| The G/G genotype of a resistin single-nucleotide polymorphism at -420 increases type 2 diabetes mellitus susceptibility by inducing promoter activity through specific binding of Sp1/3. | |
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MedLine Citation:
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PMID: 15338456 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Insulin resistance is a major cause of type 2 diabetes mellitus (T2DM). Resistin, an adipocyte-secreted hormone, antagonizes insulin. Transgenic mice that overexpress the resistin gene (Retn) in adipose tissue are insulin-resistant, whereas Retn (-/-) mice show lower fasting blood glucose, suggesting that the altered Retn promoter function could cause diabetes. To determine the role of RETN in human T2DM, we analyzed polymorphisms in its 5' flanking region. We found that the -420G/G genotype was associated with T2DM (397 cases and 406 controls) (P=.008; adjusted odds ratio = 1.97 [by logistic regression analysis]) and could accelerate the onset of disease by 4.9 years (P=.006 [by multiple regression analysis]). Meta-analysis of 1,888 cases and 1,648 controls confirmed this association (P=.013). Linkage disequilibrium analysis revealed that the -420G/G genotype itself was a primary variant determining T2DM susceptibility. Functionally, Sp1 and Sp3 transcription factors bound specifically to the susceptible DNA element that included -420G. Overexpression of Sp1 or Sp3 enhanced RETN promoter activity with -420G in Drosophila Schneider line 2 cells that lacked endogenous Sp family members. Consistent with these findings, fasting serum resistin levels were higher in subjects with T2DM who carried the -420G/G genotype. Therefore, the specific recognition of -420G by Sp1/3 increases RETN promoter activity, leading to enhanced serum resistin levels, thereby inducing human T2DM. |
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Authors:
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Haruhiko Osawa; Kazuya Yamada; Hiroshi Onuma; Akiko Murakami; Masaaki Ochi; Hiroko Kawata; Tatsuya Nishimiya; Toshiyuki Niiya; Ikki Shimizu; Wataru Nishida; Mitsuru Hashiramoto; Azuma Kanatsuka; Yasuhisa Fujii; Jun Ohashi; Hideichi Makino |
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Publication Detail:
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Type: Comparative Study; Journal Article; Research Support, Non-U.S. Gov't Date: 2004-08-26 |
Journal Detail:
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Title: American journal of human genetics Volume: 75 ISSN: 0002-9297 ISO Abbreviation: Am. J. Hum. Genet. Publication Date: 2004 Oct |
Date Detail:
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Created Date: 2004-08-31 Completed Date: 2004-12-16 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 0370475 Medline TA: Am J Hum Genet Country: United States |
Other Details:
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Languages: eng Pagination: 678-86 Citation Subset: IM |
Affiliation:
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Department of Laboratory Medicine, Ehime University School of Medicine, Ehime, Japan. |
| Data Bank Information | |
Bank Name/Acc. No.:
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RefSeq/NT_020415; NT_077812 |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Aged Base Sequence DNA-Binding Proteins / genetics, metabolism Diabetes Mellitus, Type 2 / genetics* Female Gene Frequency Genetic Predisposition to Disease* Genotype Hormones, Ectopic / blood, genetics* Humans Japan Linkage Disequilibrium Logistic Models Male Middle Aged Molecular Sequence Data Polymorphism, Single Nucleotide / genetics* Promoter Regions, Genetic / genetics Resistin Sequence Analysis, DNA Sp1 Transcription Factor / genetics, metabolism Sp3 Transcription Factor Transcription Factors / genetics, metabolism |
| Chemical | |
Reg. No./Substance:
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0/DNA-Binding Proteins; 0/Hormones, Ectopic; 0/RETN protein, human; 0/Resistin; 0/SP3 protein, human; 0/Sp1 Transcription Factor; 0/Transcription Factors; 148710-94-5/Sp3 Transcription Factor |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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