Genotype-phenotype correlation in sickle cell disease

• Main Author: Gardner, Catherine Joanne
• Other Authors: Thein, Swee Lay ; Menzel, Stephan
• Published: King's College London (University of London) 2017
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.733411

Sickle cell disease (SCD) has a complex pathophysiology initiated by the polymerisation of deoxy-sickle-haemoglobin. The single nucleotide change underpinning SCD does not account for the vast range and severity of SCD complications. This clinical heterogeneity is only partly explained by the genetic variability of fetal haemoglobin gene levels and co-inheritance of α- thalassemia. Although environmental factors also contribute to the clinical complexity of SCD, further genetic modifiers of SCD severity exist but are yet to be determined. Genetic association studies have been boosted recently not only with the advent of new genotyping tools, but also with the development of increasingly sophisticated analytical methods. New developments in phenotyping, genotyping and genotype-phenotype association approaches allow us to disentangle true genetic associations from hits due to chance. This thesis seeks to investigate biomarkers of sickle severity and to use these clinical markers in genotype-phenotype correlation studies. I have investigated three key markers of disease severity: haemolysis, frequency of acute pain episodes and mortality. Estimated median survival of 67 years in HbSS disease in our UK cohort is a significant improvement in survival compared to other recent estimates in the USA and Jamaica. I have undertaken genome-wide micro-array scanning and created an imputed genotype dataset of over 15,000,000 genetic variants. I have used these phenotype and genotype datasets to conduct genetic association studies, both genome-wide and candidate gene association studies. These analyses are based on linear mixed modelling to account for relatedness (including population stratification) within the cohort. In addition to the severity outcomes, I have also evaluated the known genetic loci for HbF and created a genetic “summary statistic” to quantify the effects of these three loci. Finally, I have also assessed the role of the erythroid regulator KLF1 in HbF levels in SCD with two laboratory-based projects.