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Article: Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease
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TitleReduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease
 
AuthorsMiao, X2 3
Leon, TYY2
Ngan, ESW2
So, MT2
Yuan, ZW1
Lui, VCH2
Chen, Y2
Wong, KKY2
Tam, PKH2
GarciaBarceló, M2
 
Issue Date2010
 
PublisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
CitationHuman Molecular Genetics, 2010, v. 19 n. 8, p. 1461-1467 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddq020
 
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.
 
ISSN0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
DOIhttp://dx.doi.org/10.1093/hmg/ddq020
 
ISI Accession Number IDWOS:000276544000007
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.

 
ReferencesReferences in Scopus
 
GrantsGenetic dissection of Hirschsprung's disease
 
DC FieldValue
dc.contributor.authorMiao, X
 
dc.contributor.authorLeon, TYY
 
dc.contributor.authorNgan, ESW
 
dc.contributor.authorSo, MT
 
dc.contributor.authorYuan, ZW
 
dc.contributor.authorLui, VCH
 
dc.contributor.authorChen, Y
 
dc.contributor.authorWong, KKY
 
dc.contributor.authorTam, PKH
 
dc.contributor.authorGarciaBarceló, M
 
dc.date.accessioned2010-09-06T08:43:04Z
 
dc.date.available2010-09-06T08:43:04Z
 
dc.date.issued2010
 
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.
 
dc.description.naturepostprint
 
dc.identifier.citationHuman Molecular Genetics, 2010, v. 19 n. 8, p. 1461-1467 [How to Cite?]
DOI: http://dx.doi.org/10.1093/hmg/ddq020
 
dc.identifier.doihttp://dx.doi.org/10.1093/hmg/ddq020
 
dc.identifier.eissn1460-2083
 
dc.identifier.epage1467
 
dc.identifier.hkuros169670
 
dc.identifier.isiWOS:000276544000007
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.

 
dc.identifier.issn0964-6906
2012 Impact Factor: 7.692
2012 SCImago Journal Rankings: 4.103
 
dc.identifier.issue8
 
dc.identifier.openurl
 
dc.identifier.pmid20089534
 
dc.identifier.scopuseid_2-s2.0-77952295135
 
dc.identifier.spage1461
 
dc.identifier.urihttp://hdl.handle.net/10722/83609
 
dc.identifier.volume19
 
dc.languageeng
 
dc.publisherOxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofHuman Molecular Genetics
 
dc.relation.projectGenetic dissection of Hirschsprung's disease
 
dc.relation.referencesReferences in Scopus
 
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/19/8/1461
 
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 disease
 
dc.typeArticle
 
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<description.abstract>Receptor tyrosine kinase (RET) single nucleotide polymorphisms (SNPs) are associated with the Hirschsprung&apos;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&gt;A rs10900296 and -1A&gt;C rs10900297 in the promoter, and C&gt;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 &apos;wild-type&apos; counterpart (G-A-C/G-A-C), with expression values ranging from 218.32&#177;125.69 (mean &#177; SE) in tissues from individuals carrying G-A-C/G-A-C to 31.42&#177;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 &#215; 10-31, 3.12 3 10-24 and 5.94 &#215; 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 (&#967;2 5 155.29, P &#171; 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. &#169; The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org.</description.abstract>
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Author Affiliations
  1. China Medical University Shenyang
  2. The University of Hong Kong
  3. Huazhong University of Science and Technology