Susceptibility Patterns for Grade C Periodontitis in Young Individuals

美国牙周病学会和欧洲牙周病联合会最近通过了 新的术语“C级牙周炎”，以确定疾病进展的高风险个体。的 这种疾病的局部形式，现在称为3-4期C级，磨牙-切牙型牙周炎（C/MIP）， 有明确的临床表现虽然不常见于其他牙周炎，C/MIP有 严重的公共卫生影响，因为它影响到全身健康的年轻人，社会经济地位低， 地位，谁通常无法负担其昂贵和复杂的治疗，因为他们受影响的牙齿往往失去了由于 导致病情迅速恶化和延误诊断这会导致早期功能和美学问题， 功能和美学康复的困难。由于其在家庭中的常见聚集性，一些研究 已经研究了与C级疾病的遗传关联，但没有在大的C/MIP队列中。因此，基因 C/MIP的贡献尚未确定。为这一提议而组建的团队已经进行了实地考察- 在过去的30年里，这一领域的突破性工作，包括鉴定候选遗传易感性， 变体、高炎症反应以及与Aa和Aa JP 2克隆的强相关性。但不同 种群具有不同的遗传倾向、环境暴露和微生物定植， 进一步复杂化了揭示这种疾病的真正病因和发病机制。因此，迫切需要 检查来自世界不同地区的C/MIP家族的大型明确队列， 全面确定这种疾病的遗传、宿主反应和微生物决定因素。的目标 这一建议是为了表征发病早、定义明确、局部化的遗传、宿主和微生物因素， 牙周炎是一种常见的牙周病。我们建议通过收集大量的C/MIP家族来做到这一点 在4个不同的大陆，1）通过WES鉴定C/MIP家族内的遗传易感性变异; 2）鉴定 通过转录组和网络分析，与C/MIP 2相关的炎症网络， 这些受影响家庭的口腔环境中的介质概况;以及3）确定共同的微生物组概况 通过宏基因组学分析和来自世界不同地区的C/MIP家族中的独特Aa菌株相关联， 与这种疾病。我们的假设是，1-C/MIP将与可识别的遗传变异， 可能在地球仪的不同区域有所不同，2-一个特定的转录组与促炎途径有关， C/MIP和3种基因型和表型不同的Aa菌株在地球仪的不同区域之间将不同， 将与具有不同功能和毒力潜力的微生物群落相关。 拟议的工作的影响是一个综合系列的互动网络的发展， 功能分析，这将导致敏感性，分子和微生物表型的表征 C/MIP在世界各地不同人群中的分布，这将为疾病的早期诊断提供标准， 为这些高度易感的家庭开发有针对性的个性化治疗。

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.