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.

What is the Contribution of Genetics to Periodontal Risk?

“…Currently, only a fraction of susceptibility genes is robustly identified, namely GLT6D1, ANRIL and COX2, IL1 and IL10 have repeatedly been associated with periodontitis (49,57,58,61,67,(71)(72)(73) AgP and CP (61,70). Probably, the identified SNPs are "genetic markers" and are not the true causative variants for both AgP and CP.…”

“…Today, more than 1300 GWAS have been performed (www.ebi.ac.uk/gwas/), but only five GWAS have been performed in association with periodontitis; one in AgP and four in CP (49)(50)(51)(52)(53). Another GWAS in periodontitis studied SNPs in association with pathologic periodontal pocket depths, rather than in association with a certain form of periodontitis (54).…”

“…The gene for a glucosyltransferase (GLT6D1) on chromosome 9 was discovered in the first periodontitis GWAS for AgP (49). The GWAS discovery cohort consisted of 141 AgP patients and 500 controls, and the second GWAS cohort in the same study for replication, consisted of 142 AgP patients and 479 controls, both cohorts with subjects of German origin.…”

Association of TH01 with human longevity revisited

“…The recruitment procedures for LLI and controls have been described in detail elsewhere. 16,17 Most of the participants provided, as part of a health and family history questionnaire, information about their nicotine consumption habits and arterial hypertension status. The study was approved by the Ethics Committee of the University Hospital Schleswig-Holstein in Kiel.…”

Genetic Background in Initiation, Progression and Treatment of Periodontal Diseases – A Review.

“…55 It encodes an unknown protein belonging to a family of proteins that is characterized by a glycosyltransferase domain-1. GLT6D1 was found to be predominantly expressed in the gingiva and T cells.…”