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Article: Fine mapping of the NRG1 hirschsprung's disease locus

TitleFine mapping of the NRG1 hirschsprung's disease locus
Authors
KeywordsChinese
Controlled Study
Ethnic Group
Gene Expression
Gene Identification
Gene Locus
Gene Mapping
Gene Mutation
Genetic Association
Genetic Predisposition
Genotype
Hirschsprung Disease
Human
Human Tissue
Major Clinical Study
Nucleotide Sequence
Single Nucleotide Polymorphism
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2011, v. 6 n. 1 How to Cite?
Abstract
The primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ~350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR. © 2011 Tang et al.
Persistent Identifierhttp://hdl.handle.net/10722/125323
ISSN
2013 Impact Factor: 3.534
2013 SCImago Journal Rankings: 1.724
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants CouncilHKU 765609M
University of Hong Kong200911159071
200811159006
University of Hong Kong Genomics Strategic Research Theme
Funding Information:

This work was supported by research grants from the Hong Kong Research Grants Council HKU 765609M to MGB and from The University of Hong Kong Seed Funding 200911159071 and 200811159006 to PT and MGB respectively. Support was also obtained from The University of Hong Kong Genomics Strategic Research Theme. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References
Grants

 

Author Affiliations
  1. Guiyang Medical College
  2. The University of Hong Kong
  3. Huazhong University of Science and Technology
DC FieldValueLanguage
dc.contributor.authorTang, CSMen_HK
dc.contributor.authorTang, WKen_HK
dc.contributor.authorSo, MTen_HK
dc.contributor.authorMiao, XPen_HK
dc.contributor.authorLeung, BMCen_HK
dc.contributor.authorYip, BHKen_HK
dc.contributor.authorLeon, TYYen_HK
dc.contributor.authorNgan, ESWen_HK
dc.contributor.authorLui, VCHen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorChan, IHYen_HK
dc.contributor.authorChung, HYen_HK
dc.contributor.authorLiu, XLen_HK
dc.contributor.authorWu, XZen_HK
dc.contributor.authorWong, KKYen_HK
dc.contributor.authorSham, PCen_HK
dc.contributor.authorCherny, SSen_HK
dc.contributor.authorTam, PKHen_HK
dc.contributor.authorGarciaBarceló, MMen_HK
dc.date.accessioned2010-10-31T11:24:38Z-
dc.date.available2010-10-31T11:24:38Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos One, 2011, v. 6 n. 1en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/125323-
dc.description.abstractThe primary pathology of Hirschsprung's disease (HSCR, colon aganglionosis) is the absence of ganglia in variable lengths of the hindgut, resulting in functional obstruction. HSCR is attributed to a failure of migration of the enteric ganglion precursors along the developing gut. RET is a key regulator of the development of the enteric nervous system (ENS) and the major HSCR-causing gene. Yet the reduced penetrance of RET DNA HSCR-associated variants together with the phenotypic variability suggest the involvement of additional genes in the disease. Through a genome-wide association study, we uncovered a ~350 kb HSCR-associated region encompassing part of the neuregulin-1 gene (NRG1). To identify the causal NRG1 variants contributing to HSCR, we genotyped 243 SNPs variants on 343 ethnic Chinese HSCR patients and 359 controls. Genotype analysis coupled with imputation narrowed down the HSCR-associated region to 21 kb, with four of the most associated SNPs (rs10088313, rs10094655, rs4624987, and rs3884552) mapping to the NRG1 promoter. We investigated whether there was correlation between the genotype at the rs10088313 locus and the amount of NRG1 expressed in human gut tissues (40 patients and 21 controls) and found differences in expression as a function of genotype. We also found significant differences in NRG1 expression levels between diseased and control individuals bearing the same rs10088313 risk genotype. This indicates that the effects of NRG1 common variants are likely to depend on other alleles or epigenetic factors present in the patients and would account for the variability in the genetic predisposition to HSCR. © 2011 Tang et al.en_HK
dc.languageengen_HK
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectChineseen_US
dc.subjectControlled Studyen_US
dc.subjectEthnic Groupen_US
dc.subjectGene Expressionen_US
dc.subjectGene Identificationen_US
dc.subjectGene Locusen_US
dc.subjectGene Mappingen_US
dc.subjectGene Mutationen_US
dc.subjectGenetic Associationen_US
dc.subjectGenetic Predispositionen_US
dc.subjectGenotypeen_US
dc.subjectHirschsprung Diseaseen_US
dc.subjectHumanen_US
dc.subjectHuman Tissueen_US
dc.subjectMajor Clinical Studyen_US
dc.subjectNucleotide Sequenceen_US
dc.subjectSingle Nucleotide Polymorphismen_US
dc.titleFine mapping of the NRG1 hirschsprung's disease locusen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1932-6203&volume=6&issue=1, article no. e16181&spage=&epage=&date=2010&atitle=Fine+mapping+of+the+NRG1+Hirschsprung’s+disease+locusen_HK
dc.identifier.emailTang, WK: evelynt@hku.hken_HK
dc.identifier.emailNgan, ESW: engan@hku.hken_HK
dc.identifier.emailLui, VCH: vchlui@hku.hken_HK
dc.identifier.emailChen, Y: ychenc@hku.hken_HK
dc.identifier.emailWong, KKY: kkywong@hku.hken_HK
dc.identifier.emailSham, PC: pcsham@hku.hken_HK
dc.identifier.emailCherny, SS: cherny@hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hku.hken_HK
dc.identifier.emailGarciaBarceló, MM: mmgarcia@hku.hken_HK
dc.identifier.authorityTang, WK=rp01629en_HK
dc.identifier.authorityNgan, ESW=rp00422en_HK
dc.identifier.authorityLui, VCH=rp00363en_HK
dc.identifier.authorityChen, Y=rp01318en_HK
dc.identifier.authorityWong, KKY=rp01392en_HK
dc.identifier.authoritySham, PC=rp00459en_HK
dc.identifier.authorityCherny, SS=rp00232en_HK
dc.identifier.authorityTam, PKH=rp00060en_HK
dc.identifier.authorityGarciaBarceló, MM=rp00445en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0016181en_HK
dc.identifier.pmid21283760-
dc.identifier.pmcidPMC3024406-
dc.identifier.scopuseid_2-s2.0-79251616918en_HK
dc.identifier.hkuros175675en_HK
dc.identifier.hkuros184635-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79251616918&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue1en_HK
dc.identifier.eissn1932-6203-
dc.identifier.isiWOS:000286522200033-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectIdentification of functional variants in Neuregulin-1 (NRG1), a newly discovered Hirschsprung s disease gene-
dc.identifier.scopusauthoridTang, CSM=35764635500en_HK
dc.identifier.scopusauthoridTang, WK=37462250200en_HK
dc.identifier.scopusauthoridSo, MT=8748542200en_HK
dc.identifier.scopusauthoridMiao, XP=7102585391en_HK
dc.identifier.scopusauthoridLeung, BMC=37461707700en_HK
dc.identifier.scopusauthoridYip, BHK=16685586100en_HK
dc.identifier.scopusauthoridLeon, TYY=10641704600en_HK
dc.identifier.scopusauthoridNgan, ESW=22234827500en_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK
dc.identifier.scopusauthoridChen, Y=36463185300en_HK
dc.identifier.scopusauthoridChan, IHY=36344597900en_HK
dc.identifier.scopusauthoridChung, PHY=34568741300en_HK
dc.identifier.scopusauthoridLiu, XL=37461750900en_HK
dc.identifier.scopusauthoridWu, XZ=36553563000en_HK
dc.identifier.scopusauthoridWong, KKY=24438686400en_HK
dc.identifier.scopusauthoridSham, PC=34573429300en_HK
dc.identifier.scopusauthoridCherny, SS=7004670001en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.scopusauthoridGarciaBarceló, MM=6701767303en_HK

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