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          Institute: MPI für molekulare Genetik     Collection: Department of Computational Molecular Biology     Display Documents



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ID: 539694.0, MPI für molekulare Genetik / Department of Computational Molecular Biology
A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis
Authors:Schaefer, A. S.; Richter, G. M.; Nothnagel, M.; Manke, T.; Dommisch, H.; Jacobs, G.; Arlt, A.; Rosenstiel, P.; Noack, B.; Groessner-Schreiber, B.; Jepsen, S.; Loos, B. G.; Schreiber, S.
Language:English
Date of Publication (YYYY-MM-DD):2010-02-01
Title of Journal:Human Molecular Genetics
Journal Abbrev.:Hum Mol Genet
Volume:19
Issue / Number:3
Start Page:553
End Page:562
Copyright:© 2010 Oxford University Press
Review Status:not specified
Audience:Experts Only
Abstract / Description: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.
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
External Publication Status:published
Document Type:Article
Communicated by:Martin Vingron
Affiliations:MPI für molekulare Genetik
External Affiliations:Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, Schittenhelmstraße 12, Kiel 24105, Germany
Institute of Medical Informatics and Statistics, University Medical Center Schleswig-Holstein, Campus Kiel,
Brunswiker Str. 10, Kiel 24105, Germany
Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Welschnonnenstraße 17, Bonn 53111, Germany
Clinical for General Medicine I, University
Medical Center Schleswig-Holstein, Campus Kiel, House 6, Arnold-Heller- Straße 3, Kiel 24105, Germany
Department of Conservative Dentistry, University Medical Center Carl Gustav Carus, Dresden University of
Technology, Fetscherstraße 74, Dresden 01307, Germany Department of Operative Dentistry and Periodontology,
University Medical Center Schleswig-Holstein, Campus Kiel, House 26, Arnold-Heller- Straße 3, Kiel 24105 Germany
Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and
VU University Amsterdam, Louwesweg 1, Amsterdam 1066 EA, The Netherlands
Identifiers:ISSN:1460-2083 (Electronic) 0964-6906 (Linking) %R ddp5... [ID No:1]
URL:http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=... [ID No:2]
DOI:10.1093/hmg/ddp508 [ID No:3]
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