title: Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults.
abstract: 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., 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 beta 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 beta hemoglobinopathies.
authors.affiliation: King's College London School of Medicine, Division of Gene and Cell Based Therapy, King's College Hospital, London SE5 9PJ, United Kingdom. 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: Xu
authors.initials: X
authors.lastname: Peng
authors.forename: Steve
authors.initials: S
authors.lastname: Best
authors.forename: Jie
authors.initials: J
authors.lastname: Jiang
authors.forename: James
authors.initials: J
authors.lastname: Close
authors.forename: Nicholas
authors.initials: N
authors.lastname: Silver
authors.forename: Ageliki
authors.initials: A
authors.lastname: Gerovasilli
authors.forename: Chen
authors.initials: C
authors.lastname: Ping
authors.forename: Masao
authors.initials: M
authors.lastname: Yamaguchi
authors.forename: Karin
authors.initials: K
authors.lastname: Wahlberg
authors.forename: Pinar
authors.initials: P
authors.lastname: Ulug
authors.forename: Tim D
authors.initials: TD
authors.lastname: Spector
authors.forename: Chad
authors.initials: C
authors.lastname: Garner
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Matsuda
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D021901:DNA, Intergenic / Q000235:genetics*; D015672:Erythroid Precursor Cells / Q000378:metabolism; D005319:Fetal Hemoglobin / Q000235:genetics / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020598:Proto-Oncogene Proteins c-myb / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics*; D018433:Twin Studies as Topic
chemical_list: D021901:DNA, Intergenic; D020598:Proto-Oncogene Proteins c-myb; D005319:Fetal Hemoglobin