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Sofia Vargas1, Andreia Coelho1, Raquel Maia2, Alexandra Dias3, Teresa Ferreira3, Anabela Morais4, Isabel Soares5, João Lavinha1, Paula Kjöllerström2, Paula Faustino1

1 ‐ Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa;
2 ‐ Unidade de Hematologia, Hospital de Dona Estefânia, CHLC;
3 ‐ Departamento de Pediatria, Hospital Prof. Doutor Fernando da Fonseca;
4 ‐ Departamento de Pediatria, Hospital de Santa Maria, CHLN;
5 ‐ Departamento de Pediatria, Hospital Garcia de Orta

- Reunião Anual da Sociedade Portuguesa de Hematologia, Figueira da Foz, (Poster) – 12 a 14 de novembro de 2015 (Poster)

Objective: Sickle Cell Disease (SCD) is a clinically heterogeneous monogenic chronic anaemia characterized by severe recurrent episodes of vaso‐occlusion, infection, and chronic haemolysis. Cerebral vasculopathy (overt stroke and silent infarcts) is one of the most devastating complications affecting these children. However, its pathophysiology is complex and the underlying mechanisms remain largely unknown.
The main objective of this study was to search for associations between putative genetic modifiers of vascular tonus, vascular cell adhesion and inflammation, and the risk for cerebral infarcts, particularly overt stroke, in the context of SCD in paediatric patients.
Patients and Methods: Sixty six children with SCD were enrolled in this work. They were divided into three groups, according to different inclusion criteria: Stroke group(n=13), included children with at least one episode of stroke between ages 5 and 13; Risk group (n=29) included children with high transcranial Doppler (TCD) velocities and children with silent infarcts on magnetic resonance imaging (MRI); and Control group (n= 24) included children without previous history of stroke, normal TCD velocities and no abnormalities on MRI.
Clinical, biochemical, haematological and imaging data were retrospectively obtained from patients’ medical records.
Several molecular biology methodologies (such as, PCR‐RFLP, Gap‐PCR, Sequencing, and Gene Scan) were used to characterize 23 genetic variants of 12 candidate genes. Statistical analysis was performed using R software.
Results and discussion: Six SNPs in genes (VCAM1, THBS1, HMOX, and NOS3), and four haplotypes (in the promoters of VCAM1 and NOS3) were found to be associated with some of the studied phenotypes. However, only two SNPs and one haplotype maintained significance after FDR correction of p‐values, with 90% confidence. The (‐2021)T variant in the promoter of VCAM1 (rs1409419) and the (‐786)C variant in NOS3 (rs2070744) were positively associated with Stroke, whereas Haplotype 5 in NOS3 was positively associated with Control group, all for allele count and dominant mode of transmission. These gene variants seem to modulate the cerebral vasculopathy due to their capacity to quantitatively modify gene expression and, consequently, their corresponding protein products biological activities.
Additionally, it was observed that patients who presented high HbF levels (>10%) were less prone to stroke ischemic events.
Moreover, Risk group showed a positive association with higher LDH levels when compared to the other groups, suggesting that higher degree of haemolysis is a risk factor for stroke.
This work was partially supported by FCTPIC/IC/83084/2007.

Keywords: Sickle cell disease, stroke, genetic modulators