047). Black patients with the Ser49Ser genotype showed a reduced survival compared with the Gly49Gly or Ser49Gly genotypes (p=0.028). There was no association between improved LVEF >20% and βAR polymorphisms. HF patients with β-blocker therapy and the Gly389 allele have reduced event-free survival compared to those carrying the Arg389 allele. Additionally, systolic HF outpatients undergoing β-blocker therapy, self‑identified as black and homozygous for Ser49Ser may have reduced event-free survival, while Glu27Glu, Arg16Arg and Gly49Gly genotypes may be associated with risk for HF.

Effect of the 894G>T polymorphism of the endothelial nitric oxide synthase on vascular reactivity following maximal dynamic exercise.

Background Considering that the role of nitric oxide as a vasodilator is increased after an acute bout of exercise and that the 894G>T polymorphism of the endothelial nitric oxide synthase seems to reduce the nitric oxide release in response to shear stress, the present study investigated the 894G>T polymorphism in relation to vascular reactivity following maximal dynamic exercise. Method We studied 110 healthy volunteers (wild-type group 45.5% and polymorphic group 54.5%). The protocol included vascular reactivity assessment at baseline and during reactive hyperemia, before, 10, 60 and 120 min after a maximal cardiopulmonary exercise test. Genomic DNA was extracted from blood samples to determine the 894G>T polymorphism. Results There were no differences between the wild-type and polymorphic groups concerning anthropometric, metabolic and hemodynamic characteristics. Blood flow, before maximal exercise, was similar between the wild-type and the polymorphic groups. The polymorphic group presented lower vascular reactivity regardless of time (P = 0.019 for group main effect), and posthoc analysis revealed that polymorphic patients had lower values than wild-type only at the 120 min measurement (P = 0.002). Concerning within-group analysis, vascular reactivity increased at 10 min after exercise (P = 0.029) returning to baseline at 120 min (P = 0.005) in the polymorphic group. Conclusion Patients with the 894G>T polymorphism had lower vascular reactivity after a single bout of exercise.

A novel point mutation in a class IV glucose-6-phosphate dehydrogenase variant (G6PD São Paulo) and polymorphic G6PD variants in São Paulo State, Brazil

In this study, we used red cell glucose-6-phosphate dehydrogenase (G6PD) activity to screen for G6PD-deficient individuals in 373 unrelated asymptomatic adult men who were working with insecticides (organophosphorus and carbamate) in dengue prevention programs in 27 cities in São Paulo State, Brazil. Twenty-one unrelated male children suspected of having erythroenzymopathy who were attended at hospitals in São Paulo city were also studied. Fifteen of the 373 adults and 12 of the 21 children were G6PD deficient. G6PD gene mutations were investigated in these G6PD-deficient individuals by using PCR-RFLP, PCR-SSCP analysis and DNA sequencing. Twelve G6PD A-202A/376G and two G6PD Seattle844C, as well as a new variant identified as G6PD São Paulo, were detected among adults, and 11 G6PD A-202A/376G and one G6PD Seattle844C were found among children. The novel mutation c.660C > G caused the replacement of isoleucine by methionine (I220M) in a region near the dimer interface of the molecule. The conservative nature of this mutation (substitution of a nonpolar aliphatic amino acid for another one) could explain why there was no corresponding change in the loss of G6PD activity (64.5% of normal activity in both cases).

Tratamento de uma coorte de pacientes com infarto agudo do miocárdio com supradesnivelamento do segmento ST

FUNDAMENTO: Trombolise e angioplastia transluminal coronariana (ATC) primaria sao tecnicas bem estabelecidas, mas grande parte dos pacientes com infarto agudo do miocardio com supradesnivelamento do segmento ST (IAM com SST) nao as recebem quando do atendimento hospitalar. OBJETIVO: Descrever tratamentos inicial e final e desfechos de uma coorte com IAM com SST. METODOS: Analisados, da internacao ate a alta, 158 pacientes com IAM com SST, de uma populacao total de 351 pacientes internados com (SCA) nos hospitais de Campos dos Goytacazes, entre 2004 e 2006. RESULTADOS: Dos 158 pacientes com IAM com SST, 67,7% chegaram ao hospital nos primeiros 180 minutos, 81,3% em 360 minutos e 8,4% apos doze horas. Realizados 148 estudos cinecoronariograficos (93,7%). Observadas lesoes de mais de 70% em 266 territorios arteriais. Tratamento inicial foi ATC em 41(26%), tromboliticos em 50 (32%), com 80% de sucesso. Tratamento clinico em 67 (42%). Cerca de 35% dos pacientes deveriam ser trombolizados mas nao o foram. No tratamento final foram 93 ATCs, 89 delas com sucesso angiografico (95,7), sangramento 2 (2,2), oclusao subaguda 2 (2,2%), disseccao tronco 1 (1,1), pseudo aneurisma 1 (1,1). Nenhum obito durante angioplastia; na evolucao, houve dois obitos (2,1%). Doze pacientes submetidos a cirurgia de revascularizacao miocardica (CRM). Tratamento clinico 53 (33%), com 11 obitos (20,7%). Letalidade global 9,5%, consideradas as tres formas de tratamento. CONCLUSAO: Pacientes atendidos em tempo adequado para reperfusao, porem 1/3 deles nao recebeu o procedimento. Tratamento predominante foi ATC, com baixa morbidade. Dois obitos na evolucao. Baixa letalidade global.

Polimorfismos beta1-adrenérgico associados com Fibrilação Atrial na Insuficiência Cardíaca Sistólica

BACKGROUND: The sympathetic nervous system is of great importance in the pathogenesis of atrial fibrillation in systolic heart failure. The identification of polymorphisms in the beta1-adrenergic receptor gene (ADBR1) represents an important step in understanding this pathogenesis. OBJECTIVE: This study assessed the association between the two functional polymorphisms of the beta1-adrenergic receptor gene (ADBR1), Ser49Gly and Arg389Gly, and the presence of atrial fibrillation in patients with systolic heart failure. METHODS: Case-control study with 144 patients with systolic heart failure, including 24 with atrial fibrillation (cases) and 120 without atrial fibrillation (controls). Genomic DNA was extracted from peripheral blood leukocytes and the genotypes of Ser49Gly and Arg389Gly polymorphisms were identified in all individuals by PCR/RFLP (polymerase chain reaction / restriction fragment length polymorphism). RESULTS: Mean age was 59 ± 13 years, 70% of patients were males, 42% had ischemic causes and 74% had hypertension. Genotypes Ser49Ser and Arg389Arg were significantly associated with atrial fibrillation (p = 0.005 and p = 0.01, respectively). After logistic regression, both adjusted for left atrial size and age, the significant association persisted (Arg389Arg - odds ratios: 2.78, 95% confidence interval = 1.02 to 7.56 and Ser49Ser - odds ratios: 8.02, 95% confidence interval = 1.02 to 63.82). CONCLUSION: Both genotypes were associated with atrial fibrillation in patients; however, only Ser49Gly polymorphism was is in Hardy-Weinberg equilibrium.

The frequency of β-globin gene haplotypes, α-thalassemia and genetic polymorphisms of methylenetetrahydrofolate reductase, factor V Leiden and prothrombin genes in children with sickle cell disease in Rio de Janeiro, Brazil

A frequencia dos haplotipos beta S e beta C do gene da globina e a prevalencia de talassemia alfa e de mutacoes nos genes da metilenotetrahidrofolato redutase (MTHFR-C677T), do fator V de Leiden e da protrombina (G20210A) foi estudada em criancas com doenca falciforme do Rio de Janeiro. O haplotipo Bantu foi o mais frequente (65,9%), 21,2% das criancas (18% heterozigotas e 3% homozigotas) apresentam talassemia com mutacao alfa 3.7kb, ao contrario da mutacao alfa 4.2kb que nao foi encontrada. Os alelos 677CT e 677TT da MTHFR foram observados em 20,2% e 4,8%, respectivamente. Os haplotipos Camaroes, Arabe-Indiano e Senegal nao foram detectados na amostra estudada, bem como mutacoes no gene do fator V de Leiden e da protrombina. Somente o haplotipo beta C CI foi observado. Esse e o primeiro estudo realizado em uma amostra proveniente do Programa de Triagem Neonatal para Hemoglobinopatias do estado do Rio de Janeiro. Apesar do Rio de Janeiro ser a segunda maior cidade brasileira e seus habitantes expressarem o elevado grau de miscigenacao ocorrida no pais, nossos resultados ainda coincidem com os registros historicos dos fluxos migratorios do gene beta S para o Brasil, bem como refletem a forte influencia de individuos de origem africana na populacao do Rio de Janeiro.

Treatment of a cohort of patients with acute myocardial infarction and ST-segment elevation

FUNDAMENTO: Trombolise e angioplastia transluminal coronariana (ATC) primaria sao tecnicas bem estabelecidas, mas grande parte dos pacientes com infarto agudo do miocardio com supradesnivelamento do segmento ST (IAM com SST) nao as recebem quando do atendimento hospitalar. OBJETIVO: Descrever tratamentos inicial e final e desfechos de uma coorte com IAM com SST. METODOS: Analisados, da internacao ate a alta, 158 pacientes com IAM com SST, de uma populacao total de 351 pacientes internados com (SCA) nos hospitais de Campos dos Goytacazes, entre 2004 e 2006. RESULTADOS: Dos 158 pacientes com IAM com SST, 67,7% chegaram ao hospital nos primeiros 180 minutos, 81,3% em 360 minutos e 8,4% apos doze horas. Realizados 148 estudos cinecoronariograficos (93,7%). Observadas lesoes de mais de 70% em 266 territorios arteriais. Tratamento inicial foi ATC em 41(26%), tromboliticos em 50 (32%), com 80% de sucesso. Tratamento clinico em 67 (42%). Cerca de 35% dos pacientes deveriam ser trombolizados mas nao o foram. No tratamento final foram 93 ATCs, 89 delas com sucesso angiografico (95,7), sangramento 2 (2,2), oclusao subaguda 2 (2,2%), disseccao tronco 1 (1,1), pseudo aneurisma 1 (1,1). Nenhum obito durante angioplastia; na evolucao, houve dois obitos (2,1%). Doze pacientes submetidos a cirurgia de revascularizacao miocardica (CRM). Tratamento clinico 53 (33%), com 11 obitos (20,7%). Letalidade global 9,5%, consideradas as tres formas de tratamento. CONCLUSAO: Pacientes atendidos em tempo adequado para reperfusao, porem 1/3 deles nao recebeu o procedimento. Tratamento predominante foi ATC, com baixa morbidade. Dois obitos na evolucao. Baixa letalidade global.