Hemorheological alterations in sickle cell anemia and their clinical consequences – The role of genetic modulators

Issue title: Selected papers of the 18th European Conference for Clinical Hemorheology and Microcirculation (ESCHM), 5-8 June, 2016, Lisbon, Portugal

Article type: Research Article

Authors: Silva, Marisa^a | Vargas, Sofia^a | Coelho, Andreia^a | Dias, Alexandra^b | Ferreira, Teresa^b | Morais, Anabela^c | Maia, Raquel^d | Kjöllerström, Paula^d | Lavinha, João^{a; e} | Faustino, Paula^{a; f; *}

Affiliations: [a] Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal | [b] Departamento de Pediatria, Núcleo de Hematologia, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal | [c] Departamento de Pediatria, Hospital de Santa Maria, CHLN, Lisboa, Portugal | [d] Unidade de Hematologia, Hospital de Dona Estefânia, CHLC, Lisboa, Portugal | [e] BioISI, Faculdade de Ciências, Universidade de Lisboa, Lisboa, Portugal | [f] Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal

Correspondence: [*] Corresponding author: Paula Faustino, PhD, Departamento de Genética Humana, Unidade de Investigação e Desenvolvimento, Instituto Nacional de Saúde Doutor Ricardo Jorge, Avenida Padre Cruz, 1649-016 Lisboa, Portugal.Tel.: +351 217508164; Fax: +351 217526410; E-mail: paula.faustino@insa.min-saude.pt.

Abstract: Sickle cell anemia (SCA) is an autosomal recessive disease caused by the HBB:c.20A>T mutation that leads to hemoglobin S synthesis. The disease presents with high clinical heterogeneity characterized by chronic hemolysis, recurrent episodes of vaso-oclusion and infection. This work aimed to characterize by in silico studies some genetic modulators of severe hemolysis and stroke risk in children with SCA, and understand their consequences at the hemorheological level. Association studies were performed between hemolysis biomarkers as well as the degree of cerebral vasculopathy and the inheritance of several polymorphic regions in genes related with vascular cell adhesion and vascular tonus in pediatric SCA patients. In silico tools (e.g. MatInspector) were applied to investigate the main variant consequences. Variants in vascular adhesion molecule-1 (VCAM1) gene promoter and endothelial nitric oxide synthase (NOS3) gene were significantly associated with higher degree of hemolysis and stroke events. They potentially modify transcription factor binding sites (e.g. VCAM1 rs1409419_T allele may lead to an EVI1 gain) or disturb the corresponding protein structure/function. Our findings emphasize the relevance of genetic variation in modulating the disease severity due to their effect on gene expression or modification of protein biological activities related with sickled erythrocyte/endothelial interactions and consequent hemorheological abnormalities.

Keywords: Sickle cell anemia, VCAM1, NOS3, genetic modulators, in silico analysis

DOI: 10.3233/CH-168048

Journal: Clinical Hemorheology and Microcirculation, vol. 64, no. 4, pp. 859-866, 2016