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

尽管牙周病(PD)的治疗和对多发性牙周炎的识别有了显著的进步 危险因素方面，遗传因素在帕金森病发病机制中的具体作用知之甚少。几个基因组- 广泛的帕金森病关联研究已经发表，但只有一个报告的基因座达到了 全基因组意义的门槛。建立流行病学研究和生物实验 PD与心血管疾病(CVD)之间的联系和共同的致病途径 糖尿病(DM)和骨质疏松症。总体目标是确定帕金森病的遗传基因座，作为迈向 对帕金森病的发病机制有了更好的认识。在女性基因组健康研究中的一项初步研究 (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/骨质疏松的共同表型变异 可以用全基因组遗传矩阵来解释。GWA骨目录的几个变体 在WGHS中，MI密度和家族史与PD相关。基于这些发现和 文献中，中心假说是帕金森病和其他疾病之间存在共同的致病联系 疾病和使用共病病例定义的全球卫生系统将有助于确定潜在的共同基因座。三 具体目标独立地提炼了PD的GWAS方法：(1)验证和扩展PD信息 通过将CDC-AAP自述牙周参数添加到妇女的年度随访调查中 健康研究；(2)通过综合性研究确定与心血管疾病、糖尿病或骨质疏松症共享的帕金森病的遗传决定因素 计算生物网络方法；以及(3)连接和协作未来的准备培训 帕金森病患者的大型牙齿基因组数据库。 这些目标也为才华横溢的牙科科学家余有华博士提供了指导培训经验 在牙周学和生物信息学方面有很强的背景。余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有共同之处。鉴于行政部门 对于这条预期研究道路的复杂性和分析性，她的培训目标是在 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、整合和解释高- 维度数据-丰富的生物信息学资源，以丰富先前的和开发新的假说。余博士和她 导师比约恩·斯特芬森博士组建了一支顾问团队，他们既是各自领域的专家，也是 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 研究帕金森病的途径，并开辟可能的研究共病情况的新途径。

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.