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

• DOI: 10.1073/pnas.0611393104
• Publication Date: 2007-06-26T01:05:26Z
• Authors: Swee Lay Thein; Stephan Menzel; Xu Peng; Steve Best; Jie Jiang; James Close; Nicholas Silver; Ageliki Gerovasilli; Chen Ping; Masao Yamaguchi; Karin Wahlberg; Pinar Ulug; Tim D. Spector; Chad Garner; Fumihiko Matsuda; Martin Farrall; Mark Lathrop
• Keywords: Adult; Erythroid Precursor Cells; 570; 0303 health sciences; Adolescent; Quantitative Trait Loci; Genetic Variation; Middle Aged; Polymorphism, Single Nucleotide; Proto-Oncogene Proteins c-myb; 03 medical and health sciences; 616; Humans; Twin Studies as Topic; Chromosomes, Human, Pair 6; DNA, Intergenic; Fetal Hemoglobin; Aged

Individual variation in fetal hemoglobin (HbF, α 2 γ 2 ) response underlies the remarkable diversity in phenotypic severity of sickle cell disease and β thalassemia. HbF levels and HbF-associated quantitative traits (e.g., F cell levels) are highly heritable. We have previously mapped a major quantitative trait locus (QTL) controlling F cell levels in an extended Asian-Indian kindred with β thalassemia to a 1.5-Mb interval on chromosome 6q23, but the causative gene(s) are not known. The QTL encompasses several genes including HBS1L , 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 HBS1L 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 F 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 HBS1L -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 β hemoglobinopathies.