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

Thein, Swee Lay; Menzel, Stephan; Peng, Xu; Best, Steve; Jiang, Jie; Close, James; Silver, Nicholas; Gerovasilli, Ageliki; Ping, Chen and Yamaguchi, Masao, et al. (2007) In Proceedings of the National Academy of Sciences of the United States of America 104(27). p.51-11346
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'... (More)

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.

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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
in
Proceedings of the National Academy of Sciences of the United States of America
volume
104
issue
27
pages
6 pages
publisher
National Acad Sciences
external identifiers
  • scopus:34547450531
ISSN
0027-8424
DOI
10.1073/pnas.0611393104
language
English
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no
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0f0e59a5-9353-48d2-9ec9-10d7f5c78593
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2017-10-25 11:09:09
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@article{0f0e59a5-9353-48d2-9ec9-10d7f5c78593,
  abstract     = {<p>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.</p>},
  author       = {Thein, Swee Lay and Menzel, Stephan and Peng, Xu and Best, Steve and Jiang, Jie and Close, James and Silver, Nicholas and Gerovasilli, Ageliki and Ping, Chen and Yamaguchi, Masao and Wahlberg, Karin and Ulug, Pinar and Spector, Tim D. and Garner, Chad and Matsuda, Fumihiko and Farrall, Martin and Lathrop, Mark},
  issn         = {0027-8424},
  keyword      = {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},
  language     = {eng},
  month        = {07},
  number       = {27},
  pages        = {51--11346},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {Intergenic variants of HBS1L-MYB are responsible for a major quantitative trait locus on chromosome 6q23 influencing fetal hemoglobin levels in adults},
  url          = {http://dx.doi.org/10.1073/pnas.0611393104},
  volume       = {104},
  year         = {2007},
}