VCRC Genetics and Genomics Program

该项目以VCRC遗传学和基因组学计划为中心，包括广泛的个人科学项目，探索i）血管炎在疾病易感性，临床表现和结果以及对治疗的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人群进行全基因组关联研究。VCRC在国际血管炎社区内建立了富有成效的合作，以进行此类共享遗传研究，并进行候选基因研究和外显子组测序，以识别含有罕见变异的基因。基因组DNA已经从> 1700个 已经入组VCRC研究的患者，在未来5年内，这一数字将大幅增加。 基因表达谱和表观遗传学为疾病的病理生理学提供了互补的见解，也可用于鉴定重要临床结果的生物标志物。为此目的，将分析从两项VCRC临床试验中收集的RNA。VCRC纵向研究中现有的样本采集方案可以很容易地进行调整，以纵向采集DNA（表观遗传学）和RNA（基因表达）。 本项目的具体目标是：1）继续收集多种形式血管炎患者的基因组DNA和相关的综合临床数据，以进行大规模的合作遗传学研究; 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，以识别与血管炎风险相关的罕见变异基因; 4）研究活动性疾病和缓解期血管炎患者全血的基因表达谱，以鉴定与疾病活动性、对治疗的反应和/或长期预后相关的特征和分子途径; 5）研究DNA甲基化模式（表观遗传学）在白色血细胞中，以深入了解血管炎的病理生理学，并研究可用于 诊断或预后。

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.