Sjögren's International Collaborative Clinical Alliance Next Generation Studies (SICCA-NextGen)

摘要 Sjögren的国际协作临床联盟(SICCA)成立于2003年，旨在提高 通过1)发展/验证对干燥综合征(SS)患者的认识、诊断和治疗 SS的标准化分类标准；以及2)开发纵向数据和生物质谱库， 可被研究界用于未来SS的流行病学、发病机制和遗传学研究。vbl.使用 严格的研究设计和标准化的数据/标本收集方案，SICCA的调查人员来自9个 全球领先的学术研究小组从3514人的队列中收集了一个独特的生物库 有非常好的表型数据特征的参与者(有771的后续数据/样本)。多重 实现了可交付成果，包括1)暂时制定和验证SS的分类标准 由美国风湿病学会(ACR)于2011年批准(随后开发/验证 ACR和EULAR于2016年批准的一套分类标准)；2)全基因组关联研究， 根据血统突出了SS的遗传异质性，并建立了独一无二的遗传库 通过DBGaP向公众提供SS；以及3)一项传播计划，该计划产生了重要的新发现 关于SS表型。作为对FOA PAR-17-154的回应，我们的提案利用了独特的NIDCR资助 通过利用现有基础设施和扩大的团队提供资源，并使我们能够利用最近的爆炸性事件 在免疫学、基因组学和表观遗传学领域的发展，以更好地了解SS和 确定治疗途径和新的生物标记物。使用以前收集的临床数据/生物检疫，以及 对所有参与者进行全基因组基因分型，我们建议定义转录和表观遗传学 在细胞和组织水平上的SS。这将通过生成全基因组DNA来增强SICCA注册 单细胞信使核糖核酸、大宗信使核糖核酸和miRNA的甲基化和全基因组测序，并实现高影响 SS潜在生物学途径的研究。鉴于表观基因组和基因之间的关系 表达、特定的表观遗传修饰和转录谱可能代表新的生物标志物 自身免疫性疾病。我们还提出了一个扩展的传播计划，可以利用这些组学数据集 从而让世界各地的党卫军调查人员参与发现。我们的目标是1)产生转录组和甲基化 为了探索特征良好的SICCA参与者亚组之间的转录多样性 表观遗传学和遗传图谱，跨细胞和组织类型；2)探索组学图谱和基因组图谱之间的相关性 严重疾病表现的迹象，包括生发中心形成(GCF)和局灶性病变 淋巴细胞性涎腺炎在LSG活检中有高病灶评分，高丙种球蛋白血症，以及 低补体血症；以及3)表征SICCA患者亚群组学特征的纵向变化。 虽然SS的传统表型特征是稳定的，但我们假设组学特征可能更动态 随着时间的推移，提供与疾病进展和结果相关的生物过程的洞察。

ABSTRACT The Sjögren’s International Collaborative Clinical Alliance (SICCA) was established in 2003 to improve the understanding, diagnosis and treatment of patients with Sjögren’s syndrome (SS) by 1) developing/validating standardized classification criteria for SS; and 2) developing a longitudinal data and biospecimen repository that could be used by the research community for future epidemiologic, pathogenesis, and genetic studies of SS. Using rigorous study design and, standardized data/specimen collection protocols, SICCA investigators from nine leading academic research groups across the globe assembled a unique biorepository from a cohort of 3,514 participants with extremely well characterized phenotypic data (with follow-up data/specimens on 771). Multiple deliverables were achieved including 1) development and validation of classification criteria for SS provisionally approved by the American College of Rheumatology (ACR) in 2011 (followed by the development/validation of a set of classification criteria approved by ACR and EULAR in 2016); 2) a Genome-Wide Association Study that highlighted the genetic heterogeneity of SS according to ancestry, and established a unique genetic repository for SS available for public use through dbGAP; and 3) a dissemination plan, which has yielded important new findings regarding the SS phenotype. In response to FOA PAR-17-154, our proposal leverages unique NIDCR-funded resources by utilizing existing infrastructure and an expanded team, and positions us to exploit recent explosive growth in the fields of immunology, genomics and epigenetics to better understand the pathogenesis of SS and identify therapeutic pathways, and new biomarkers. Using previously collected clinical data/biospecimens, and genome-wide genotyping performed on all participants, we propose to define the transcriptomics and epigenetics of SS at the cell and tissue levels. This will enhance the SICCA registry by generating genome-wide DNA methylation and whole-genome sequencing of single-cell mRNA, bulk mRNA, and miRNA and enable high impact studies of underlying biologic pathways of SS. Given the relationship between the epigenome and gene expression, specific epigenetic modifications and transcriptomic profiles may represent novel biomarkers in autoimmune diseases. We also propose an expanded dissemination plan that can leverage these omics data sets thereby engaging SS investigators worldwide in discovery. We aim to 1) Generate transcriptome and methylation profiles in order to explore transcriptomic diversity across subsets of SICCA participants with well characterized epigenetic and genetic profiles, across cell and tissue types; 2) Explore correlations between omics profiles and signs of severe disease manifestations, including presence of germinal-center-formation (GCF) and focal lymphocytic sialadenitis with a high focus score in LSG biopsies, hypergammaglobulinemia, and hypocomplementemia; and 3) Characterize longitudinal changes in omics profiles of subsets of SICCA patients. While traditional phenotypic features of SS are stable, we hypothesize that omics profiles may be more dynamic across time, providing insight into biologic processes associated with disease progression and outcome.