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Genetic variants in endothelial nitric oxide synthase gene are modifiers of the hemolysis phenotype in Sickle Cell Anemia

Laura Aguiar1,2,3, Andreia Matos1,3, Ângela Gil1,3, Conceição Afonso1, Lígia Braga4, João Lavinha2, Paula Kjöllerström4, Paula Faustino2, Manuel Bicho1,3, Ângela Inácio1,3

1 - Laboratório de Genética, Faculdade de Medicina da Universidade de Lisboa;
2 -Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa;
3 - Instituto De Investigação Científica Bento Da Rocha Cabral (IICBRC), Lisboa;
4 - Unidade de Hematologia do Hospital de Dona Estefânia (HDE), CHLC

- 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 hereditary anemia characterized by the presence of hemoglobin S (Hb S). This disease is caused by a single mutation in beta-globin gene with a corresponding amino acid substitution at the sixth position of the beta-globin chain. The easily ability of Hb S to polymerize in deoxygenated conditions gives rise to abnormal sickled red blood cells. Vaso-occlusion and hemolytic anemia are the major features of this disease, however SCA patients present clinical and hematologic variability that cannot be only explained by the single mutation in the beta-globin gene. Others genetic modifiers and environmental effects are important in the clinical phenotype.
Patients and Methods: We have studied the association between hematological and biochemical parameters (Hb S, total Hb, red cell distribution width (RDW), neutrophils, transmembrane reductase, methemoglobin reductase, serum lactate dehydrogenase (LDH), total bilirubin and reticulocyte count) and some genetic variants, from several candidate genes, in 26 paediatric SCA patients.
Results: Our results show a significant statistical association between two endothelial nitric oxide synthase (eNOS) single nucleotide polymorphisms (SNPs) and two haemolysis parameters. Both the rs2070744_TT and the rs1799983_GG genotypes are associated with an increased reticulocyte count (p =0.02 and 0.01, respectively) and higher serum LDH level (p = 0.04 and 0.04, respectively).
Conclusion: Our findings suggest that polymorphisms in the eNOS gene may act as genetic modifiers of the haemolysis process that could provide utility for the prediction of increased susceptibility to haemolysis-related complications. Furthermore, our results reinforce the importance of nitric oxide (NO) bioactivity in SCA. We presume that NO, and possible its precursors such as L-arginine or L-citrulline, might be used as pharmacological tools to improve the quality of life of these patients.

Keywords: Sickle cell anemia, hemolysis, genetic modulators, eNOS