Genetic architecture of hemoglobin F control

Purpose of review Much effort has been spent on understanding the regulation of fetal hemoglobin (HbF, alpha(2)gamma(2)) production and its reactivation in adults, as elevated HbF levels are correlated with reduced morbidity and mortality in sickle cell anemia and beta thalassemia, diseases that represent a major public health problem. Interindividual HbF variation is largely genetically controlled, but the inheritance patterns are not clear. Recent findings HbF persistence, measured either as percentage HbF or as percentage F cells, is increasingly understood as a quantitative genetic trait; multiple genes together with an environmental component determine the measured value in any given individual. Recent genome-wide studies have shown that common genetic polymorphisms account for a large proportion of the common variation in HbF levels, not only in healthy adults but also in patients with these beta hemoglobinopathies. Genetic variation at only three major loci (Xmn1-HBG2, HBS1L-MYB intergenic region on chromosome 6q23 and BCL11A on chromosome 2p16) account for a relatively large proportion (20-50%) of the phenotypic variation in HbF levels. Two of the major quantitative trait loci include oncogenes emphasizing the importance of cell proliferation and differentiation as an important contribution to the HbF phenotype. Summary The review traces our progress in the understanding of HbF persistence in adults as a quantitative trait and the changing genetic methodology that has helped in the dissection of the genetic architecture underlying HbF variability. We also speculate on the plausible mechanisms underlying the increased HbF production.