Human Molecular Genetics Advance Access [Accepted Manuscript] published online on November 6, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp508
A Genome-wide Association Study Identifies GLT6D1 as a Susceptibility Locus for Periodontitis
1 Christian-Albrechts-University Kiel, Institute for Clinical Molecular Biology, Schittenhelmstraße 12, 24105 Kiel, Germany 2 University Medical Center Schleswig-Holstein, Campus Kiel, Institute of Medical Informatics and Statistics, Brunswiker Str. 10, 24105 Kiel, Germany 3 Max Planck Institute for Molecular Genetics, Computational Molecular Biology, Ihnestraße 73, 14195 Berlin, Germany 4 Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Welschnonnenstraße 17, 53111 Bonn, Germany 5 University Medical Center Schleswig-Holstein, Campus Kiel, Clinical for General Medicine I, Arnold-Heller- Straße 3, House 6, 24105 Kiel, Germany 6 Department of Conservative Dentistry, University Medical Center Carl Gustav Carus, Dresden University of Technology, Fetscherstraße 74, 01307 Dresden, Germany 7 University Medical Center Schleswig-Holstein, Campus Kiel, Department of Operative Dentistry and Periodontology, Arnold-Heller- Straße 3, House 26, 24105 Kiel, Germany 8 Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University Amsterdam, Louwesweg 1, 1066 EA Amsterdam, the Netherlands
* Address for correspondence: Christian-Albrechts-University Kiel, Institute for Clinical Molecular Biology, Schittenhelmstraße 12, 24105 Kiel, Germany. Tel.: +49-(0)431-597-3882, Fax: +49-(0)431-597-3730, Email: a.schaefer{at}ikmb.uni-kiel.de
Received August 17, 2009; Revised October 30, 2009; Accepted November 3, 2009
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 (GWAS) 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 1,758 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.
a These authors contributed equally to this work.