Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait focus on chromosome 6q23 influencing fetal hemoglobin levels in adults

Individual variation in fetal hemoglobin (HbF, alpha(2)gamma(2) response underlies the remarkable diversity in phenotypic severity of sickle cell disease and beta thalassemia. HbF levels and HbF-associated quantitative traits (e.g., IF cell levels) are highly heritable. We have previously mapped a major quantitative trait locus (QTQ controlling IF cell levels in an extended Asian-Indian kindred with 13 thalassernia to a 1.5-Mb interval on chromosome 6q23, but the causative gene(s) are not known. The QTL encompasses several genes including HBSlL, a member of the GTP-binding protein family that is expressed in erythroid progenitor cells. In this high-resolution association study, we have identified multiple genetic variants within and 5' to HB51L at 6q23 that are strongly associated with F cell levels in families of Northern European ancestry (P = 10(-75)). The region accounts for 17.6% of the IF cell variance in northern Europeans. Although mRNA levels of HBS1L and MYB in erythroid precursors grown in vitro are positively correlated, only HBS1L expression correlates with high F cell alleles. The results support a key role for the HBM-related genetic variants in HbF control and illustrate the biological complexity of the mechanism of 6q QTL as a modifier of fetal hemoglobin levels in the beta hemoglobincipathies.