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Protein Z and Endothelin-1 genetic polymorphisms in pediatric Egyptian sickle cell disease patients.

ABSTRACT: Sickle cell disease (SCD) is a monogenic disease associated with multisystem morbidity. Vasculopathy caused by delicate imbalance between coagulation and endothelial systems plays a pivotal role in disease course. As Protein Z and Endothelin-1 genetic polymorphisms may increase the thrombotic risk, the aim of the current work was to verify the possible impact of Protein Z (PROZ G79A) and Endothelin-1 (EDN1 G5665T) polymorphisms on the clinic-laboratory features of the SCD in a cohort of Egyptian pediatric patients. Genotyping of Protein Z G79A and Endothelin-1 G5665T was carried out by polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) assay for 100 SCD patients and 100 controls. Protein -Z G79A polymorphism was not associated with vascular complications in the studied SCD patients. Endothelin-1 G5665T polymorphism was associated with pulmonary dysfunction (pulmonary artery hypertension and acute chest syndrome) and severe vaso-occlusive crises (VOC). Endothelin-1 G5665T polymorphism could be considered as a molecular predictor for pulmonary dysfunction and severe VOC in SCD. Further researches with larger cohorts are recommended to understand the pathophysiology of SCD and to explain the inter-patients' variability of disease severity.

SUBMITTER: Khorshied MM

PROVIDER: S-EPMC6816928 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Protein Z and Endothelin-1 genetic polymorphisms in pediatric Egyptian sickle cell disease patients.

Khorshied Mervat M MM Mohamed Nohair S NS Hamza Rania S RS Ali Rasha M RM El-Ghamrawy Mona K MK

Journal of clinical laboratory analysis 20170526 2

<h4>Background</h4>Sickle cell disease (SCD) is a monogenic disease associated with multisystem morbidity. Vasculopathy caused by delicate imbalance between coagulation and endothelial systems plays a pivotal role in disease course. As Protein Z and Endothelin-1 genetic polymorphisms may increase the thrombotic risk, the aim of the current work was to verify the possible impact of Protein Z (PROZ G79A) and Endothelin-1 (EDN1 G5665T) polymorphisms on the clinic-laboratory features of the SCD in a ...[more]

PMID: 28548215

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Project description:Sickle cell disease (SCD) is a red blood cell disorder associated with hemolysis and inflammation affecting hematopoietic system homeostasis. While both innate and T cell driven adaptive immune responses are involved in driving SCD-linked inflammation, the involvement of the B cell compartment in the pathophysiology of SCD, especially in pediatric patients, is much less understood. To determine the range of immune changes, we assessed the frequency of twelve immune populations via flow cytometry and levels of B cell related cytokines of the peripheral blood (PB) of pediatric (n=13) and adult (n=12) patients with SCD on hydroxyurea as compared to pediatric (n=5) and adult (n=10) race-matched controls. We also evaluated bulk RNA sequencing of the PB of pediatric SCD patients and controls. The majority of SCD patients carried the hemoglobin SS genotype (92.3% pediatrics and 66.7% adults). Mean Hydroxyurea dose was 23.4 mg/kg and 20.0 mg/kg for pediatric SCD (PSCD) and adult SCD (ASCD), respectively. Laboratory data revealed anemia with mean hemoglobin 9.4 g/dl in PSCD and 9.7 g/dl in ASCD with elevated hemolysis in pediatric and adult SCD with mean reticulocyte count of 7.1% in PSCD and 8.8% in ASCD with mean absolute reticulocyte count (ARC) 203 ± 94 for pediatric SCD and 214 ± 169 for adult SCD. Flow cytometry data revealed 1.9-fold increase (p value 0.012) of CD3+CD4+ cells in pediatric SCD versus pediatric controls; this change was not seen in adult SCD versus adult controls (decrease 17%, p value 0.302). Pediatric SCD patients had 3.5-fold increase (p=0.005) in CD19+ B cells without further increase in differentiated B cells, and this change was not seen in adult SCD versus adult controls (increase 7%, p value 0.815). We performed bulk RNA sequencing on the PB of pediatric patients with SCD as compared to the pediatric controls. Obtained transcriptomic data indicated significant changes in transcripts linked to humoral immunity. Over Representation Analysis (ORA) of cell type revealed upregulation of transcripts linked to pro-B cells (27 genes, top 3:E2F2,RAD51,ASPM) and plasma cells (37 genes, top 3:IGF1,TNFRSF17,DERL3). Analysis of B cell related cytokines revealed significant increase in IL2 (p value 0.013), IL4 (p value 0.026), TNFβ (p value 0.039), and IL13 (p value 0.034) inpediatric SCD versus pediatric controls withno significance for these cytokines in adult SCD versus adult controls. BAFF was elevated in both pediatric and adult SCD versus age-matched controls (p value0.041 and p value 0.005, respectively). In sum, our data indicate significant changes in CD4+ and CD19+ cells andsuggest significant alteration of the B cell maturation in pediatric SCD samples. Our findings point to previously unreported effect of SCD on the humoral immune system in children with SCD treated with hydroxyurea, warranting further investigation.

Dataset Information

Protein Z and Endothelin-1 genetic polymorphisms in pediatric Egyptian sickle cell disease patients.

Publications

Protein Z and Endothelin-1 genetic polymorphisms in pediatric Egyptian sickle cell disease patients.

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