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Article: Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease

TitleReduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease
Authors
Issue Date2010
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
Citation
Human Molecular Genetics, 2010, v. 19 n. 8, p. 1461-1467 How to Cite?
Abstract
Receptor tyrosine kinase (RET) single nucleotide polymorphisms (SNPs) are associated with the Hirschsprung's disease (HSCR). We investigated whether the amount of RET expressed in the ganglionic gut of human was dependent on the genotype of three regulatory SNPs (-5G>A rs10900296 and -1A>C rs10900297 in the promoter, and C>T rs2435357 in intron 1). We examined the effects of three regulatory SNPs on the RET gene expression in 67 human ganglionic gut tissues using quantitative real-time PCR. Also, 315 Chinese HSCR patients and 325 ethnically matched controls were genotyped for the three SNPs by polymerase chain reaction (PCR) and direct sequencing. The expression of RET mRNA in human gut tissue did indeed correlate with the genotypes of the individuals. The lowest RET expression was found for those individuals homozygous for the three risk alleles (A-C-T/A-C-T), and the highest for those homozygous for the 'wild-type' counterpart (G-A-C/G-A-C), with expression values ranging from 218.32±125.69 (mean ± SE) in tissues from individuals carrying G-A-C/G-A-C to 31.42±8.42 for individuals carrying A-C-T/A-C-T (P 5 0.018). As expected, alleles -5A, -1C and intron 1 T were associated with HSCR (P 5 5.94 × 10-31, 3.12 3 10-24 and 5.94 × 10-37, respectively) as was the haplotype encompassing the three associated alleles (A-C-T) when compared with the wild-type counterpart G-A-C (χ2 5 155.29, P « 0.0001). To our knowledge, this is the first RET expression genotype-phenotype correlation study conducted on human subjects to indicate common genetic variants in the regulatory region of RET may play a role in mediating susceptibility to HSCR, by conferring a significant reduction of the RET expression. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.
Persistent Identifierhttp://hdl.handle.net/10722/83609
ISSN
2013 Impact Factor: 6.677
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants Council765407M
HKU 775907M
University of Hong Kong200709159003
200611159028
University of Hong Kong Genomics Strategic Research Theme
Funding Information:

This work was supported by research grants from the Hong Kong Research Grants Council 765407M and HKU 775907M and from The University of Hong Kong Seed Funding 200709159003 and 200611159028 to M. G. B. and P. T., respectively. Support was also obtained from The University of Hong Kong Genomics Strategic Research Theme.

References
Grants

 

Author Affiliations
  1. China Medical University Shenyang
  2. The University of Hong Kong
  3. Huazhong University of Science and Technology
DC FieldValueLanguage
dc.contributor.authorMiao, Xen_HK
dc.contributor.authorLeon, TYYen_HK
dc.contributor.authorNgan, ESWen_HK
dc.contributor.authorSo, MTen_HK
dc.contributor.authorYuan, ZWen_HK
dc.contributor.authorLui, VCHen_HK
dc.contributor.authorChen, Yen_HK
dc.contributor.authorWong, KKYen_HK
dc.contributor.authorTam, PKHen_HK
dc.contributor.authorGarciaBarceló, Men_HK
dc.date.accessioned2010-09-06T08:43:04Z-
dc.date.available2010-09-06T08:43:04Z-
dc.date.issued2010en_HK
dc.identifier.citationHuman Molecular Genetics, 2010, v. 19 n. 8, p. 1461-1467en_HK
dc.identifier.issn0964-6906en_HK
dc.identifier.urihttp://hdl.handle.net/10722/83609-
dc.description.abstractReceptor tyrosine kinase (RET) single nucleotide polymorphisms (SNPs) are associated with the Hirschsprung's disease (HSCR). We investigated whether the amount of RET expressed in the ganglionic gut of human was dependent on the genotype of three regulatory SNPs (-5G>A rs10900296 and -1A>C rs10900297 in the promoter, and C>T rs2435357 in intron 1). We examined the effects of three regulatory SNPs on the RET gene expression in 67 human ganglionic gut tissues using quantitative real-time PCR. Also, 315 Chinese HSCR patients and 325 ethnically matched controls were genotyped for the three SNPs by polymerase chain reaction (PCR) and direct sequencing. The expression of RET mRNA in human gut tissue did indeed correlate with the genotypes of the individuals. The lowest RET expression was found for those individuals homozygous for the three risk alleles (A-C-T/A-C-T), and the highest for those homozygous for the 'wild-type' counterpart (G-A-C/G-A-C), with expression values ranging from 218.32±125.69 (mean ± SE) in tissues from individuals carrying G-A-C/G-A-C to 31.42±8.42 for individuals carrying A-C-T/A-C-T (P 5 0.018). As expected, alleles -5A, -1C and intron 1 T were associated with HSCR (P 5 5.94 × 10-31, 3.12 3 10-24 and 5.94 × 10-37, respectively) as was the haplotype encompassing the three associated alleles (A-C-T) when compared with the wild-type counterpart G-A-C (χ2 5 155.29, P « 0.0001). To our knowledge, this is the first RET expression genotype-phenotype correlation study conducted on human subjects to indicate common genetic variants in the regulatory region of RET may play a role in mediating susceptibility to HSCR, by conferring a significant reduction of the RET expression. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.en_HK
dc.languageengen_HK
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/en_HK
dc.relation.ispartofHuman Molecular Geneticsen_HK
dc.rightsThis is a pre-copy-editing, author-produced PDF of an article accepted for publication in Human Molecular Genetics following peer review. The definitive publisher-authenticated version Human Molecular Genetics, 2010, v. 19 n. 8, p. 1461-1467 is available online at: http://hmg.oxfordjournals.org/content/19/8/1461en_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subject.meshDown-Regulation-
dc.subject.meshGenetic Predisposition to Disease-
dc.subject.meshHirschsprung Disease - enzymology - genetics-
dc.subject.meshIntestine, Large - enzymology-
dc.subject.meshReceptor Protein-Tyrosine Kinases - genetics - metabolism-
dc.titleReduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's diseaseen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0964-6906&volume=19&issue=8&spage=1461&epage=1467&date=2010&atitle=Reduced+RET+expression+in+gut+tissue+on+individuals+carrying+risk+alleles+of+Hirschsprung%27s+diseaseen_HK
dc.identifier.emailNgan, ESW: engan@hkucc.hku.hken_HK
dc.identifier.emailLui, VCH: vchlui@hkucc.hku.hken_HK
dc.identifier.emailChen, Y: ychenc@hkucc.hku.hken_HK
dc.identifier.emailWong, KKY: kkywong@hkucc.hku.hken_HK
dc.identifier.emailTam, PKH: paultam@hkucc.hku.hken_HK
dc.identifier.emailGarciaBarceló, M: mmgarcia@hkucc.hku.hken_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.authorityTam, PKH=rp00060en_HK
dc.identifier.authorityGarciaBarceló, M=rp00445en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1093/hmg/ddq020en_HK
dc.identifier.pmid20089534en_HK
dc.identifier.scopuseid_2-s2.0-77952295135en_HK
dc.identifier.hkuros169670en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77952295135&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume19en_HK
dc.identifier.issue8en_HK
dc.identifier.spage1461en_HK
dc.identifier.epage1467en_HK
dc.identifier.eissn1460-2083-
dc.identifier.isiWOS:000276544000007-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectGenetic dissection of Hirschsprung's disease-
dc.identifier.scopusauthoridMiao, X=7102585391en_HK
dc.identifier.scopusauthoridLeon, TYY=10641704600en_HK
dc.identifier.scopusauthoridNgan, ESW=22234827500en_HK
dc.identifier.scopusauthoridSo, MT=8748542200en_HK
dc.identifier.scopusauthoridYuan, ZW=10641253300en_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK
dc.identifier.scopusauthoridChen, Y=36463185300en_HK
dc.identifier.scopusauthoridWong, KKY=24438686400en_HK
dc.identifier.scopusauthoridTam, PKH=7202539421en_HK
dc.identifier.scopusauthoridGarciaBarceló, M=6701767303en_HK

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