Genetic comparison of sickle cell anaemia cohorts from Brazil and the United States reveals high levels of divergence

Genetic analysis of admixed populations raises special concerns with regard to study design and data processing, particularly to avoid population stratification biases. The point mutation responsible for sickle cell anaemia codes for a variant hemoglobin, sickle hemoglobin or HbS, whose presence drives the pathophysiology of disease. Here we propose to explore ancestry and population structure in a genome-wide study with particular emphasis on chromosome 11 in two SCA admixed cohorts obtained from urban populations of Brazil (Pernambuco and Sao Paulo) and the United States (Pennsylvania). Ancestry inference showed different proportions of European, African and American backgrounds in the composition of our samples. Brazilians were more admixed, had a lower African background (43% vs. 78% on the genomic level and 44% vs. 76% on chromosome 11) and presented a signature of positive selection and Iberian introgression in the HbS region, driving a high differentiation of this locus between the two cohorts. The genetic structures of the SCA cohorts from Brazil and US differ considerably on the genome-wide, chromosome 11 and HbS mutation locus levels9CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP8367/2011-1; 150398/2013-1; 304455/2012-1; 310938/2014-7; 305218/2017-48367/2011-1; 150398/2013-1; 304455/2012-1; 310938/2014-7; 305218/2017-42008/57441-0; 2014/00984-3; 2012/06438-5; 2015/13152-9; 2008/10596-

Association between ANXA2*5681 polymorphism (rs7170178) and osteonecrosis in haemoglobin SS-genotyped patients

sem informação1883e8e11CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQ444656/2014-6; 483714/2013-

Polymorphism In The Hmox1 Gene Is Associated With High Levels Of Fetal Hemoglobin In Brazilian Patients With Sickle Cell Anemia.

The aim of this study was to investigate the association between three polymorphisms involved in the oxidative stress pathway and fetal hemoglobin (Hb F) levels in patients with sickle cell anemia in a Brazilian population. One hundred and seven patients with sickle cell anemia were recruited for genomic DNA extraction. The levels of Hb F, sex and age were evaluated. Three polymorphisms, rs4673:T>C and rs9932581:G>A in the CYBA gene and rs2071746:A>T in the HMOX1 gene, were identified through direct sequencing. Hb F levels were not associated with sex, age, or the polymorphisms rs4673:T>C and rs9932581:G>A. However, the TT genotype of the rs2071746:A>T polymorphism was associated with increased levels of Hb F (p value = 0.0131). We observed an association between the TT genotype of the rs2071746:A>T polymorphism, present in the HMOX1 gene, and increased levels of Hb F, indicating the presence of a new marker related to Hb F levels in sickle cell anemia patients.37315-2

Pancreatic iron stores assessed by magnetic resonance imaging (MRI) in beta thalassemic patients

Purpose: To assess the correlation between MRI findings of the pancreas with those of the heart and liver in patients with beta thalassemia; to compare the pancreas T2* MRI results with glucose and ferritin levels and labile plasma iron (LPI). Materials and methods: We retrospectively evaluated chronically transfused patients, testing glucose with enzymatic tests, serum ferritin with chemiluminescence, LPI with cellular fluorescence, and T2* MRI to assess iron content in the heart, liver, and pancreas. MRI results were compared with one another and with serum glucose, ferritin, and LPI. Liver iron concentration (LIC) was determined in 11 patients' liver biopsies by atomic absorption spectrometry. Results: 289 MRI studies were available from 115 patients during the period studied. 9.4% of patients had overt diabetes and an additional 16% of patients had impaired fasting glucose. Both pancreatic and cardiac R2* had predictive power (p < 0.0001) for identifying diabetes. Cardiac and pancreatic R2* were modestly correlated with one another (r(2) = 0.20, p < 0.0001). Both were weakly correlated with LIC (r(2) = 0.09, p < 0.0001 for both) and serum ferritin (r(2) = 0.14, p < 0.0001 and r(2) = 0.03, p < 0.02, respectively). None of the three served as a screening tool for single observations. There is a strong log-log, or power-law, relationship between ratio of signal intensity (SIR) values and pancreas R2* with an r(2) of 0.91. Conclusions: Pancreatic iron overload can be assessed by MRI, but siderosis in other organs did not correlate significantly with pancreatic hemosiderosis. (C) 2011 Elsevier Ireland Ltd. All rights reserved.Brazilian Ministry of HealthBrazilian Ministry of Healt

Global gene expression reveals an increase of HMGB1 and APEX1 proteins and their involvement in oxidative stress, apoptosis and inflammation pathways among beta-thalassaemia intermedia and major phenotypes

Beta-thalassaemia (BT) is classified according to blood transfusion requirement as minor (BTMi), intermedia (BTI) and major (BTM). BTM is the most severe form, requiring regular transfusions while transfusion need is only occasional in BTI. Differential gene expression between patients has not been assessed so far. Here, we evaluated the global gene expression profiles during differentiation of human erythroid cells of two patients carrying the same mutation [CD39, (C -> T)], though displaying different phenotypes (BTI and BTM). Considering the role of reactive oxygen species (ROS) in the pathophysiology of thalassaemia, we focused on differentially expressed genes involved in metabolic pathways triggered by ROS, such as inflammation and apoptosis, and, from these, we selected the Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APEX1) and High Mobility Group Box1 (HMGB1) genes, whose role in BT is not well established. An in-depth expression analysis of transcriptional and protein levels in patients carrying a range of mutations associated with BT phenotypes indicated that APEX1 was increased in both BTI and BTM. Furthermore, higher amounts of HMGB1 was found in the plasma of BTI patients. Our findings suggest that these proteins have important roles in BT and could represent new targets for further studies aiming to improve the management of the disease1864608619CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO - CNPQCOORDENAÇÃO DE APERFEIÇOAMENTO DE PESSOAL DE NÍVEL SUPERIOR - CAPESFUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESPsem informaçãosem informação2011/50358-

Global analysis of erythroid cells redox status reveals the involvement of Prdx1 and Prdx2 in the severity of beta thalassemia.

β-thalassemia is a worldwide distributed monogenic red cell disorder, characterized by an absent or reduced beta globin chain synthesis. The unbalance of alpha-gamma chain and the presence of pathological free iron promote severe oxidative damage, playing crucial a role in erythrocyte hemolysis, exacerbating ineffective erythropoiesis and decreasing the lifespan of red blood cells (RBC). Catalase, glutathione peroxidase and peroxiredoxins act together to protect RBCs from hydrogen peroxide insult. Among them, peroxiredoxins stand out for their overall abundance and reactivity. In RBCs, Prdx2 is the third most abundant protein, although Prdxs 1 and 6 isoforms are also found in lower amounts. Despite the importance of these enzymes, Prdx1 and Prdx2 may have their peroxidase activity inactivated by hyperoxidation at high hydroperoxide concentrations, which also promotes the molecular chaperone activity of these proteins. Some studies have demonstrated the importance of Prdx1 and Prdx2 for the development and maintenance of erythrocytes in hemolytic anemia. Now, we performed a global analysis comparatively evaluating the expression profile of several antioxidant enzymes and their physiological reducing agents in patients with beta thalassemia intermedia (BTI) and healthy individuals. Furthermore, increased levels of ROS were observed not only in RBC, but also in neutrophils and mononuclear cells of BTI patients. The level of transcripts and the protein content of Prx1 were increased in reticulocyte and RBCs of BTI patients and the protein content was also found to be higher when compared to beta thalassemia major (BTM), suggesting that this peroxidase could cooperate with Prx2 in the removal of H2O2. Furthermore, Prdx2 production is highly increased in RBCs of BTM patients that present high amounts of hyperoxidized species. A significant increase in the content of Trx1, Srx1 and Sod1 in RBCs of BTI patients suggested protective roles for these enzymes in BTI patients. Finally, the upregulation of Nrf2 and Keap1 transcription factors found in BTI patients may be involved in the regulation of the antioxidant enzymes analyzed in this work

Triagem familiar para o gene HBB*S e detecção de novos casos de traço falciforme em Pernambuco

OBJETIVO: Estimar o incremento no número adicional de afetados com base na prevalência de síndromes falciformes em familiares de casos-índice. MÉTODOS: Estudo transversal em familiares de amostra aleatória dos casos-índice identificados por programa de triagem neonatal em Pernambuco, no período de 2001 a 2005. O modelo de triagem familiar ampliado incluiu 463 membros familiares de 21 casos-índice. Os familiares foram categorizados como: núcleo reduzido (NR -pai, mãe e irmãos); de primeiro grau (N1 - avós, tios e primos de primeiro grau); de segundo grau (N2 - filhos dos primos de primeiro grau); ampliado (NA - NR+N1+N2) e ampliado de primeiro grau (NA1 -NR+N1). A confirmação da presença de HBB*S e detecção de hemoglobinas anormais foram realizadas por meio da High Performance Liquid Chromathgraphy. A associação entre a presença de HBB*S e variáveis foi testada pelo cálculo da razão de prevalência e respectivos IC 95% e a diferença entre médias verificadas pelo teste t de Student, ao nível de significância de 5%. RESULTADOS: A anemia falciforme era desconhecida por 81% dos familiares; o gene HBB*S esteve presente em 114 familiares. Observou-se que 53,3% da população estudada estava na faixa considerada reprodutiva e 80% das pessoas portadoras do gene HBB*S já tinham gerado filhos. A freqüência foi maior no núcleo NR (69%), mas também elevada no N1 (22,8%). O NA1 resultou na detecção de 69 portadores adicionais (aumento de 172%). CONCLUSÕES: Os resultados indicam que a triagem familiar para identificação de portadores de síndrome falciforme deve ser estendida para os familiares até o primeiro grau