Discovering the genetics underlying foetal haemoglobin production in adults

Abstract

Sickle cell disease (SCD) and beta thalassaemia, caused by lesions that affect the HBB (beta globin gene), form the most common human genetic disorders world-wide, and represent a major public health problem. Inter-individual variation in foetal haemoglobin (HbF) expression is a known and heritable disease modifier; high HbF levels are correlated with reduced morbidity and mortality in both diseases. This review traces our progress in the understanding of the persistence of HbF in adults as a quantitative trait and the genetic approaches used in teasing out the loci contributing to its variability in normal populations and in patients with haemoglobinopathies. Three major loci -- Xmn1-HBG2 single nucleotide polymorphism, HBS1L-MYB intergenic region on chromosome 6q, and BCL11A -- contribute 20-50% of the trait variance in patients with sickle cell anaemia and healthy European Caucasians. It is likely that the remaining trait variance is due to numerous other loci, many contributing modest effects. Identification of the three major loci has not yet been translated into new therapeutic approaches for HbF reactivation but an immediate application would be an improved prediction of one's ability to produce HbF, which in turn, may improve prediction of disease severity.