Susceptibility Patterns for Grade C Periodontitis in Young Individuals

The American Academy of Periodontology and European Federation of Periodontology have recently adopted the new terminology, “Grade C Periodontitis,” to identify individuals with a high risk for disease progression. The localized form of this disease, now termed Stage 3-4 Grade C, molar-incisor pattern periodontitis (C/MIP), exhibits a very well-defined clinical presentation. Although less common than other periodontitis, C/MIP has a significant public health impact, as it affects systemically healthy, young individuals, of low social economic status, who usually cannot afford its expensive and complex treatment, as their affected teeth are often lost due to its rapid progression and delayed diagnosis. This leads to early function and aesthetics issues and life-long difficulties for functional and aesthetic rehabilitation. Due its common aggregation in families, several studies have searched for genetic associations with grade C disease, but not in large cohorts of C/MIP. Thus, genetic contributions for C/MIP are not yet identified. The team put together for this proposal have conducted ground- breaking work in this field over the last 3 decades, including the identification of candidate genetic susceptibility variants, hyper-inflammatory response, and strong association with Aa and Aa JP2 clone. However, different populations have different genetic predispositions, environmental exposures, and microbial colonization, which further complicates unveiling the true etiology and pathogenesis of this disease. Thus, there is a critical need to examine a large well-defined cohort of C/MIP families from different world regions to systematically and comprehensively determine the genetic, host response, and microbial determinants of this disease. The goal of this proposal is to characterize the genetic, host, and microbial factors of the early onset, well-defined, localized form of periodontitis in populations worldwide. We propose to do this by gathering large cohort of C/MIP families in 4 different continents to 1)identify genetic susceptibility variants within C/MIP families via WES; 2)Identify the inflammatory networks associated with C/MIP 2, via transcriptome and network analysis and inflammatory mediator profile in the oral environment of these affected families; and 3) Determine common microbiome profiles via metagenomic analysis and unique Aa strains in C/MIP families from different regions of the world associated with this disease. Our hypotheses are that 1-C/MIP will be associated with identifiable genetic variants, which may vary in different regions of the globe, 2-a specific transcriptome is linked to pro-inflammatory pathways in C/MIP, and 3-genotypically and phenotypically different strains of Aa will differ among regions of the globe and will correlate with microbiome communities of distinct functionality and virulence potential. The impact of the proposed work is the development of an integrative series of interaction network and functional analyses, which will lead to the characterization of susceptibility, molecular, and microbial phenotypes of C/MIP in different populations around the world, which will provide criteria for early disease diagnosis and development of targeted and individualized therapies for these highly susceptible families.