Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus 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., 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.
Thein
Swee Lay
SL
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
Menzel
Stephan
S
Peng
Xu
X
Best
Steve
S
Jiang
Jie
J
Close
James
J
Silver
Nicholas
N
Gerovasilli
Ageliki
A
Ping
Chen
C
Yamaguchi
Masao
M
Wahlberg
Karin
K
Ulug
Pinar
P
Spector
Tim D
TD
Garner
Chad
C
Matsuda
Fumihiko
F
Farrall
Martin
M
Lathrop
Mark
M
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
D021901:DNA, Intergenic; D020598:Proto-Oncogene Proteins c-myb; D005319:Fetal Hemoglobin