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

TitleA 3-bp deletion in the HBS1L-MYB intergenic region on chromosome 6q23 is associated with HbF expression
Authors
Issue Date2011
PublisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/
Citation
Blood, 2011, v. 117 n. 18, p. 4935-4945 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/139942
ISSN
2014 Impact Factor: 10.452
2014 SCImago Journal Rankings: 5.246
PubMed Central ID
ISI Accession Number ID
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.).

References

 

DC FieldValueLanguage
dc.contributor.authorFarrell, JJen_HK
dc.contributor.authorSherva, RMen_HK
dc.contributor.authorChen, ZYen_HK
dc.contributor.authorLuo, HYen_HK
dc.contributor.authorChu, BFen_HK
dc.contributor.authorHa, SYen_HK
dc.contributor.authorLi, CKen_HK
dc.contributor.authorLee, ACWen_HK
dc.contributor.authorLi, RCHen_HK
dc.contributor.authorLi, CKen_HK
dc.contributor.authorYuen, HLen_HK
dc.contributor.authorSo, JCCen_HK
dc.contributor.authorMa, ESKen_HK
dc.contributor.authorChan, LCen_HK
dc.contributor.authorChan, Ven_HK
dc.contributor.authorSebastiani, Pen_HK
dc.contributor.authorFarrer, LAen_HK
dc.contributor.authorBaldwin, CTen_HK
dc.contributor.authorSteinberg, MHen_HK
dc.contributor.authorChui, DHKen_HK
dc.date.accessioned2011-09-23T06:02:15Z-
dc.date.available2011-09-23T06:02:15Z-
dc.date.issued2011en_HK
dc.identifier.citationBlood, 2011, v. 117 n. 18, p. 4935-4945en_HK
dc.identifier.issn0006-4971en_HK
dc.identifier.urihttp://hdl.handle.net/10722/139942-
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.en_HK
dc.languageengen_US
dc.publisherAmerican Society of Hematology. The Journal's web site is located at http://bloodjournal.hematologylibrary.org/en_HK
dc.relation.ispartofBlooden_HK
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 expressionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0006-4971&volume=117&issue=18&spage=4935&epage=4945&date=2011&atitle=A+3-bp+deletion+in+the+HBS1L-MYB+intergenic+region+on+chromosome+6q23+is+associated+with+HbF+expression-
dc.identifier.emailSo, JCC:scc@pathology.hku.hken_HK
dc.identifier.emailChan, LC:chanlc@hkucc.hku.hken_HK
dc.identifier.emailChan, V:vnychana@hkucc.hku.hken_HK
dc.identifier.authoritySo, JCC=rp00391en_HK
dc.identifier.authorityChan, LC=rp00373en_HK
dc.identifier.authorityChan, V=rp00320en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1182/blood-2010-11-317081en_HK
dc.identifier.pmid21385855-
dc.identifier.pmcidPMC3100700-
dc.identifier.scopuseid_2-s2.0-79955977896en_HK
dc.identifier.hkuros192825en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79955977896&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume117en_HK
dc.identifier.issue18en_HK
dc.identifier.spage4935en_HK
dc.identifier.epage4945en_HK
dc.identifier.isiWOS:000290275700038-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridFarrell, JJ=7201697549en_HK
dc.identifier.scopusauthoridSherva, RM=23092394800en_HK
dc.identifier.scopusauthoridChen, ZY=35315648100en_HK
dc.identifier.scopusauthoridLuo, HY=37116363100en_HK
dc.identifier.scopusauthoridChu, BF=43760917400en_HK
dc.identifier.scopusauthoridHa, SY=7202501115en_HK
dc.identifier.scopusauthoridLi, CK=35261905500en_HK
dc.identifier.scopusauthoridLee, ACW=7405631431en_HK
dc.identifier.scopusauthoridLi, RCH=24177143900en_HK
dc.identifier.scopusauthoridLi, CK=34968282800en_HK
dc.identifier.scopusauthoridYuen, HL=7103253677en_HK
dc.identifier.scopusauthoridSo, JCC=7102919978en_HK
dc.identifier.scopusauthoridMa, ESK=7202039934en_HK
dc.identifier.scopusauthoridChan, LC=7403540707en_HK
dc.identifier.scopusauthoridChan, V=7202654865en_HK
dc.identifier.scopusauthoridSebastiani, P=7004155020en_HK
dc.identifier.scopusauthoridFarrer, LA=7005139839en_HK
dc.identifier.scopusauthoridBaldwin, CT=7201893542en_HK
dc.identifier.scopusauthoridSteinberg, MH=34772018000en_HK
dc.identifier.scopusauthoridChui, DHK=7005111153en_HK
dc.identifier.citeulike8976138-

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