Exploring genomic determinants of periodontal disease via shared genetic pathways with cardiovascular disease, diabetes, and bone density

通过与心血管疾病、糖尿病和骨密度共享的遗传途径探索牙周病的基因组决定因素

• 批准号: 9451794
• 负责人: Yau-Hua Yu
• 金额: $ 13.86万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9451794
• 关键词: Academy; Adult; Advisory Committees; Affect; American; Applications Grants; Area; Bioinformatics; Biological; Bone Density; Cardiovascular Diseases; Catalogs; Caucasians; Centers for Disease Control and Prevention (U.S.); Clinical; Clinical Research; Cohort Studies; Collaborations; Comorbidity; Complex; Data; Data Collection; Data Set; Databases; Dental; Dental Records; Dentists; Development; Diabetes Mellitus; Disease; Enrollment; Epidemiology; Family history of; Framingham Heart Study; Funding; Future; Genes; Genetic; Genetic Determinism; Genome; Genomics; Goals; Health; Incidence; Interview; Investigation; Knowledge; Learning; Link; Literature; Mentors; Mentorship; Meta-Analysis; Molecular Profiling; Myocardial Infarction; National Health and Nutrition Examination Survey; Osteoporosis; Outcome; Participant; Pathogenesis; Pathway Analysis; Pathway interactions; Patient Self-Report; Patients; Periodontal Attachment Loss; Periodontal Diseases; Periodontitis; Phenotype; Phonation; Population; Proteins; Publishing; Reporting; Research; Research Design; Research Personnel; Research Proposals; Resources; Risk; Risk Factors; Sampling; Scientist; Site; Smoke; Surveys; Talents; Telephone; Training; Twin Studies; Update; Validation; Variant; Veterans; Woman; Women' s Health; Work; base; career; database of Genotypes and Phenotypes; disease diagnosis; epidemiology study; epigenetic regulation; experience; experimental study; follow-up; genetic epidemiology; genome database; genome wide association study; genome-wide; high dimensionality; precision medicine; programs; skills; social; trait; validation studies; whole genome

Despite significant improvement in treating periodontal disease (PD) and the identification of multiple risk factors, little is known about the specific contribution of genetics to PD pathogenesis. Several genome- wide association studies (GWAS) of PD have been published, but only one reported locus has reached the threshold for genome-wide significance. Epidemiological studies and biological experiments established associations and suggested common pathogenetic pathways between PD and cardiovascular disease (CVD), diabetes (DM), and osteoporosis. The overall objective is to identify genetic loci for PD as a first step toward a better understanding of PD pathogenesis. In a preliminary study in the Women's Genome Health Study (WGHS), new-onset cases of PD were associated with a family history of myocardial infarction (MI). Further preliminary analyses presented shared phenotypic variation of PD/CVD, PD/DM, or PD/osteoporosis that could be accounted by the whole-genome genetic matrices. Several variants from the GWAS catalog of bone density and family history of MI were found correlated with PD in the WGHS. Based on these findings and the literature, the central hypothesis is that there are common pathogenetic links between PD and these other diseases and that GWAS using the comorbidity case definitions will help identify potential common loci. Three specific aims independently refine the approach to GWAS of PD: (1) Validate and expand the PD information by adding the CDC-AAP self-reported periodontal parameters to the annual follow-up survey in the Women's Health Study; (2) Identify genetic determinants of PD shared with CVD, DM, or osteoporosis via an integrative computational biological networks approach; and (3) Preparatory training to connect and collaborate with future large dental-genomic databases for GWAS of PD. These aims also provide a mentored training experience for Dr. Yau-Hua Yu, a talented dentist scientist with a strong background in periodontology and bioinformatics. Dr. Yu's career goal is to integrate epidemiological, genomic and clinical studies to elucidate the systemic links and genetic components that periodontal disease shares with cardiovascular disease, diabetes and osteoporosis. Given the administrative and analytical complexity of this intended research path, her training goal is to acquire skills and experience in the following areas: 1) Data collection, analysis, interpretation and validation studies for self-reported outcomes. 2) Management, quantitative analysis and interpretation of large-scale genetic epidemiological datasets across multiple sites and technological platforms. 3) Accession, integration and interpretation of high- dimensional data-rich bioinformatics resources to enrich prior and develop new hypotheses. Dr. Yu and her mentor, Dr. Bjorn Steffensen, have assembled a team of advisors who are experts in their fields as well as leaders of the large cohort studies required for the proposed work. The proposed work will highlight future research paths for PD and open possible new avenues of investigation for comorbid conditions.

尽管在治疗牙周病（PD）方面取得了显着进步，并且发现了多种牙周病 尽管存在危险因素，但人们对遗传学对 PD 发病机制的具体贡献知之甚少。几个基因组- PD 的广泛关联研究 (GWAS) 已发表，但只有一个报道的位点达到了 全基因组意义的阈值。流行病学研究和生物学实验建立 PD 和心血管疾病 (CVD) 之间的关联并提出了常见的发病途径， 糖尿病（DM）和骨质疏松症。总体目标是确定 PD 的遗传位点，作为迈向这一目标的第一步。 更好地了解 PD 发病机制。女性基因组健康研究的初步研究 (WGHS)，新发 PD 病例与心肌梗死 (MI) 家族史相关。更远 初步分析显示了 PD/CVD、PD/DM 或 PD/骨质疏松症的共同表型变异 可以通过全基因组遗传矩阵来解释。 GWAS 骨骼目录中的几种变体 在 WGHS 中发现 MI 密度和家族史与 PD 相关。基于这些发现和 文献中，中心假设是 PD 与其他这些疾病之间存在共同的致病联系。 疾病，并且使用合并症病例定义的 GWAS 将有助于识别潜在的共同位点。三 具体目标独立完善PD的GWAS方法：（1）验证和扩展PD信息 将 CDC-AAP 自我报告的牙周参数添加到妇女健康中心的年度随访调查中 健康研究； (2) 通过综合方法确定 PD 与 CVD、DM 或骨质疏松症共有的遗传决定因素 计算生物网络方法； (3) 与未来联系和协作的准备培训 PD GWAS 大型牙科基因组数据库。 这些目标还为才华横溢的牙医科学家余友华博士提供了指导培训经验 具有深厚的牙周病学和生物信息学背景。于博士的职业目标是整合 流行病学、基因组和临床研究，以阐明系统性联系和遗传成分 牙周病与心血管疾病、糖尿病和骨质疏松症一样。鉴于行政 以及该预期研究路径的分析复杂性，她的培训目标是获得以下方面的技能和经验 以下领域： 1) 自我报告的数据收集、分析、解释和验证研究 结果。 2）大规模遗传流行病学管理、定量分析与解读 跨多个站点和技术平台的数据集。 3）高水平的加入、整合和解释 维度数据丰富的生物信息学资源可以丰富先前的假设并发展新的假设。于博士和她 导师 Bjorn Steffensen 博士组建了一支顾问团队，他们都是各自领域的专家 拟议工作所需的大型队列研究的领导者。拟议的工作将突出未来 帕金森病的研究路径，并为共病的研究开辟可能的新途径。