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  A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis

Schaefer, A. S., Richter, G. M., Nothnagel, M., Manke, T., Dommisch, H., Jacobs, G., et al. (2010). A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis. Human Molecular Genetics, 19(3), 553-562. doi:10.1093/hmg/ddp508.

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Genre: Journal Article
Alternative Title : Hum Mol Genet

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 Creators:
Schaefer, A. S., Author
Richter, G. M., Author
Nothnagel, M., Author
Manke, T.1, Author              
Dommisch, H., Author
Jacobs, G., Author
Arlt, A., Author
Rosenstiel, P., Author
Noack, B., Author
Groessner-Schreiber, B., Author
Jepsen, S., Author
Loos, B. G., Author
Schreiber, S., Author
Affiliations:
1Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433547              

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Free keywords: Adult; Aged; Aggressive Periodontitis/*enzymology/genetics; Case-Control Studies; Cell Line; GATA3 Transcription Factor/genetics/metabolism; *Genetic Predisposition to Disease; *Genome-Wide Association Study; Humans; Male; Middle Aged; Polymorphism, Single Nucleotide
 Abstract: Periodontitis is a widespread, complex inflammatory disease of the mouth, which results in a loss of gingival tissue and alveolar bone, with aggressive periodontitis (AgP) as its most severe form. To identify genetic risk factors for periodontitis, we conducted a genome-wide association study in German AgP patients. We found AgP to be strongly associated with the intronic SNP rs1537415, which is located in the glycosyltransferase gene GLT6D1. We replicated the association in a panel of Dutch generalized and localized AgP patients. In the combined analysis including 1758 subjects, rs1537415 reached a genome-wide significance level of P= 5.51 x 10(-9), OR = 1.59 (95% CI 1.36-1.86). The associated rare G allele of rs1537415 showed an enrichment of 10% in periodontitis cases (48.4% in comparison with 38.8% in controls). Fine-mapping and a haplotype analysis indicated that rs1537415 showed the strongest association signal. Sequencing identified no further associated variant. Tissue-specific expression analysis of GLT6D1 indicated high transcript levels in the leukocytes, the gingiva and testis. Analysis of potential transcription factor binding sites at this locus predicted a significant reduction of GATA-3 binding affinity, and an electrophoretic mobility assay indicated a T cell specific reduction of protein binding for the G allele. Overexpression of GATA-3 in HEK293 cells resulted in allele-specific binding of GATA-3, indicating the identity of GATA-3 as the binding protein. The identified association of GLT6D1 with AgP implicates this locus as an important susceptibility factor, and GATA-3 as a potential signaling component in the pathophysiology of periodontitis.

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Language(s): eng - English
 Dates: 2010-02-01
 Publication Status: Published in print
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Title: Human Molecular Genetics
  Alternative Title : Hum Mol Genet
Source Genre: Journal
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Pages: - Volume / Issue: 19 (3) Sequence Number: - Start / End Page: 553 - 562 Identifier: ISSN: 1460-2083 (Electronic) 0964-6906 (Linking) %R ddp508 [pii] 10.1093/hmg/ddp508