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CDKN2BAS is associated with periodontitis in different European populations and is activated by bacterial infection
  1. Arne S Schaefer1,
  2. Gesa M Richter1,
  3. Henrik Dommisch2,
  4. Markus Reinartz2,
  5. Michael Nothnagel3,
  6. Barbara Noack4,
  7. Marja L Laine5,
  8. Mathias Folwaczny6,
  9. Birte Groessner-Schreiber7,
  10. Bruno G Loos5,
  11. Søren Jepsen2,
  12. Stefan Schreiber1
  1. 1Christian-Albrechts-University Kiel, Institute for Clinical Molecular Biology, Kiel, Germany
  2. 2Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany
  3. 3University Medical Center Schleswig-Holstein, Campus Kiel, Institute of Medical Informatics and Statistics, Kiel, Germany
  4. 4University Medical Center Carl Gustav Carus der Technischen Universität Dresden, Zentrum für Zahn-, Mund- und Kieferheilkunde, Poliklinik für Zahnerhaltung, Dresden, Germany
  5. 5Department of Periodontology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and VU University, Amsterdam, the Netherlands
  6. 6Department of Preventive Dentistry and Periodontology, University of Munich, Munich, Germany
  7. 7University Medical Center Schleswig-Holstein, Campus Kiel, Department of Operative Dentistry and Periodontology, Kiel, Germany
  1. Correspondence to Dr Arne S Schaefer, Christian-Albrechts-University Kiel, Institute for Clinical Molecular Biology, Arnold-Heller-Str. 3, 24105 Kiel, Germany; a.schaefer{at}


Epidemiological studies have 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=313). In a second step, we tested the significant SNP associations in an independent AgP and CP population of German origin (n=1264). For the tagSNPs rs1360590, rs3217992, and rs518394, we could validate the associations with AgP before and after adjustment for the covariates smoking, gender and diabetes, with SNP rs3217992 being the most significant (OR 1.48, 95% CI 1.19 to 1.85; p=0.0004). 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 h of stimulation with Porphyromonas gingivalis in Streptococcus gordonii pre-treated gingival fibroblast (HGF) and cultured gingival epithelial cells (GECs), we observed a 25-fold and fourfold 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.

  • periodontitis
  • CHD
  • association
  • bacterial stimulation
  • cardiovascular medicine
  • diabetes
  • infection
  • molecular genetics
  • genetic epidemiology

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  • Funding This study was supported by a research grant from the “Research Center for Inflammation Medicine” of the Medical Faculty, Christian-Albrechts-University, University Medical Center Schleswig-Holstein, Campus Kiel, (Arne S Schaefer, Gesa M Richter), by the German Ministry of Education and Research (BMBF) through a National Genome Research Network (NGFN) grant (Michael Nothnagel, 01GS0809), by grants of the German Research Foundation (DFG) (KFO208) (TP3: Arne S Schaefer, Gesa M Richter, Søren Jepsen) (TP2: Henrik Dommisch, Markus Reinartz, Søren Jepsen), by the BMBF through the POPGEN biobank project (01GR0468), by a grant from BONFOR of the Medical Faculty, University of Bonn (Søren Jepsen), and a grant from the ARPA Research Foundation (Birte Grössner-Schreiber, Søren Jepsen), Regensburg, Germany.

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval This study was conducted with the approval of the Medical Ethical Committee, Universities of Bonn, Dresden, Kiel and Munich, Germany, and Medical Ethical Committee, Academic Medical Center, University of Amsterdam, the Netherlands.

  • Provenance and peer review Not commissioned; externally peer reviewed.