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Differential familial-exomic profile between incisor-molar pattern and generalized grade C periodontitis affecting south and North-American young population

Grant number: 21/14430-3
Support Opportunities:Scholarships abroad - Research
Effective date (Start): January 10, 2023
Effective date (End): November 09, 2023
Field of knowledge:Health Sciences - Dentistry - Periodontology
Principal Investigator:Renato Corrêa Viana Casarin
Grantee:Renato Corrêa Viana Casarin
Host Investigator: Luciana Macchion Shaddox
Host Institution: Faculdade de Odontologia de Piracicaba (FOP). Universidade Estadual de Campinas (UNICAMP). Piracicaba , SP, Brazil
Research place: University of Kentucky (UK), United States  

Abstract

Grade C Periodontitis was recently adopted by The American Academy of Periodontology and European Federation of Periodontology to identify individuals with a high risk for disease progression. Within the different patterns of this grading code, the systemically healthy youngers affected by a severe and fast progression disease are included. 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, usually affecting very young population around 15-20 years old. Moreover, the generalized form (C/Gen) affects more than 30% of teeth, resulting in advanced bone and tooth loss at early ages. Although less common than other periodontitis, C/MIP and C/Gen 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. Although several studies included genetic disorders as a factor contributing to it development, up to date, there are rare studies including families and a wide and open-ended approach to identify candidate genetic susceptibility variants of periodontitis affecting youngers. Moreover, there's still need an effort to better characterize the C/MIP and C/Gen, once both are considered different disease although affecting young population. 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, the aim of this proposal is to characterize the genetic factors of early-onset periodontal disease that affects younger people through an exomic analysis of families affected by the disease. In addition, the genetic signature of each condition - C/MIP and C/Gen will be further analyzed and validated in a large-scale unrelated population in North America and Brazil. For this, eight pairs of a proband affected by Periodontitis grade C/MIP and a healthy sibling and another 8 pairs of a proband affected by C/Gen and healthy sibling will be included in the first step of this study. First, the DNA of oral epithelial cells will be collected and, after preparing the libraries (Illumina® DNA Prep with Enrichment, (S) Tagmentation) the exomic profile will be determined (Illumina HiSeq 2000) with a sequencing of 60 million paired-end reads per sample. A family filtering approach will be applied, I e similar variants between proband and healthy sibling will be excluded. The resulting variants will be compared, first between C/MIP subjects and then between C/Gen. Final results will include common variants between phenotypes and those specific to each pattern. To determine the significant variants, in silico and functional analyzes will be performed, considering specific software impact patterns (SIFT, Polyphen2, MutationTaster and CADD score - Combined Annotation-Dependent Depletion), In addition, in a second step, the significant variants resulting from this prior analysis will be validated in an unrelated population including 200 C/MIP individuals, 200 C/Gen individuals and 400 healthy unrelated individuals, by specific probes and a PCR reaction. All statistical analyzes will be performed by tests and corrections suitable for each step, considering a significance level of 5%. (AU)

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