title: Genetic variation in CD36, HBA, NOS3 and VCAM1 is associated with chronic haemolysis level in sickle cell anaemia: a longitudinal study.
abstract: Chronic haemolysis stands out as one of the hallmarks of sickle cell anaemia, a clinically heterogeneous autosomal recessive monogenic anaemia. However, the genetic architecture of this sub-phenotype is still poorly understood. Here, we report the results of an association study between haemolysis biomarkers (serum LDH, total bilirubin and reticulocyte count) and the inheritance of 41 genetic variants of ten candidate genes in a series of 99 paediatric SS patients (median current age of 9.9 yr) followed up in two general hospitals in Greater Lisboa area (median follow-up per patient of 5.0 yr). Although in a large number of tests a seemingly significant (i.e. P < 0.05) association was observed, the following ones were confirmed upon correction for multiple comparisons: (i) an increased serum LDH level was associated with haplotype 7 within VCAM1 gene; (ii) a lower total bilirubin was associated with the 3.7-kb deletion at HBA gene, rs2070744_T allele at NOS3 gene, and haplotype 9 within VCAM1 promoter; and (iii) a diminished reticulocyte count was associated with the 3.7-kb deletion at HBA, whereas an increased count was associated with rs1984112_G allele at CD36 gene. On the whole, our findings suggest a complex genetic architecture for the sickle cell anaemia haemolysis process involving multiple pathways, namely control of vascular cell adhesion, NO synthesis and erythrocyte volume and haemoglobinisation.
authors.affiliation: Departamento de Genética Humana, Instituto Nacional de Saúde Doutor Ricardo Jorge, Lisboa, Portugal.
authors.forename: Andreia
authors.initials: A
authors.lastname: Coelho
authors.forename: Alexandra
authors.initials: A
authors.lastname: Dias
authors.forename: Anabela
authors.initials: A
authors.lastname: Morais
authors.forename: Baltazar
authors.initials: B
authors.lastname: Nunes
authors.forename: Emanuel
authors.initials: E
authors.lastname: Ferreira
authors.forename: Isabel
authors.initials: I
authors.lastname: Picanço
authors.forename: Paula
authors.initials: P
authors.lastname: Faustino
authors.forename: João
authors.initials: J
authors.lastname: Lavinha
mesh_terms: D000483:Alleles; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000235:genetics; D018955:CD36 Antigens / Q000235:genetics*; D002648:Child; D004912:Erythrocytes / Q000166:cytology; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006441:Hemoglobin A / Q000235:genetics*; D006454:Hemoglobins / Q000378:metabolism; D006461:Hemolysis / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D010641:Phenotype; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*; D017085:alpha-Thalassemia / Q000378:metabolism
chemical_list: D018955:CD36 Antigens; D006454:Hemoglobins; D019010:Vascular Cell Adhesion Molecule-1; D009569:Nitric Oxide; D006441:Hemoglobin A; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III
keywords: NO metabolism; adhesion molecules; alpha-thalassaemia; association; haemolysis; sickle cell