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Title: Genetic and biological markers of severity in sickle cell disease
Author: Drasar, Emma Rachel
ISNI:       0000 0004 6347 6057
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2014
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Sickle cell disease (SCD) is remarkable for the variability of its phenotype despite its genetic simplicity, with family and population studies indicating a strong genetic influence. The best characterised genetic modifiers are genes controlling HbF levels and co-inheritance of alpha-thalassaemia. Other genetic and biological factors may also influence disease severity and the development of complications. King’s Health Partners have the largest adult cohort of SCD patients in the United Kingdom, approximately 2400 patients. Characterising this group (using laboratory variables, evidence of clinical complications and admission data) has formed the basis for my studies. Telomere length and Duffy antigen receptor for chemokines (DARC) status and two complications, sickle nephropathy and sickle hepatopathy were investigated. Relative telomere length (measured using qPCR) was significantly longer in patients with SCD than controls and positively correlates with white blood count. Shorter telomeres were found in patients on hydroxycarbamide treatment and those with Hb SC. We hypothesise that longer telomeres result from up-regulation of telomerase due to inflammation. Polymorphisms in DARC have a high prevalence in people of African ancestry and explain benign ethnic neutropenia. We found positive associations with Duffy positive phenotype and a reduced time to readmission and the development of leg ulcers. We investigated if sickle-related renal impairment was associated with the APOL1, DARC and HMOX1 genes. Duffy positive phenotype was associated with the development of macroalbuminuria and the presence of 1 or more APOL1 risk alleles was associated with the development of renal impairment (as measured by MDRD eGFR). We assessed the prevalence of liver disease in our population using Enhanced Liver Fibrosis score (a combination of serum markers associated with liver fibrosis) and transient elastography (Fibroscan®). Using this approach we found that transfusional iron overload and haemolysis appear to play a key role in the pathogenesis of sickle hepatopathy.
Supervisor: Thein, Swee Lay ; Vasavda, Nisha ; Menzel, Stephan Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available