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

Research output: Contribution to journalArticle


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.


  • 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
External organisations
  • King's College Hospital
Research areas and keywords


  • Adolescent, Adult, Aged, Chromosomes, Human, Pair 6, DNA, Intergenic, Erythroid Precursor Cells, Fetal Hemoglobin, Genetic Variation, Humans, Middle Aged, Polymorphism, Single Nucleotide, Proto-Oncogene Proteins c-myb, Quantitative Trait Loci, Twin Studies as Topic, Journal Article, Research Support, Non-U.S. Gov't
Original languageEnglish
Pages (from-to)11346-51
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number27
Publication statusPublished - 2007 Jul 3
Publication categoryResearch
Externally publishedYes