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Genetic Modulation of Cerebral Vasculopathy in Children with Sickle Cell Anemia

2018-01-10Lecture Open access
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dc.contributor.authorSilva, Marisa
dc.contributor.authorVargas, Sofia
dc.contributor.authorCoelho, Andreia
dc.contributor.authorMendonça, Joana
dc.contributor.authorVieira, Luís
dc.contributor.authorKjollerstrom, Paula
dc.contributor.authorMaia, Raquel
dc.contributor.authorSilva, Rita
dc.contributor.authorDias, Alexandra
dc.contributor.authorFerreira, Teresa
dc.contributor.authorMorais, Anabela
dc.contributor.authorMota Soares, Isabel
dc.contributor.authorLavinha, João
dc.contributor.authorFaustino, Paula
dc.date.accessioned2019-03-14T15:49:05Z
dc.date.available2019-03-14T15:49:05Z
dc.date.issued2018-01-10
dc.descriptionPalestras de difusão da cultura científica dirigidas aos colaboradores internos do INSA, podendo incluir participantes externos envolvidos nos estudos e colegas de investigação da área de trabalho em questão.
dc.description.abstractSickle cell anemia (SCA) arises from homozygosity for the mutation c.20A>T in the HBB gene which originates hemoglobin S (HbS). In hypoxic conditions, HbS polymerizes inside erythrocytes deforming them and ultimately leading to hemolysis and vaso-occlusion. SCA shows a multifactorial-like behaviour with a high heterogeneity of clinical features, with stroke being the most severe of them. This heterogeneity may arise from underlying genetic modifiers, namely those affecting vascular hemostasis. These include genes like the ones encoding VCAM-1 and its ligand integrin α4 (expressed in activated human endothelium and leucocytes/stress reticulocytes, respectively), but also eNOS (expressed in human endothelium and regulating vascular tone). The aim of this study was to identify putative genetic modulators of stroke risk by analyzing 70 pediatric SCA patients, grouped according to their degree of cerebral vasculopathy. Molecular analysis was performed using Next-Generation Sequencing (NGS) and Sanger Sequencing. R software was used for statistical analyses and association studies. In silico studies were performed using PHASE, TFbind, PROMO and Human Splicing Finder software tools. We identified six different VCAM1 promoter variants and seven haplotypes. The VCAM1 promoter rs1409419_T allele was associated with stroke events, while one VCAM1 promoter haplotype was found to be protective of stroke. In the ITGA4 gene, forty variants were found, six of them novel. All patients presented with at least one variant in this gene. We observed co-inheritance of specific sets of ITGA4 variants indicating the presence of haplotypes not previously described. Three NOS3 variants were analysed and seven haplotypes were identified. The NOS3 promoter rs2070744_C allele was associated with stroke events, while the intron 4 VNTR 27bp_4a allele was found to be in association with risk of stroke. Our results reinforce the role of endothelial molecules and blood cell interaction in SCA severity. The association between specific variants in VCAM1 and ITGA4, as well as in NOS3, with certain cerebral vasculopathy predictors further enhances their putative modulating effect on pediatric stroke severity and prognosis. These findings provide additional clues on the SCA pathophysiology and uncover features of both genes that may prove to be crucial as potential therapeutic targets.pt_PT
dc.description.versionN/Apt_PT
dc.identifier.urihttp://hdl.handle.net/10400.18/6205
dc.language.isoengpt_PT
dc.peerreviewednopt_PT
dc.subjectSickle Cell Anemiapt_PT
dc.subjectDrepanocitosept_PT
dc.subjectHemoglobinopatiaspt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectVasculopatia Cerebralpt_PT
dc.subjectAVCpt_PT
dc.subjectFactores Genéticos Modificadorespt_PT
dc.subjectAssociação Genótipo/fenótipopt_PT
dc.titleGenetic Modulation of Cerebral Vasculopathy in Children with Sickle Cell Anemiapt_PT
dc.typelecture
dspace.entity.typePublication
oaire.citation.conferencePlaceLisboa, Portugalpt_PT
oaire.citation.titleSeminários do Departamento de Genética Humana 2018, INSA, 10 janeiro 2018pt_PT
rcaap.rightsopenAccesspt_PT
rcaap.typelecturept_PT

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