Geimeinsame genetisch determinierte Risikofaktoren für kardiovaskuläre und parodontale Erkrankungen – Daten aus dem PopGen-Projekt

The discovery of genetic etiologies and the identification of molecular-genetic pathomechanisms are only usable for clinical translation if a large proportion of the inheritable risk can be explained, i.e. to understand how a polygenic susceptibility shared by various disease phenotypes translates into different morphological manifestations. The oral cavity is considered as the gateway through which infectious agents can invade the human body where they can trigger inflammatory responses with more systemic effects. Epidemiological studies demonstrated an association between the presence of coronary heart disease (CHD) and periodontitis, which is dependent on the severity of periodontal disease. Recent studies demonstrated similarities in the spectrum of bacteria in the oral cavity and in coronary plaques, and both diseases are characterized by an imbalanced immune reaction and a chronic inflammatory process, pointing to physiologically relevant correlations between periodontitis and CHD.
Recently, a major genetic susceptibility locus for CHD was identified by various genome-wide association studies (GWAS), located within the chromosomal region 9p21.3, mapping to the large antisense RNA CDKN2BAS, largely known as ANRIL. This association was replicated, verified by a subsequent meta-analysis, and by a large-scale replication study, making this genetic region the best replicated CHD associated risk locus to date. We demonstrated the association of a highly increased risk for aggressive periodontitis (AgP) with specific variants of CDKN2BAS, making it the first shared genetic risk factor between CHD and periodontitis. We could replicate this association in a further independent population of Dutch AgP cases, and we were able to show for the first time in-vivo gene expression of CDKN2BAS in different gingival tissues. Upon stimulation with pathogenic bacteria, we showed a significant 25-fold and 4-fold increase of CDNKN2BAS expression in gingival fibroblast and epidermial cells, and observed significant differences in transcript levels for the neighbouring gene CDKN2A after bacterial stimulation, indicating specific regulation by bacterial infection. The functional characterization of CDKN2BAS is currently ongoing.
In addition, we formulated an agenda that enables us to identify further shared genetic susceptibility loci of CHD and periodontitis on a genome-wide scale. This approach will give insight into the nature of their shared underlying inflammatory components and mode of action, which potentially will help to develop new approaches for their therapy. To this end, we performed a joint analysis of two data-sets of CHD and a data-set of periodontitis, which indicated shared associations for several new genetic risk loci which are currently being replicated.

Freitag, 12. November 2010
Zeit: 15:00-15:30 Uhr
Ort: Forum, Applaus
Ebene/Etage: 0
Dr. Arne S. Schäfer

Dr. Arne S. Schäfer 
 
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