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

摘要 舍格伦国际合作临床联盟（SICCA）成立于2003年，旨在改善 了解、诊断和治疗干燥综合征（SS）患者，通过1）开发/验证 SS的标准化分类标准;以及2）开发纵向数据和生物标本库， 可用于研究社区未来的流行病学，发病机制和遗传学研究的SS。使用 严格的研究设计和标准化的数据/标本采集方案，来自9个国家的SICCA研究人员 地球仪的领先学术研究小组从3，514个队列中组装了一个独特的生物储存库 具有非常好的表征表型数据的参与者（具有771例的随访数据/标本）。多 取得的成果包括：1）制定和验证SS的临时分类标准 2011年由美国流变学学院（ACR）批准（随后开发/验证了 ACR和EULAR在2016年批准的一套分类标准）; 2）全基因组关联研究， 强调了SS根据祖先的遗传异质性，并建立了一个独特的遗传库， 可通过dbGAP供公众使用的SS;以及3）传播计划，该计划产生了重要的新发现 关于SS表型。为了响应FOA PAR-17-154，我们的提案利用了NIDCR资助的独特的 通过利用现有的基础设施和扩大的团队，我们可以利用最近的爆炸性 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的发病机制， 确定治疗途径和新的生物标志物。使用先前收集的临床数据/生物标本，以及 对所有参与者进行全基因组基因分型，我们建议定义转录组学和表观遗传学 SS在细胞和组织水平。这将通过生成全基因组DNA来增强SICCA登记 甲基化和单细胞mRNA、批量mRNA和miRNA的全基因组测序， SS的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，特异性表观遗传修饰和转录组学谱可能代表了新的生物标志物， 自身免疫性疾病我们还提出了一个扩大的传播计划，可以利用这些组学数据集 从而让全世界的党卫军调查人员参与到发现中来。我们的目标是1）生成转录组和甲基化 为了探索具有良好特征的SICCA参与者子集的转录组多样性， 表观遗传和遗传概况，跨细胞和组织类型; 2）探索组学概况和 严重疾病表现的体征，包括存在生殖中心形成（GCF）和局灶性 淋巴细胞性涎腺炎，LSG活检病灶评分高，高丙种球蛋白血症， 低补体血症;和3）表征SICCA患者亚组的组学谱的纵向变化。 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具动态性 随着时间的推移，提供与疾病进展和结果相关的生物学过程的见解。

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.