Correlation between SCD Genotype and vascular and endothelial complication

Abstract

SUMMARY S ickle cell disease (SCD) is a multisystem disease, associated with episodes of acute illness and progressive organ damage. SCD has a wide spectrum of complications. Vascular dysfunction which is due to complex and multifactorial interactions manifests as the clinical phenotypes of SCD. Many factors contribute to this variability in SCD and its clinical outcome. Of these, genetic determinants are hypothesized to influence the risk of developing some disease complications. This study aimed to assess the relation between different genotypes among children and adolescents with SCD and vascular markers, iron overload as well as vascular complications and subclinical atherosclerosis. Thirty-eight SCD patients (21 males and 17 females), in steady state were recruited from the regular attendants of the Pediatric Hematology Clinic, Pediatric Hospital, Ain Shams University. Patients were compared with 40 age- and sex-matched healthy subjects (25 males and 15 females) enrolled as controls. The median age of SCD patients was 10 years (range: 1-18 years) while that of controls was 9.5 years (range: 3-17 years). All patients were subjected to full history and thorough clinical examination with special emphasis on history of sickling crisis, cardiopulmonary disease, acute chest syndrome, stroke, bone manifestations, nephropathy, spleen status, transfusion history and hydroxyurea/chelation therapy. Laboratory investigations included hematological profile, liver and kidney functions, markers of hemolysis (lactate dehydrogenase [LDH] and indirect bilirubin) and serum ferritin. Soluble CD163 (sCD163) was measured by enzyme linked immunosorbent assay while analysis of platelet microparticles (PMPs) was done by flow cytometry. Pediatric SCD severity index was assessed based on both clinical and laboratory variables. DNA genotyping was identified using on polymerase chain reaction and reverse hybridization. Echocardiography and assessment of carotid intima media thickness were performed. Levels of sCD163 and PMPs as well as CIMT were significantly higher in SCD patients than control group. Based upon DNA genotyping, patients were categorized as either homozygous sickle cell disease (HbSS) or heterozygous sickle cell disease (Hb S/β); 24 (63.2%) patients had sickle cell anemia (SCA; S/S homozygote Codon 6[A>T] HbS), 10 (26.3%) patients had sickle βº thalassemia (Codon 6[A>T] HbS/βº IVS2-1[G>A]) and 4 (10.5%) patients had sickle β+ thalassemia. Comparison between patients with SCA (n=24) and those with sickle β-thalassemia (n=14) revealed no significant difference as regards age, sex, anthropometric measures, Tanner stage, family history or residency. A trend towards higher incidence of consanguineous marriage among families of patients with sickle β-thalassemia was found. Patients with SCA had significantly higher incidence of pulmonary hypertension, acute chest syndrome, frequent sickling crisis, avascular bone necrosis and nephropathy while those with sickle β-thalassemia had higher incidence of splenectomy, viral hepatitits and heart disease (p<0.05). The degree of hemolysis and iron overload was increased in sickle β-thalassemia patients compared with SCA group as shown by elevated transfusion index, LDH and serum ferritin. Patients with SCA displayed an evident state of inflammation, vascular injury and subclinical atherosclerosis reflected by high white blood cells, monocyte count, HbS, sCD163 levels, PMPs and CIMT compared with the heterozygous group.