Article: Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease
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- Publisher Website: 10.1093/hmg/ddq020
- Scopus: eid_2-s2.0-77952295135
- PMID: 20089534
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| Title | Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| Authors | Miao, X2 3 Leon, TYY2 Ngan, ESW2 So, MT2 Yuan, ZW1 Lui, VCH2 Chen, Y2 Wong, KKY2 Tam, PKH2 GarciaBarceló, M2 | ||||||||
| Issue Date | 2010 | ||||||||
| Publisher | Oxford 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?] DOI: http://dx.doi.org/10.1093/hmg/ddq020 | ||||||||
| 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. | ||||||||
| ISSN | 0964-6906 2011 Impact Factor: 7.636 2011 SCImago Journal Rankings: 1.308 | ||||||||
| DOI | http://dx.doi.org/10.1093/hmg/ddq020 | ||||||||
| ISI Accession Number ID | WOS:000276544000007
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 | References in Scopus | ||||||||
| Grants | Genetic dissection of Hirschsprung's disease Fine mapping of a Hirschsprung's disease locus on the 3p21candidate region Functional analysis of RET coding region mutations |
| dc.contributor.author | Miao, X | ||||||||
|---|---|---|---|---|---|---|---|---|---|
| dc.contributor.author | Leon, TYY | ||||||||
| dc.contributor.author | Ngan, ESW | ||||||||
| dc.contributor.author | So, MT | ||||||||
| dc.contributor.author | Yuan, ZW | ||||||||
| dc.contributor.author | Lui, VCH | ||||||||
| dc.contributor.author | Chen, Y | ||||||||
| dc.contributor.author | Wong, KKY | ||||||||
| dc.contributor.author | Tam, PKH | ||||||||
| dc.contributor.author | GarciaBarceló, M | ||||||||
| dc.date.accessioned | 2010-09-06T08:43:04Z | ||||||||
| dc.date.available | 2010-09-06T08:43:04Z | ||||||||
| dc.date.issued | 2010 | ||||||||
| dc.description.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. | ||||||||
| dc.description.grant | Genetic dissection of Hirschsprung's disease | ||||||||
| dc.description.grant | Fine mapping of a Hirschsprung's disease locus on the 3p21candidate region | ||||||||
| dc.description.grant | Functional analysis of RET coding region mutations | ||||||||
| dc.description.grantcode | 96945 | ||||||||
| dc.description.grantcode | 97944 | ||||||||
| dc.description.grantcode | 96043 | ||||||||
| dc.description.nature | postprint | ||||||||
| dc.identifier.citation | Human Molecular Genetics, 2010, v. 19 n. 8, p. 1461-1467 [How to Cite?] DOI: http://dx.doi.org/10.1093/hmg/ddq020 | ||||||||
| dc.identifier.doi | http://dx.doi.org/10.1093/hmg/ddq020 | ||||||||
| dc.identifier.epage | 1467 | ||||||||
| dc.identifier.hkuros | 169670 | ||||||||
| dc.identifier.isi | WOS:000276544000007
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.issn | 0964-6906 2011 Impact Factor: 7.636 2011 SCImago Journal Rankings: 1.308 | ||||||||
| dc.identifier.issue | 8 | ||||||||
| dc.identifier.openurl | | ||||||||
| dc.identifier.pmid | 20089534 | ||||||||
| dc.identifier.scopus | eid_2-s2.0-77952295135 | ||||||||
| dc.identifier.spage | 1461 | ||||||||
| dc.identifier.uri | http://hdl.handle.net/10722/83609 | ||||||||
| dc.identifier.volume | 19 | ||||||||
| dc.language | eng | ||||||||
| dc.publisher | Oxford University Press. The Journal's web site is located at http://hmg.oxfordjournals.org/ | ||||||||
| dc.publisher.place | United Kingdom | ||||||||
| dc.relation.ispartof | Human Molecular Genetics | ||||||||
| dc.relation.references | References in Scopus | ||||||||
| dc.rights | This 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.rights | Creative Commons: Attribution 3.0 Hong Kong License | ||||||||
| dc.subject.mesh | Down-Regulation | ||||||||
| dc.subject.mesh | Genetic Predisposition to Disease | ||||||||
| dc.subject.mesh | Hirschsprung Disease - enzymology - genetics | ||||||||
| dc.subject.mesh | Intestine, Large - enzymology | ||||||||
| dc.subject.mesh | Receptor Protein-Tyrosine Kinases - genetics - metabolism | ||||||||
| dc.title | Reduced RET expression in gut tissue of individuals carrying risk alleles of Hirschsprung's disease | ||||||||
| dc.type | Article |
Author Affiliations
- China Medical University Shenyang
- The University of Hong Kong
- Huazhong University of Science and Technology