Utilize este identificador para referenciar este registo: http://hdl.handle.net/10400.18/3285
Título: Stroke risk in children with sickle cell anemia – the importance of genetic modulators of hemolysis
Autor: Vargas, Sofia
Coelho, Andreia
Maia, Raquel
Dias, Alexandra
Ferreira, Teresa
Morais, Anabela
Mota-Soares, Isabel
Lavinha, João
Kjollerstrom, Paula
Faustino, Paula
Palavras-chave: Doenças Genéticas
Sickle Cell Disease
Doença das Células Falciformes
Genetic Modifiers
Moduladores Genéticos
Hemoglobina Fetal
Data: Nov-2015
Resumo: Sickle cell anemia (SCA) is an autosomal recessive disease, caused by the mutation HBB:c.20A>T, originating hemoglobin (Hb) S that, upon deoxygenation, polymerises inside the erythrocyte, deforming it and leading to premature hemolysis. The disease presents high clinical heterogeneity, stroke being the most devastating manifestation. It occurs in 11% of patients by 20 years of age. In this study we aimed to identify genetic modulators of stroke risk in SCA. Sixty six children with SCA were categorised according to their degree of cerebral vasculopathy: Stroke (n=13), Risk (n=29) and Control (n= 24). Relevant data were collected from patients’ medical records. We characterized 23 polymorphic regions in genes related to vascular cell adhesion (VCAM-1, THBS-1, CD36), vascular tonus (NOS3, ET-1), and inflammation (TNF-α, HMOX-1) as well as in known globin expression modulators (HBB cluster haplotype; HBA and BCL11A genotypes). Data analyses were performed using R software. VCAM-1 rs1409419 allele C and NOS3 rs207044 allele C were associated to stroke events, while VCAM-1 rs1409419 allele T was found to be protective. Allele 4a of NOS3 27 bp VNTR appeared to be associated to stroke risk and the 4b allele to protection. HMOX-1 longer STRs seemed to predispose to stroke. Higher HbF levels (associated to Senegal haplotype or BCL11A rs11886868 allele T) were found in Control group, and higher lactate dehydrogenase levels were found in Risk group. The genetic variants above modulate cerebral vasculopathy development due to their quantitative effect on gene expression, their corresponding protein products and biological activities. Our findings reinforce the relevance of vascular tonus, vascular cell adhesion, and ultimately NO bioavailability and hemolysis rate in modulating SCA stroke development and provide the first evidence of a protective role of HbF against stroke occurrence.
Peer review: yes
URI: http://hdl.handle.net/10400.18/3285
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