Browsing by Author "Nicolau, Marta"
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- Fetal hemoglobin level and stroke risk in children with sickle cell anemiaPublication . Nicolau, Marta; Vargas, Sofia; Coelho, Andreia; Silva, Marisa; Mendonça, Joana; Vieira, Luís; Kjollerstrom, Paula; Maia, Raquel; Silva, Rute; Dias, Alexandra; Ferreira, Teresa; Morais, Anabela; Mota Soares, Isabel; Lavinha, João; Faustino, PaulaSickle Cell Anemia (SCA) is a hereditary anemia caused by a missense mutation in HBB and it is characterized by chronic hemolysis, recurrent episodes of vaso-occlusion and infection. Cerebral vasculopathy is one of the most devastating complications of the disease and even young children with SCA have a high risk of stroke. It is known that both environmental and genetic determinants are able to modulate the onset, course and outcome of the disease. Among those, the level of fetal hemoglobin (HbF) has been proposed as the most significant disease modulator. Thus, in this work, we aimed to investigate if the level of HbF in SCA children is related with the risk of stroke and if it is modulated by variants in genes, such as HBG2, BCL11A, HBS1L-MYB, and KLF1. Sixty-seven children (3 years of age) with SCA were enrolled in this study. Hematological and imaging data were retrospectively obtained from patients’ medical records at Greater Lisbon area hospitals. Patients were grouped according to their degree of cerebral vasculopathy evaluated by transcranial Doppler velocities and magnetic resonance imaging. Molecular analyses were performed using Next-Generation Sequencing, Sanger sequencing and PCR-RFLP. In silico studies and statistical analyses were done using the PolyPhen-2 and SPSS softwares, respectively. The association studies revealed that low HbF levels were associated with stroke events in SCA children (p=0.005). At the molecular level, it was observed that patients with the rarest genotypes in HBG2 (rs7482144_TT+TC) presented higher levels of HbF (p=0.031). Additionally, the rs11886868_C and the rs4671393_A alleles in BCL11A also seemed to predispose to higher HbF levels. Moreover, eleven distinct variants in KLF1 were detected (one of them novel, the p.Q342H) with 83% of the patients having at least one variant in this gene. The group of patients who have co-inherited the above mentioned variants in HBG2 and BCL11A together with at least one KLF1 variant presented the highest HbF levels (p=0.021). Our results corroborate previous studies suggesting that a low level of HbF in SCA patients is a risk factor for stroke. Furthermore, we report for the first time the importance of KLF1 variants in combination with other genetic modifiers to the final phenotypic expression of HbF in SCA children with different degrees of cerebral vasculopathy. Consequently, this study allowed the delineation of a genetic pattern with prognostic value for SCA.
- 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.
- A hemoglobina fetal como fator modificador da gravidade clínica da anemia das células falciformes: o exemplo dos acidentes vasculares cerebraisPublication . Nicolau, Marta; Faustino, Paula; Caniça, ManuelaA anemia das células falciformes (SCA) é uma anemia hemolítica hereditária de transmissão autossómica recessiva devida à mutação HBB:c.20A>T no gene da β-globina que dá origem à hemoglobina S (HbS). A HbS quando em desoxigenação polimeriza no glóbulo vermelho, conferindo-lhe a forma de foice e tornando-o rígido e frágil. A SCA caracteriza-se por manifestações clínicas de gravidade variável que podem incluir, por ex., hemólise crónica, crises vaso-oclusivas e acidente vascular cerebral (AVC). A variabilidade fenotípica é devida a fatores ambientais e genéticos, e o nível de hemoglobina fetal (Hb F) é considerado o principal modulador da doença. Neste trabalho pretendeu-se investigar em crianças com SCA se o nível de HbF é modulado pelo seus genótipos em regiões polimórficas conhecidas nos genes HBG2, BCL11A, HBS1L-MYB e KLF1 e, por outro lado, se o nível de HbF está relacionado com o grau de hemólise que apresentam e o risco de desenvolvimento de AVC. Foram estudadas 67 crianças com SCA de origem Africana. Estas foram agrupadas de acordo com o grau de vasculopatia cerebral (Controlo, Risco e AVC). Para o estudo molecular foi usada a PCR-RFLP, sequenciação de Sanger e sequenciação de nova geração. Efetuaram-se estudos in silico e análise estatística em SPSS. Os resultados permitiram concluir que um nível baixo de HbF é um fator de risco para o desenvolvimento de AVC (p=0,005). Observou-se também que os doentes com os genótipos mais raros em HBG2 (rs7482144_TT+TC) apresentam níveis mais elevados de HbF (p=0,031). No gene BCL11A concluiu-se que o genótipo rs11886868_CC e o rs4671393_alelo_A apresentam-se tendencialmente associados a níveis mais elevados de HbF e, pelo contrário, os polimorfismos estudados em HBS1L-MYB não revelaram associação com os níveis de HbF. A análise do gene KLF1 revelou que 82,8% dos doentes possuía pelo menos uma variante neste gene, foram detetadas 11 variantes diferentes sendo uma delas não descrita, a Q342H, mas de efeito benigno na proteína. Concluiu-se que é de grande interesse considerar o efeito conjunto das referidas variantes nos genes analisados uma vez que a combinação no indivíduo das variantes mais raras versus as mais comuns está relacionada com os níveis de HbF (p=0,021) constituindo portanto um perfil genético de valor prognóstico. Os fatores genéticos analisados mostraram ser importantes modificadores dos níveis de HbF e poderão vir a constituir alvos de abordagem terapêutica.