Periodontitis (PD) is an inflammatory disease of the periodontal tissues. It results in the loss of tooth support and, if left untreated it can lead to ooth loss. PD affects 47.2% of the population over the age of 30. According to the WHO, PD is a major cause of tooth loss in adults. Although bacterial biofilm is central in disease pathogenesis, host response plays an important role in the progression and severity of PD. Indeed, genetic studies indicate that PD is 50% heritable. Discovering genetic traits that correlate with bone loss is essential in identifying individuals prone to the disease as well as in discerning signaling cascades that underlie disease pathophysiology. Clinical genetic studies pose significant challenges due to complex and heterogeneous genetic makeup of patients and difficulties in controlling environmental factors that influence the disease. Since human and murine complexes share similar structural, functional and genetic traits, a mouse model is ideal for genome-wide association studies (GWAS) where controlling the genetic and environmental framework is critical. We propose to perform GWAS of periodontal bone loss utilizing the Hybrid Mouse Diversity Panel (HMDP). The HMDP panel consists of 100 classic and recombinant inbred (RI) mouse strains selected for systematic genetic analyses of complex traits. In our preliminary studies, we employed a mouse model of experimental periodontal bone loss by injecting P. gingivalis-derived LPS in the interdental papillae of maxillary molars. As proof of principle, we applied this model to 29 inbred strains, including 5 parental strains that derived th RI strains. Through micro-CT analysis, BUB/BnJ was the most susceptible strain to LPS-induced bone loss compared to the most resistant strain, SEA/GnJ. Based on these data, heritability estimate for periodontal bone loss was 49%, a value that closely resembles heritability measurements of 50% reported for patients. Preliminary data support a significant role of the genetic framework in LPS-induced periodontal bone loss. We propose two Specific Aims to achieve our objective to identify genetic variants that contribute to the severity of periodontal bone loss.
Specific Aim 1 : To assess periodontal bone loss for the complete HMDP.
Specific Aim 2 : To perform GWAS of LPS-induced periodontal bone loss in HMDP mice. Having performed proof of principle studies that demonstrate a difference in the periodontal bone loss pattern, we propose to identify quantitative trait loci;more specifically, genes associated with te LPS-induced bone loss. In future studies, we intend to validate our findings and expand to a systems biology approach combining genomic, transcriptomic and proteomic methodologies to completely characterize the bone loss. Ultimately, our studies will contribute in predicting patients genetically predisposed to PD and in identifying the biological basis of disease susceptibility.

Public Health Relevance

Gum disease, known as periodontitis, is an inflammatory disease of the supporting tissues of the teeth that affects 47.2% of the population over the age of 30 and, if left untreated, can lead to tooth loss. Because genetic studies have demonstrated that periodontitis is 50% heritable, our research seeks to pinpoint genetic factors that are associated in periodontal bone loss, which will help identify patients at risk. Moreover, our studies will assist in the creation of diagnostic methodologies, allowing us to tailor healthcare t individual patients based on genetic makeup and environmental factors.

Agency
National Institute of Health (NIH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21DE023901-01A1
Application #
8772724
Study Section
Oral, Dental and Craniofacial Sciences Study Section (ODCS)
Program Officer
Harris, Emily L
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California Los Angeles
Department
None
Type
Schools of Dentistry/Oral Hygn
DUNS #
City
Los Angeles
State
CA
Country
United States
Zip Code
90095