CDKN2BAS is associated with periodontitis in different European populations and is activated by bacterial infection

Arne S Schaefer (1) , Gesa M Richter (1) , Henrik Dommisch (2) , Markus Reinartz (2) , Michael Nothnagel (3) , Barbara Noack (4) , Marja L Laine (5) , Mathias Folwaczny (6) , Groessner-Schreiber Birte (7) , Bruno L Loos (5) , Søren Jepsen (8) , Stefan Schreiber (1)

1 Institute for Clinical Molecular Biology, Christian-Albrechts-University Kiel
2 University Hospital Bonn
3 Institute of Medical Informatics and Statistics
4 University Medical Center Carl Gustav Carus, Dresden University of Technology Department of Conserva
5 Acta - Les instituts techniques agricoles
6 Department of Preventive Dentistry and Periodontology, University of Munich
7 Department of Operative Dentistry and Periodontology, University Medical Center Schleswig-Holstein,
8 Rheinische Friedrich-Wilhelms-Universität Bonn

Epidemiological studies indicated a relationship between coronary heart disease (CHD) and periodontitis. Recently, CDKN2BAS was reported as a shared genetic risk factor of CHD and aggressive periodontitis (AgP), but the causative variant has remained unknown. To identify and validate risk variants in different European populations, we first explored 150 kb of the genetic region of CDKN2BAS including the adjacent genes CDKN2A and CDKN2B, covering 51 tagging single nucleotide polymorphisms (tagSNPs) in AgP and chronic periodontitis (CP) in individuals of Dutch origin (n=734). In a second step, we tested the significant SNP associations in an independent AgP and CP population of German origin (n=1,264) For the tagSNPs rs1360590, rs3217992, and rs518394, we could validate the associations with AgP prior and after adjustment for the covariates smoking, gender and diabetes, with SNP rs3217992 being the most significant (p=0.0004, odds ratio (OR)=1.48 [95% confidence interval (CI 95%) 1.19-1.85]). We further showed in-vivo gene expression of CDKN2BAS, CDKN2A, CDKN2B, and CDK4 in healthy and inflamed gingival epithelium (GE) and connective tissue (CT), and detected a significantly higher expression of CDKN2BAS in healthy CT compared to GE (p=0.004). After 24 hours of stimulation with P. gingivalis in S. gordonii pre-treated gingival fibroblast (HGF) and cultured gingival epithelial cells (GECs), we observed 25-fold and 4-fold increase of CDKN2BAS gene expression in HGFs (p=0.003) and GECs (p=0.004), respectively. Considering the global importance of CDKN2BAS in the disease risk of CHD, this observation supports the theory of inflammatory components in the disease physiology of CHD.

Mots clés: Cardiovascular Medicine; Diabetes; Infection; Molecular genetics; Genetic epidemiology

Arne S Schaefer, Gesa M Richter, Henrik Dommisch, Markus Reinartz, Michael Nothnagel, et al.. CDKN2BAS is associated with periodontitis in different European populations and is activated by bacterial infection. Journal of Medical Genetics, 2010, 48 (1), pp.38. ⟨10.1136/jmg.2010.078998⟩. ⟨hal-00580102⟩