Common genetic variants are the cause of differences in the appearance, composition and function of red blood cells, the principal oxygen carrier in the mammalian circulation. The Red Cell Genetics group strives to detect which genes, and their naturally occurring variation, influence these traits. One of these, the variable persistence of HbF is an important modifier of the severity of sickle cell disease (SCD). Phenotypic SCD variability is the second focus of our work. Together with clinical researchers at allied hospitals, we are studying a fully genotyped cohort of about 1,000 SCD patients from the South London region.
We are conducting and analysing genome-wide association studies and fine-mapping loci across diverse patient populations, involving collaborators from Tanzania, Nigeria and Brazil. Our close partnership with John Strouboulis’ erythroid biology group allows us to functionally characterise variants in erythroid culture systems. The HbF modifier locus discovered by our group in 2007 (BCL11A) is the target in current gene therapy and gene editing clinical trials. GWAS data from our expanded cohorts will identify new loci or better define functional variants at known loci, which might be suitable to targeted gene editing with the goal to provide new treatment options for SCD patients.
Thein SL et al. Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults. Proc Natl Acad Sci U S A 2007
Menzel S et al. Genome-wide association maps a QTL influencing F cell production to a Zn finger protein on chromosome 2p15. Nat Genet. 2007
Brewin JN et al. Genome wide association study of silent cerebral infarction in sickle cell disease (HbSS and HbSC). Haematologica 2021