title: Control of fetal hemoglobin: new insights emerging from genomics and clinical implications.
abstract: Increased levels of fetal hemoglobin (HbF, alpha(2)gamma(2)) are of no consequence in healthy adults, but confer major clinical benefits in patients with sickle cell anemia (SCA) and beta thalassemia, diseases that represent major public health problems. Inter-individual HbF variation is largely genetically controlled, with one extreme caused by mutations involving the beta globin gene (HBB) complex, historically referred to as pancellular hereditary persistence of fetal hemoglobin (HPFH). These Mendelian forms of HPFH are rare and do not explain the common form of heterocellular HPFH which represents the upper tail of normal HbF variation, and is clearly inherited as a quantitative genetic trait. Genetic studies have identified three major quantitative trait loci (QTLs) (Xmn1-HBG2, HBS1L-MYB intergenic region on chromosome 6q23, and BCL11A on chromosome 2p16) that account for 20-50% of the common variation in HbF levels in patients with SCA and beta thalassemia, and in healthy adults. Two of the major QTLs include oncogenes, emphasizing the importance of cell proliferation and differentiation as an important contribution to the HbF phenotype. The review traces the story of HbF quantitative genetics that uncannily mirrors the changing focus in genetic methodology, from candidate genes through positional cloning, to genome-wide association, that have expedited the dissection of the genetic architecture underlying HbF variability. These genetic results have already provided remarkable insights into molecular mechanisms that underlie the hemoglobin 'switch'.
authors.affiliation: Division of Gene and Cell Based Therapy, King's College London School of Medicine, Molecular Haematology, Denmark Hill Campus, London SE5 9NU, UK. sl.thein@kcl.ac.uk
authors.forename: Swee Lay
authors.initials: SL
authors.lastname: Thein
authors.forename: Stephan
authors.initials: S
authors.lastname: Menzel
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Chad
authors.initials: C
authors.lastname: Garner
mesh_terms: D000818:Animals; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D005319:Fetal Hemoglobin / Q000235:genetics*; D014644:Genetic Variation; D023281:Genomics; D006801:Humans; D040641:Quantitative Trait Loci / Q000235:genetics; D019655:Quantitative Trait, Heritable
chemical_list: D005319:Fetal Hemoglobin