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" Identification of Genetic Risk Factors Predisposing to the Inflammatory Oral Disease Periodontitis "
Munz, Matthias
Schäfer, Arne
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Latin Dissertation
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English
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| Record Number
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1053331
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| Doc. No
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TL52448
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| Main Entry
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Munz, Matthias
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| Title & Author
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Identification of Genetic Risk Factors Predisposing to the Inflammatory Oral Disease Periodontitis\ Munz, MatthiasSchäfer, Arne
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| College
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Freie Universitaet Berlin (Germany)
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| Date
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2018
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| Degree
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Ph.D.
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2018
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| Note
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80 p.
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| Abstract
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Periodontitis (PD) is a bacterially induced disease of the oral cavity and, in the long term, can lead to tooth loss due to the inflammatory degradation of the alveolar bone. For the severe forms of PD, there is a prevalence rate of 11% worldwide, making it one of the most common inflammatory diseases. Aggressive periodontitis (AgP) is an early (<35 years) and particularly severe clinical form of PD, whereas chronic periodontitis (CP) usually has a slow and more moderate course. The estimated heritability of PD is 50%. Twin studies and examples where individuals share the same environment and lifestyle yet have different risk for disease, illustrate the strong influence of hereditary factors on the pathogenesis of PD. Several randomized clinical trials have demonstrated a relationship between PD and coronary artery disease (CAD), with an epidemiological relationship between the two disease to be independent of smoking as a common risk factor. CAD is a complex disease of the arteries with a strong inflammatory component. Plaque formation in the arteries can impair the blood supply, which can trigger a heart attack. Previous studies have identified genetic risk variants at several loci in the human genome that predispose to PD. The gene locus GLT6D1 is associated with AgP at genome-wide significance. Furthermore, common genetic risk variants of PD and CAD were identified for the gene sites ANRIL, Plasminogen and VAMP3. However, the known genetic risk factors explain only a small fraction of the heritability of PD. Indeed the underlying genetic risk factors remain largely unknown. The identification of yet unknown genetic risk factors can significantly contribute to a better understanding of the causes and molecular mechanisms of PD as well as the genetic and molecular relationship to CAD and to the improvement of diagnosis and treatment of PD. In my thesis, I carried out genome-wide association studies and meta-analyses with the aim of systematically identifying further risk genes. I had access to the, to date, world's largest AgP sample with 851 cases and 6,580 controls of Dutch and German descents. In addition, I used a non-genotyped AgP sample with 220 cases and 560 controls of Turkish descent which were used to confirm single genetic variants. For CP samples I had a total of 4,244 cases and 3,328 controls of German and European-American descent which were also taken into account. I could identify new risk variants of PD that either reached genome-wide significance levels (P < 5 x 10-8) or could be independently validated. These variants are located proximal to the genes DEFA1A3, SIGLEC5, LOC107964137, MTND1P5, VAMP8, PF4/PPBP/CXCL5, IL37. In silico functional characterization of these loci points to specific processes that play a role in wound healing and in bacterial immune defense. A pleiotropic variant at VAMP8 also increases susceptibility to CAD and suggests a possible molecular mechanism underlying the epidemiological link between PD and CAD. The results confirm that the relationship between PD and CAD cannot be explained solely by shared lifestyle factors. However, the SNP-gene relationships shown in this work require further experimental studies.
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| Descriptor
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Genetics
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Pathology
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Schäfer, Arne
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Freie Universitaet Berlin (Germany)
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