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Genetic modulators of fetal hemoglobin expression and ischemic stroke occurrence in African descendant children with sickle cell anemia

2019-09-02Journal article Restricted access
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dc.contributor.authorNicolau, Marta
dc.contributor.authorVargas, Sofia
dc.contributor.authorSilva, Marisa
dc.contributor.authorCoelho, Andreia
dc.contributor.authorFerreira, Emanuel
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.accessioned2020-04-24T14:10:50Z
dc.date.available2020-04-24T14:10:50Z
dc.date.issued2019-09-02
dc.description.abstractSickle 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.pt_PT
dc.description.sponsorshipThis work was partially funded by Fundação para a Ciência e a Tecnologia (FCT) grant PIC/IC/83084/2007, ISAMB, and INSA project 2012DGH720. Additionally, it is a result of the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), FCT.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationAnn Hematol. 2019 Dec;98(12):2673-2681. doi: 10.1007/s00277-019-03783-y. Epub 2019 Sep 2pt_PT
dc.identifier.doihttps://doi.org/10.1007/s00277-019-03783-ypt_PT
dc.identifier.issn0939-5555
dc.identifier.urihttp://hdl.handle.net/10400.18/6512
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringerpt_PT
dc.relationDEVELOPMENT AND VALIDATION OF VASO-OCCLUSION EARLY PREDICTORS IN A MENDELIAN MODEL OF VASCULAR DISEASE
dc.relation.publisherversionhttps://link.springer.com/article/10.1007/s00277-019-03783-ypt_PT
dc.subjectSickle Cell Anemiapt_PT
dc.subjectCerebrovascular Diseasept_PT
dc.subjectGenetic Rsk Factorspt_PT
dc.subjectFetal Hemoglobinpt_PT
dc.subjectKLF1 genept_PT
dc.subjectModificadores Genéticospt_PT
dc.subjectÁfricapt_PT
dc.subjectDoenças Genéticaspt_PT
dc.subjectAnemia das Células Falciformespt_PT
dc.subjectHemoglobinopatiaspt_PT
dc.subjectDrepanocitosept_PT
dc.subjectHemoglobina Fetalpt_PT
dc.subjectAVCpt_PT
dc.titleGenetic modulators of fetal hemoglobin expression and ischemic stroke occurrence in African descendant children with sickle cell anemiapt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleDEVELOPMENT AND VALIDATION OF VASO-OCCLUSION EARLY PREDICTORS IN A MENDELIAN MODEL OF VASCULAR DISEASE
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/5646-ICCMS/PIC%2FIC%2F83084%2F2007/PT
oaire.citation.conferencePlaceGermanypt_PT
oaire.citation.endPage2681pt_PT
oaire.citation.issue12pt_PT
oaire.citation.startPage2673pt_PT
oaire.citation.titleAnnals of Hematologypt_PT
oaire.citation.volume98pt_PT
oaire.fundingStream5646-ICCMS
person.familyNameFaustino
person.givenNamePaula
person.identifier.ciencia-idF01A-353A-433E
person.identifier.orcid0000-0002-6269-4867
person.identifier.ridM-3519-2014
person.identifier.scopus-author-id8158641100
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.embargofctDe acordo com política editorial da revista.pt_PT
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication94303e78-8b7d-4e24-811d-3af3b1a4e330
relation.isAuthorOfPublication.latestForDiscovery94303e78-8b7d-4e24-811d-3af3b1a4e330
relation.isProjectOfPublication466fa8ec-15ed-4907-9ca9-5fc5c0916fc4
relation.isProjectOfPublication.latestForDiscovery466fa8ec-15ed-4907-9ca9-5fc5c0916fc4

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