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
- 19ª Reunião da Sociedade Portuguesa de Genética Humana, Porto, (Poster) – 5-7 de novembro de 2015
Objective: 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.
Patients and Methods: 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.
Results: 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.
Conclusion: 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.
This work was partially funded by FCT-PIC/IC/83084/2007
Keywords: Sickle cell anemia, stroke, genetic modulators