title: A genome-wide association study identifies GLT6D1 as a susceptibility locus for periodontitis.
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.
authors.affiliation: Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel, Schittenhelmstrasse 12, Kiel, Germany. a.schaefer@ikmb.uni-kiel.de
authors.forename: Arne S
authors.initials: AS
authors.lastname: Schaefer
authors.forename: Gesa M
authors.initials: GM
authors.lastname: Richter
authors.forename: Michael
authors.initials: M
authors.lastname: Nothnagel
authors.forename: Thomas
authors.initials: T
authors.lastname: Manke
authors.forename: Henrik
authors.initials: H
authors.lastname: Dommisch
authors.forename: Gunnar
authors.initials: G
authors.lastname: Jacobs
authors.forename: Alexander
authors.initials: A
authors.lastname: Arlt
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Barbara
authors.initials: B
authors.lastname: Noack
authors.forename: Birte
authors.initials: B
authors.lastname: Groessner-Schreiber
authors.forename: Søren
authors.initials: S
authors.lastname: Jepsen
authors.forename: Bruno G
authors.initials: BG
authors.lastname: Loos
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
mesh_terms: D000328:Adult; D000368:Aged; D010520:Aggressive Periodontitis / Q000201:enzymology* / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human