Genomewide association studies in peri-implant bone loss

项目摘要/摘要： 牙科植入物给牙科带来了革命性的变化。不幸的是，随着时间的推移，植入物会出现并发症，包括围产期- 种植炎(PI)。45%的接受牙种植体的患者受到PI的影响，14.5%的患者 中度至重度PI。到目前为止，PI的病理生理机制还不完全清楚，PI解决后 治疗，只在大约50%的植入物中观察到。考虑到超过500万个植入物被放置在 在美国，植入物的流行率预计到2026年将增加到23%，PI是一个重要的 需要解决的临床问题，以获得最佳的患者结果。PI具有相似的特征 然而，牙周炎，PI的进展更具侵袭性，最终导致种植体丢失。此外，即使是 尽管这两种疾病具有共同的风险因素，包括宿主/遗传影响，但遗传学在 圆周率在很大程度上是未知的。了解遗传病的患病率和治疗结果 PI对数百万正在考虑或正在接受牙科植入物治疗的人来说是必不可少的。我们的长期目标 是确定与种植体周围骨丢失相关的遗传特征，并识别 疾病病理生理学的基础。我们在这里的目标是进行全基因组关联研究(GWAS) 利用小鼠模型(杂交小鼠多样性小组-HMDP)确定与种植体周围骨丢失有关的特征。 我们的中心假设是数量训练基因座(QTL)与PI易感性相关，并提供了对 适当的治疗策略。我们的假设是在我们的初步研究基础上提出的，使用了一条绳索- 建立A/J、C3H/HeJ和C57BL/6J三种小鼠种植体周围骨丢失模型。通过µ-CT 分析，我们观察到统计学上显著的种植体周围的应变依赖性骨丢失，支持 基因框架在结扎导致种植体周围骨丢失中的重要作用。我们选择用鼠标 模型，因为临床遗传学研究由于复杂和异质性而带来了巨大的挑战 患者的遗传构成和控制环境因素的困难。因为人类和老鼠共享 相似的结构、功能和遗传特征，小鼠模型将对控制 遗传和环境框架至关重要。HMDP面板由100多个商业组件组成 可供选择用于系统遗传分析的近交系小鼠品系。此面板已通过多项验证 疾病包括糖尿病、心血管疾病和牙周炎。我们计划测试我们的中心假设 并以以下具体目的完成本研究的目的：进行结扎诱导的GWA HMDP种植体周围骨丢失。我们已经开发了成功执行所需的专业知识 这项提议。这些研究的完成将有助于对PI易感性、预后、 并将揭示PI与牙周炎之间的机制差异。我们的成功将极大地 为美国国立卫生研究院的使命做出贡献，积极影响科学和卫生保健，并为 一个更全面的研究方案。

Project Summary/Abstract: Dental implants revolutionized dentistry. Unfortunately, implants have complications over time, including peri- implantitis (PI). PI affects 45% of patients who received dental implants, with 14.5% of the patients having moderate to severe PI. To date the pathophysiology of PI is not completely understood and PI resolution, after treatment, is only observed in approximately 50% of implants. Given that more than 5 million implants are placed in the US per year, and that the prevalence of implants is expected to increase to 23% in 2026, PI is a significant clinical concern that needs to be addressed for optimal patient outcomes. PI shares similar characteristics with periodontitis however, PI progresses more aggressively and ultimately leads to implant loss. Furthermore, even though these two conditions share common risk factors, including host/genetic influences, the role of genetics in PI is largely unknown. Understanding the genetic underpinnings on the prevalence and treatment outcomes of PI is essential to the millions of people considering or currently treated with dental implants. Our long-term goal is to identify genetic traits that correlate with peri-implant bone loss and to discern the signaling cascades that underlie disease pathophysiology. Our objective here is to perform Genome-Wide Association Studies (GWAS) to identify traits involved in peri-implant bone loss utilizing a mouse model (Hybrid Mouse Diversity Panel-HMDP). Our central hypothesis is that quantitative train loci (QTLs) associate with PI susceptibility and provide insight on appropriate treatment strategies. Our hypothesis is formulated on our preliminary studies using a ligature- induced peri-implant bone loss model in three mouse strains (A/J, C3H/HeJ and C57BL/6J). Through µ-CT analysis, we observed statistically significant strain-dependent bone loss around dental implants, supporting a significant role of the genetic framework in ligature-induced peri-implant bone loss. We elected to use a mouse model because clinical genetic studies pose significant challenges due to the complex and heterogeneous genetic make-up of patients and difficulties in controlling environmental factors. Since humans and mice share similar structural, functional and genetic traits, a mouse model would be effective for GWAS where controlling the genetic and environmental framework is critical. The HMDP panel consists of more than 100 commercially available inbred mouse strains selected for systematic genetic analyses. This panel has been validated for many conditions including diabetes, cardiovascular disease and periodontitis. We plan to test our central hypothesis and accomplish the objective of this study with the following specific aim to perform GWAS of ligature-induced peri-implant bone loss in the HMDP. We have developed the necessary expertise for the successful execution of the proposal. Completion of these studies will facilitate a new understanding of PI susceptibility, prognosis, treatment and will reveal mechanistic differences between PI vs. periodontitis. Our success will significantly contribute to the NIH mission and positively impact science and health care and provide valuable information for a more comprehensive research proposal.