Article: A 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression

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TitleA 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression
AuthorsFarrell, JJ7
Sherva, RM7
Chen, ZY7
Luo, HY7
Chu, BF7
Ha, SY2
Li, CK6
Lee, ACW1
Li, RCH1
Li, CK3
Yuen, HL5
So, JCC2
Ma, ESK2
Chan, LC2
Chan, V2
Sebastiani, P4
Farrer, LA7
Baldwin, CT7
Steinberg, MH7
Chui, DHK7
Issue Date2011
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
CitationBlood, 2011, v. 117 n. 18, p. 4935-4945 [How to Cite?]
DOI: http://dx.doi.org/10.1182/blood-2010-11-317081
AbstractFetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese β-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations. © 2011 by The American Society of Hematology.
ISSN0006-4971
2011 Impact Factor: 9.898
2011 SCImago Journal Rankings: 1.698
DOIhttp://dx.doi.org/10.1182/blood-2010-11-317081
ISI Accession Number IDWOS:000290275700038
Funding AgencyGrant Number
National Institute of Diabetes and Digestive and Kidney DiseasesRO1 DK069646
National Heart, Lung, and Blood InstituteRO1 HL068970
Funding Information:

This investigation was supported by National Institute of Diabetes and Digestive and Kidney Diseases (grant RO1 DK069646; D.H.K.C.) and National Heart, Lung, and Blood Institute (grant RO1 HL068970; M.H.S.).

PubMed Central IDPMC3100700
ReferencesReferences in Scopus
DC Field
Value
dc.contributor.authorFarrell, JJ
dc.contributor.authorSherva, RM
dc.contributor.authorChen, ZY
dc.contributor.authorLuo, HY
dc.contributor.authorChu, BF
dc.contributor.authorHa, SY
dc.contributor.authorLi, CK
dc.contributor.authorLee, ACW
dc.contributor.authorLi, RCH
dc.contributor.authorLi, CK
dc.contributor.authorYuen, HL
dc.contributor.authorSo, JCC
dc.contributor.authorMa, ESK
dc.contributor.authorChan, LC
dc.contributor.authorChan, V
dc.contributor.authorSebastiani, P
dc.contributor.authorFarrer, LA
dc.contributor.authorBaldwin, CT
dc.contributor.authorSteinberg, MH
dc.contributor.authorChui, DHK
dc.date.accessioned2011-09-23T06:02:15Z
dc.date.available2011-09-23T06:02:15Z
dc.date.issued2011
dc.description.abstractFetal hemoglobin (HbF) is regulated as a multigenic trait. By genome-wide association study, we confirmed that HBS1L-MYB intergenic polymorphisms (HMIP) and BCL11A polymorphisms are highly associated with HbF in Chinese β-thalassemia heterozygotes. In this population, the variance in HbF resulting from the HMIP is 13.5%; that resulting from the BCL11A polymorphism is 6.4%. To identify the functional variant in HMIP, we used 1000 Genomes Project data, single nucleotide polymorphism imputation, comparisons of association results across populations, potential transcription factor binding sites, and analysis of phylogenetic conservation. Based on these studies, a hitherto unreported association between HbF expression and a 3-bp deletion, between 135 460 326 and 135 460 328 bp on chromosome 6q23 was found. This 3-bp deletion is in complete linkage disequilibrium with rs9399137, which is the single nucleotide polymorphism in HMIP most significantly associated with HbF among Chinese, Europeans, and Africans. Chromatin immunoprecipitation assays confirmed erythropoiesis-related transcription factors binding to this region in K562 cells. Based on transient expression of a luciferase reporter plasmid, the DNA fragment encompassing the 3-bp deletion polymorphism has enhancer-like activity that is further augmented by the introduction of the 3-bp deletion. This 3-bp deletion polymorphism is probably the most significant functional motif accounting for HMIP modulation of HbF in all 3 populations. © 2011 by The American Society of Hematology.
dc.description.natureLink_to_subscribed_fulltext
dc.identifier.citationBlood, 2011, v. 117 n. 18, p. 4935-4945 [How to Cite?]
DOI: http://dx.doi.org/10.1182/blood-2010-11-317081
dc.identifier.citeulike8976138
dc.identifier.doihttp://dx.doi.org/10.1182/blood-2010-11-317081
dc.identifier.epage4945
dc.identifier.hkuros192825
dc.identifier.isiWOS:000290275700038
Funding AgencyGrant Number
National Institute of Diabetes and Digestive and Kidney DiseasesRO1 DK069646
National Heart, Lung, and Blood InstituteRO1 HL068970
Funding Information:

This investigation was supported by National Institute of Diabetes and Digestive and Kidney Diseases (grant RO1 DK069646; D.H.K.C.) and National Heart, Lung, and Blood Institute (grant RO1 HL068970; M.H.S.).

dc.identifier.issn0006-4971
2011 Impact Factor: 9.898
2011 SCImago Journal Rankings: 1.698
dc.identifier.issue18
dc.identifier.openurl
dc.identifier.pmcidPMC3100700
dc.identifier.pmid21385855
dc.identifier.scopuseid_2-s2.0-79955977896
dc.identifier.spage4935
dc.identifier.urihttp://hdl.handle.net/10722/139942
dc.identifier.volume117
dc.languageeng
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
dc.publisher.placeUnited States
dc.relation.ispartofBlood
dc.relation.referencesReferences in Scopus
dc.rightsThis research was originally published in The Hematologist: ASH News and Reports. Author(s). Title. The Hematologist: ASH News and Reports. Year;Vol,Issue:pp-pp. © the American Society of Hematology.
dc.subject.meshAsian Continental Ancestry Group - genetics
dc.subject.meshChromosomes, Human, Pair 6 - genetics
dc.subject.meshFetal Hemoglobin - genetics
dc.subject.meshGenes, myb
dc.subject.meshSequence Deletion
dc.titleA 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression
dc.typeArticle
Author Affiliations
  1. Tuen Mun Hospital
  2. The University of Hong Kong
  3. Princess Margaret Hospital Hong Kong
  4. Boston University School of Public Health
  5. Queen Elizabeth Hospital Hong Kong
  6. Prince of Wales Hospital Hong Kong
  7. Boston University School of Medicine