Percorrer por autor "Ferreira, Emanuel"
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- Biomarkers and genetic modulators of cerebral vasculopathy in sub-Saharan ancestry children with sickle cell anemiaPublication . Silva, Marisa; Vargas, Sofia; Coelho, Andreia; Ferreira, Emanuel; Mendonça, Joana; Vieira, Luís; Maia, Raquel; Dias, Alexandra; Ferreira, Teresa; Morais, Anabela; Mota Soares, Isabel; Lavinha, João; Silva, Rita; Kjollerstrom, Paula; Faustino, PaulaWe investigated biomarkers and genetic modulators of the cerebral vasculopathy (CV) subphenotype in pediatric sickle cell anemia (SCA) patients of sub-Saharan African ancestry. We found that one VCAM1 promoter haplotype (haplotype 7) and VCAM1 single nucleotide variant rs1409419_T were associated with stroke events, stroke risk, as measured by time-averaged mean of maximum velocity in the middle cerebral artery, and with high serum levels of the hemolysis biomarker lactate dehydrogenase. Furthermore, VCAM-1 ligand coding gene ITGA4 variants rs113276800_A and rs3770138_T showed a positive association with stroke events. An additional positive relationship between a genetic variant and stroke risk was observed for ENPP1 rs1044498_A. Conversely, NOS3 variants were negatively associated with silent cerebral infarct events (VNTR 4b_allele and haplotype V) and CV globally (haplotype VII). The -alpha3.7kb–thal deletion did not show association with CV.However, it was associated with higher red blood cell and neutrophil counts, and lower mean corpuscular volume, mean corpuscular hemoglobin and red cell distribution width. Our results underline the importance of genetic modulators of the CV sub-phenotype and their potential as SCA therapeutic targets. We also propose that a biomarker panel comprising biochemical, hematological, imaging and genetic data would be instrumental for CV prediction, and prevention.
- Factores genéticos moduladores do fenótipo da drepanocitosePublication . Ferreira, Emanuel; Faustino, Paula; Dias, DeodáliaA hemoglobina é uma proteína essencial, constituinte maioritário dos eritrócitos, cuja principal função é o transporte de oxigénio no organismo. Esta é constituída por quatro cadeias globínicas, cada uma ligada a um grupo heme, que contém um ião Fe2+ ao qual se liga uma molécula de O2. As patologias associadas à hemoglobina (Hb) têm o nome genérico de hemoglobinopatias. Estas poderão ser do tipo quantitativo (as talassémias) ou qualitativo (as variantes da hemoglobina). De entre estas últimas salienta-se a mais comum, denominada Drepanocitose ou Anemia das células falciformes. A Drepanocitose é uma doença autossómica recessiva, que se caracteriza pela presença em homozigotia de uma mutação de A > T no codão 6 de gene da beta-globina (HBB). Os doentes drepanocíticos são incapazes de sintetizar a hemoglobina predominante no adulto normal, a HbA. Pelo contrário, é sintetizada uma variante de hemoglobina, a HbS, que tem propriedades de falciformização no eritrócito e origina, consequentemente, eventos de vaso-oclusão e anemia hemolítica crónica. Embora a Drepanocitose seja uma doença monogénica, os seus fenótipos (hematológico e clínico) têm gravidade variável pois são modificados por vários factores ambientais e genéticos. Este trabalho tinha como objectivos caracterizar uma população de 108 indivíduos para a presença da mutação drepanocítica, da deleção α-talassémica de 3,7 kb, quanto ao haplótipo no agrupamento génico β-globina e para uma série de polimorfismos em BCL11A e HBS1L-MYB. Seguidamente, pretendeu-se verificar se os genótipos caracterizados nestes loci seriam moduladores do nível de Hb Fetal (HbF; um parâmetro já aceite como sendo benéfico nesta patologia) e/ou do curso clínico da doença (medido através do número de crises de dor aguda que levaram a internamento dos doentes devidas, na sua maioria, à vaso-oclusão). Verificou-se que a população drepanocítica analisada apresenta 29% de frequência alélica para a deleção α-talassémia de 3,7 kb. Observou-se que os indivíduos drepanocíticos que co-herdaram α-talassémia apresentam microcitose, hipocromia e níveis baixos de Hb total. Não foi encontrada associação entre presença da deleção de 3,7kb e o nível de HbF. No entanto, relativamente à relação entre a presença desta deleção e a gravidade da doença, observaram-se melhorias significativas nos heterozigóticos. Observou-se que os heterozigóticos para esta deleção tinham 29% menos risco de terem crises com internamento do que os homozigóticos e os que não co-herdaram α-talassémia apresentam apenas menos 12% de risco. Concluimos, portanto, que a co-herança da delecção α-talassémica de 3,7 kb confere um efeito benéfico quando em heterozigotia e um efeito nefasto quando em homozigotia. Concluiu-se que a maior parte dos indivíduos apresentava o haplótipo Bantu no agrupamento génico da β-globina, seguido do Benim. Embora não se tendo observado associação entre o haplótipo e o nível de HbF, observou-se que, tendencialmente, a homozigotia para o haplótipo Bantu corresponde a níveis mais baixos de HbF e a homozigotia para o haplótipo Senegal encontra-se, tendencialmente, associado a níveis elevados de HbF. Não se verificou associação entre os polimorfismos globínicos, estudados na região promotora do gene Gγ-globina (rs112215533, rs112075505 e rs112479156) e o nível de HbF. No que diz respeito aos polimorfismos em BCL11A (rs11886868, rs4671393, rs10189857 e rs45506594) verificaram-se associações estatisticamente significativas entre a presença dos alelos menos frequentes para os dois primeiros polimorfismos e o nível de HbF (respectivamente, p = 0,001 e p < 0,001). Observaram-se também melhorias do curso clínico da doença aquando da presença destes alelos. Relativamente ao SNP rs11886868, concluiu-se que os indivíduos heterozigóticos para o alelo mais raro (TC) tinham 36% menos risco de terem crises com internamento que os TT, enquanto que nos homozigóticos para esse alelo (CC) a melhoria ascendia a 62% menos de risco que os TT. Relativamente ao polimorfismo rs4671393 pôde constatar-se que a presença do alelo menos frequente em heterozigotia (AG) conferia a esses doentes 38% menos risco de terem crises com internamento que os GG, e que esse valor era de menos 60% para os AA, também relativamente aos GG. No que se refere ao outro polimorfismo não globínico estudado, SNP rs9402686 em HBS1L-MYB, não se verificou associação com o nível de HbF. Em conclusão, com este estudo conseguiram-se identificar dois polimorfismos (em BCL11A, SNP rs11886868 e rs4671393) associados a níveis de HbF mais elevados e a um curso clínico mais suave da drepanocitose, podendo assim ser utilizados como preditores precoces da gravidade da doença e para adequar a terapêutica às necessidades de cada doente.
- Genetic modulators of fetal hemoglobin expression and ischemic stroke occurrence in African descendant children with sickle cell anemiaPublication . Nicolau, Marta; Vargas, Sofia; Silva, Marisa; Coelho, Andreia; Ferreira, Emanuel; Mendonça, Joana; Vieira, Luís; Kjollerstrom, Paula; Maia, Raquel; Silva, Rita; Dias, Alexandra; Ferreira, Teresa; Morais, Anabela; Mota Soares, Isabel; Lavinha, João; Faustino, PaulaSickle cell anemia (SCA) is an autosomal recessive monogenic disease with significant clinical variability. Cerebrovascular disease, particularly ischemic stroke, is one of the most severe complications of SCA in children. This study aimed to investigate the influence of genetic variants on the levels of fetal hemoglobin (Hb F) and biochemical parameters related with chronic hemolysis, as well as on ischemic stroke risk, in ninety-one unrelated SCA patients, children of sub-Saharan progenitors. Our results show that a higher Hb F level has an inverse relationship with the occurrence of stroke, since the group of patients who suffered stroke presents a significantly lower mean Hb F level (5.34 ± 4.57% versus 9.36 ± 6.48%; p = 0.024). Furthermore, the co-inheritance of alpha-thalassemia improves the chronic hemolytic pattern, evidenced by a decreased reticulocyte count (8.61 ± 3.58% versus 12.85 ± 4.71%; p < 0.001). In addition, our findings have confirmed the importance of HBG2 and BCL11A loci in the regulation of Hb F expression in sub-Saharan African SCA patients, as rs7482144_A, rs11886868_C, and rs4671393_A alleles are significantly associated with a considerable increase in Hb F levels (p = 0.019, p = 0.026, and p = 0.028, respectively). Concerning KLF1, twelve different variants were identified, two of them novel. Seventy-three patients (80.2%) presented at least one variant in this gene. However, no correlation was observed between the presence of these variants and Hb F level, severity of hemolysis, or stroke occurrence, which is consistent with their in silico-predicted minor functional consequences. Thus, we conclude that the prevalence of functional KLF1 variants in a sub-Saharan African background does not seem to be relevant to SCA clinical modulation.
- Genetic variation in CD36, HBA, NOS3 and VCAM1 is associated with chronic haemolysis level in sickle cell anaemia: a longitudinal studyPublication . Coelho, Andreia; Dias, Alexandra; Morais, Anabela; Nunes, Baltazar; Ferreira, Emanuel; Picanço, Isabel; Faustino, Paula; Lavinha, JoãoChronic haemolysis stands out as one of the hallmarks of sickle cell anaemia, a clinically heterogeneous autosomal recessive monogenic anaemia. However, the genetic architecture of this sub-phenotype is still poorly understood. Here, we report the results of an association study between haemolysis biomarkers (serum LDH, total bilirubin and reticulocyte count) and the inheritance of 41 genetic variants of ten candidate genes in a series of 99 paediatric SS patients (median current age of 9.9 yr) followed up in two general hospitals in Greater Lisboa area (median follow-up per patient of 5.0 yr). Although in a large number of tests a seemingly significant (i.e. P < 0.05) association was observed, the following ones were confirmed upon correction for multiple comparisons: (i) an increased serum LDH level was associated with haplotype 7 within VCAM1 gene; (ii) a lower total bilirubin was associated with the 3.7-kb deletion at HBA gene, rs2070744_T allele at NOS3 gene, and haplotype 9 within VCAM1 promoter; and (iii) a diminished reticulocyte count was associated with the 3.7-kb deletion at HBA, whereas an increased count was associated with rs1984112_G allele at CD36 gene. On the whole, our findings suggest a complex genetic architecture for the sickle cell anaemia haemolysis process involving multiple pathways, namely control of vascular cell adhesion, NO synthesis and erythrocyte volume and haemoglobinisation.
- Haemolysis in sickle cell anaemia: a genotype/phenotype association studyPublication . Lavinha, João; Coelho, Andreia; Dias, Alexandra; Morais, Anabela; Ferreira, Emanuel; Picanço, Isabel; Nunes, Baltazar; Faustino, PaulaSickle-cell anaemia (SCA) is a clinically heterogeneous autosomal recessive monogenic chronic anaemia characterized by recurrent episodes of severe vaso-occlusion, haemolysis and infection. Several genetic and environmental modifiers have been suggested to modulate the onset and course of SCA. As part of a wider research on the development and validation of vaso-occlusion early predictors in SCA, we have studied the association between haemolysis biomarkers (LDH, total bilirrubin and reticulocyte count) and the inheritance of genetic variants of ten candidate genes in a series of 99 paediatric SS patients (median current age of 9.9 years) followed-up in two general hospitals in Greater Lisbon area (median follow-up/patient of 5.0 years). Although in a large number of tests a seemingly significant (i.e., p<0.05) association was observed, only the following ones were confirmed upon correction for the false discovery rate: (a) An elevated LDH was associated to haplotype 7 within VCAM1 gene. (b) A lower total bilirrubin was associated to the 3.7kb deletion at HBA gene, rs2070744_T allele and haplotypes 3 and 4 at NOS3 gene and haplotype 9 within VCAM1 gene and rs3783598_G and rs3917024_T alleles at VCAM1 gene promoter. (c) A diminished reticulocyte count was associated to the 3.7kb deletion at HBA gene, whereas an elevated count was associated to rs1984112_G allele at CD36 gene. Furthermore, at the phenotypic level all three haemolysis biomarkers were positively associated to left ventricle dilation, a common chronic complication of SCA. On the whole, our findings suggest a complex genetic architecture for the haemolytic endophenotype in SCA involving multiple pathways, namely control of erythrocyte volume and haemoglobinisation, vascular cell adhesion, NO synthesis and lipid metabolism. Further mechanistic studies are needed to explore these avenues leading to a better understanding of the inter- and intra-individual clinical variability of SCA. Acknowledgement: Work partially funded by FCT grants PIC/IC/83084/2007 and CIGMH.
- Haemolysis in sickle cell anaemia: a genotype/phenotype association studyPublication . Coelho, Andreia; Dias, Alexandra; Morais, Anabela; Nunes, Baltazar; Ferreira, Emanuel; Picanço, Isabel; Faustino, Paula; Lavinha, JoãoIntroduction: Sickle cell anaemia (SCA) is a clinically heterogeneous autosomal recessive monogenic anaemia characterised by chronic haemolysis and recurrent episodes of severe vaso-occlusion and infection. Several environmental and genetic determinants have been suggested to modulate the onset, course and outcome of SCA. The level of chronic haemolysis has been considered a critical measure of SCA severity and a possible proximate cause of some disease complications such as stroke, pulmonary hypertension, priapism, leg ulceration and cholelithiasis. Thus, we proposed to search for genetic modifiers of this sub-phenotype and gain insights into the underlying mechanisms. Patients and Methods: We studied the association between commonly measured haemolysis biomarkers (LDH, total bilirubin and reticulocyte count) and the inheritance of 41 genetic variants (34 SNP, 6 indel, 1 STR) of 10 candidate genes in a longitudinally observed series of 99 paediatric homozygous SCA patients (median current age of 9.9 yr) followed up in two general hospitals in Greater Lisboa area (median follow-up per patient of 5.0 yr). Candidate gene genotyping was performed by PCR-RFLP, Sanger sequencing, Gene Scan or Gap-PCR. All genotype distributions were tested for adherence to the Hardy-Weinberg equilibrium. When appropriate, haplotypes were inferred by software PHASE, version 2.1.1 Results: Although in a large number of tests seemingly significant association was observed only the following ones were confirmed upon correction for multiple comparisons: i) an increased serum LDH level was associated with haplotype 7 within VCAM1 gene; ii) a lower total bilirubin was associated with the 3.7-kb deletion at HBA gene, rs2070744_T allele at NOS3 gene, and haplotype 9 within VCAM1 promoter; and iii) a diminished reticulocyte count was associated with the 3.7-kb deletion at HBA, whereas an increased count was associated with rs1984112_G allele at CD36 gene. Conclusion: On the whole, our findings suggest a complex genetic architecture for the SCA haemolysis process involving multiple pathways, namely control of vascular cell adhesion, NO synthesis and erythrocyte volume and haemoglobinisation.
- The effect of genetic polymorphisms in trans-acting factor genes as modulators of fetal hemoglobin level in sickle cell diseasePublication . Coelho, Andreia; Miranda, Armandina; Ferreira, Emanuel; Faustino, PaulaSickle Cell Anemia (SCA), one of the most common autosomal recessive hereditary anemia, is caused by a mutation in the β-globin gene (HBB:c.20A>T) on 11p15.5. This gives rise to a variant named HbS (with the ability to polymerize under certain conditions) as opposed to the normal adult HbA. Although being a monogenic disease, the clinical phenotype of SCA is heterogeneous, ranging from relatively mild to severe, due to the modifying effect of both environmental and genetic factors. Of the latter, the level of fetal hemoglobin (HbF) is one of the most important, being itself conditioned by globinic cis-acting elements as well as non-globinic trans-acting factors. To contribute to a better understanding of the non-globinic genetic factors modulating the expression level of HbF in SCA, we genotyped (by PCR-RFLP) 110 SCA patients, for the SNP rs11886868 located in intron 2 of the BCL11A gene (2p16.1). Also, 79 SCA patients were screened for two other SNPs located in the HBS1L-MYB intergenic region on chromosome 6 (rs4895441 and rs6929404). Patients were divided in two groups, one with HbF<8% and other with HbF>8%, and the genotypic and allelic frequencies compared between both groups. Regarding to SNP rs11886868 in the BCL11A gene, we found significant differences between genotypic and allelic frequencies distribution and the HbF levels (p=0.0010 and p=0.0013, respectively). In this SCA population, our results revealed a strong association between the allele C of SNP rs11886868 and HbF levels. Concerning SNPs in the HBS1L-MYB intergenic region (rs4895441 and rs6929404), no association was found with HbF levels. The results gathered in this study confirm that genetic polymorphisms in some transacting factor genes can modulate the HbF level in SCD and, consequently, its pathophysiology. This knowledge may give new insights into new therapeutic strategies development for this pathology.
- Variação genética associada ao nível de hemólise crónica na drepanocitose: um estudo longitudinalPublication . Coelho, Andreia; Dias, Alexandra; Morais, Anabela; Nunes, Baltazar; Ferreira, Emanuel; Picanço, Isabel; Faustino, Paula; Lavinha, João