Genomewide association studies in peri-implant bone loss

项目概要/摘要： 牙科植入物彻底改变了牙科。不幸的是，随着时间的推移，植入物会出现并发症，包括... 种植体炎（PI）。PI影响45%接受牙科种植体的患者，其中14.5%的患者 中度至重度PI。迄今为止，PI的病理生理学尚未完全了解，PI消退后， 仅在约50%的植入物中观察到。鉴于有超过500万个植入物 在美国，每年，植入物的流行率预计将增加到23%，在2026年，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局。PI具有与 然而，在牙周炎中，PI进展得更积极，并最终导致种植体损失。而且就算 尽管这两种疾病有着共同的风险因素，包括宿主/遗传影响，但遗传在 PI基本上是未知的。了解遗传基础的患病率和治疗结果 PI是必不可少的数以百万计的人考虑或目前接受牙科植入物治疗。我们的长期目标 是识别与种植体周围骨质流失相关的遗传特征，并辨别 是疾病病理生理学的基础我们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）鉴定与种植体周围骨丢失有关的性状。 我们的中心假设是，数量训练位点（QTL）与PI的敏感性，并提供洞察 适当的治疗策略。我们的假设是在我们的初步研究中用一个连字- 在三种小鼠品系（A/J、C3 H/HeJ和C57 BL/6 J）中诱导种植体周围骨丢失模型。通过µ-CT 分析中，我们观察到牙科种植体周围的应变依赖性骨丢失具有统计学意义，支持 基因框架在结扎诱导的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构成重大挑战， 患者的遗传构成和控制环境因素的困难。因为人类和老鼠 类似的结构、功能和遗传特征，小鼠模型将对GWAS有效， 遗传和环境框架至关重要。HMDP面板由100多个商用 选择可用的近交系小鼠品系用于系统遗传分析。该面板已被验证为许多 包括糖尿病、心血管疾病和牙周炎的病症。我们计划验证我们的核心假设 并完成本研究的目的，具体目标如下： HMDP中的种植体周围骨丢失。我们已经为成功执行开发了必要的专业知识 的提案。这些研究的完成将有助于对PI易感性、预后、 治疗，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 有助于国家卫生研究院的使命和积极影响科学和卫生保健，并提供有价值的信息， 更全面的研究计划。

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.