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）和识别多种牙周病方面有了显着的进步， 虽然遗传因素对PD发病机制的影响很大，但人们对遗传因素对PD发病机制的具体作用知之甚少。几个基因组- 已经发表了PD的广泛关联研究（GWAS），但只有一个报告的位点达到了 全基因组显著性的阈值。开展流行病学研究和生物学实验 PD和心血管疾病（CVD）之间的关联和建议的共同发病途径， 糖尿病（DM）和骨质疏松症。总体目标是确定PD的遗传基因座，作为 更好地了解PD发病机制。在妇女基因组健康研究的一项初步研究中， （WGHS），新发PD病例与心肌梗死（MI）家族史相关。进一步 初步分析显示，PD/CVD、PD/DM或PD/骨质疏松症共有表型变异， 可以用全基因组遗传矩阵来解释。GWAS骨目录中的几种变体 在WGHS中发现MI的密度和家族史与PD相关。根据这些发现和 根据文献，中心假设是PD和这些其他疾病之间存在共同的发病联系。 GWAS使用共病病例定义将有助于确定潜在的共同位点。三 具体的目标独立地完善了PD的GWAS方法：（1）收集和扩展PD信息 通过将CDC-AAP自我报告的牙周参数添加到女性的年度随访调查中， 健康研究;（2）通过综合分析，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）准备培训，以连接和合作，与未来 PD GWAS的大型牙齿基因组数据库。 这些目标也为有才华的牙医科学家Yau-Hua Yu博士提供了一个指导培训经验 在牙周病学和生物信息学方面有很强的背景。余博士的职业目标是融入 流行病学、基因组学和临床研究，以阐明 牙周病与心血管疾病、糖尿病和骨质疏松症有共同之处。鉴于行政 和分析的复杂性，她的培训目标是获得技能和经验， （1）对自我报告的数据进行收集、分析、解释和验证研究 结果。2)大规模遗传流行病学的管理、定量分析和解释 跨多个站点和技术平台的数据集。3)加入、融入和解释《公约》 多维数据丰富的生物信息学资源，以丰富先验和发展新的假设。余博士和她 导师Bjorn Steffensen博士组建了一个顾问团队，他们是各自领域的专家， 拟议工作所需的大型队列研究的领导人。这项工作将突出未来 研究路径PD和开放可能的新途径的调查共病条件。