VCRC Genetics and Genomics Program

VCRC 遗传学和基因组学计划

• 批准号: 8919980
• 负责人: Peter A Merkel
• 金额: $ 2.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8919980
• 关键词: Biological Markers; Blood Vessels; Candidate Disease Gene; Clinical; Clinical Data; Clinical Research; Clinical Trials; Collaborations; Communities; Complex; DNA; DNA Methylation; Diagnosis; Disease; Disease remission; Disease susceptibility; Enrollment; Epigenetic Process; Functional disorder; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Research; Genetic study; Genomic DNA; Genomics; Individual; Inflammatory; International; Leukocytes; Link; Longitudinal Studies; Molecular; Molecular Profiling; Outcome; Pathway interactions; Patients; Population Study; Protocols documentation; RNA; Rare Diseases; Recording of previous events; Research; Research Infrastructure; Risk; Series; Source; Technology; Vasculitis; Whole Blood; base; exome sequencing; genome wide association study; insight; methylation pattern; outcome forecast; programs; rare variant; response; sample collection

This Project centers on the VCRC Genetics and Genomics Program and includes a broad range of individual scientific projects exploring i) the genetic basis of vasculitis in terms of disease susceptibility, clinical expression and outcome, and response to treatment; ii) the molecular pathophysiology of vasculitis; and iii) potential biomarkers useful for the management of these complex diseases. The recent history of genetics research in rare diseases makes it clear that only through collaboration and cooperation can study populations of meaningful sizes be assembled to conduct genome-wide association studies. The VCRC has established productive collaborations within the international vasculitis communities to conduct such shared genetic research, and also to conduct candidate gene studies and to perform exome sequencing to identify genes containing rare variants. Genomic DNA has been obtained from the > 1700 patients already enrolled in VCRC studies, and that number will increase greatly during the next 5 years. Gene expression profiling and epigenetics provide complementary insights into the pathophysiology of disease and can also be used to identify biomarkers of important clinical outcomes. RNA already collected from two VCRC clinical trials will be analyzed for this purpose. The existing protocols for sample collection in the VCRC Longitudinal Studies can easily be adapted to collect DNA (epigenetics) and RNA (gene expression) longitudinally. The Specific Aims of this Project are to: 1) continue to collect genomic DNA and linked comprehensive clinical data from patients with multiple forms of vasculitis to conduct large-scale collaborative genetics studies; 2) conduct a series of candidate gene analyses and genome-wide association studies; 3) conduct studies of exome sequencing in order to identify genes with rare variants associated with risk of vasculitis; 4) study gene expression profiles from the whole blood of patients with vasculitis during active disease and remission, to identify signatures and molecular pathways related to disease activity, response to therapy, and/or long-term prognosis; and 5) study DNA methylation patterns (epigenetics) in white blood cells to gain insight into pathophysiology of vasculitis and to investigate another potential source of biomarkers useful for diagnosis or prognosis.

该项目以 VCRC 遗传学和基因组学计划为中心，包括广泛的单个科学项目，探索 i) 血管炎在疾病易感性、临床表现和结果以及治疗反应方面的遗传基础； ii) 血管炎的分子病理生理学； iii) 可用于管理这些复杂疾病的潜在生物标志物。罕见疾病遗传学研究的最新历史清楚地表明，只有通过协作与合作，才能聚集有意义规模的研究群体来进行全基因组关联研究。 VCRC 已在国际血管炎界建立了富有成效的合作，以开展此类共享基因研究，并开展候选基因研究并进行外显子组测序，以鉴定含有罕见变异的基因。基因组 DNA 已从 > 1700 患者已经参加了 VCRC 研究，并且这个数字在未来 5 年内将大大增加。 基因表达谱和表观遗传学提供了对疾病病理生理学的补充见解，也可用于识别重要临床结果的生物标志物。为此目的，将从两项 VCRC 临床试验中收集的 RNA 进行分析。 VCRC 纵向研究中现有的样本收集方案可以轻松地适应纵向收集 DNA（表观遗传学）和 RNA（基因表达）。 该项目的具体目标是：1）继续收集多种形式血管炎患者的基因组DNA并关联全面的临床数据，以进行大规模的协作遗传学研究； 2）进行一系列候选基因分析和全基因组关联研究； 3) 进行外显子组测序研究，以确定具有与血管炎风险相关的罕见变异的基因； 4) 研究活动期和缓解期血管炎患者全血的基因表达谱，以确定与疾病活动、治疗反应和/或长期预后相关的特征和分子途径； 5) 研究白细胞中的 DNA 甲基化模式（表观遗传学），以深入了解血管炎的病理生理学，并研究可用于治疗血管炎的生物标志物的另一个潜在来源。 诊断或预后。