Genetic and Genomic Dissection of Psoriatic Arthritis

银屑病关节炎的遗传学和基因组解析

• 批准号: 10668441
• 负责人: JAMES TILFORD ELDER
• 金额: $ 58.61万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10668441
• 关键词: Address; Alleles; Area; Arthritis; Autoimmune; Autoimmune Diseases; Behavior; Biochemical; Blood; Blood Banks; Blood specimen; CD8B1 gene; Cardiovascular Diseases; Cellular Assay; Chronic small plaque psoriasis; Clinic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Collaborations; Collection; Cutaneous; DNA; Data; Dedications; Dermatology; Dissection; Elements; Exhibits; Genes; Genetic; Genetic Load; Genetic Markers; Genetic study; Genomics; Genotype; HLA-C Antigens; Health; Hospitals; Immunity; In Vitro; Individual; Inflammatory; Interferons; International; Life; Longitudinal cohort; Machine Learning; Memory; Messenger RNA; Meta-Analysis; Michigan; MicroRNAs; Modeling; Mutagenesis; Osteoblasts; Osteoclasts; Pathogenesis; Patients; Predisposition; Proteins; Psoriasis; Psoriatic Arthritis; RNA; Regulatory Element; Regulatory T-Lymphocyte; Research; Resources; Rheumatology; Risk; Role; STAT3 gene; Sampling; Serum; Signal Transduction; Site; Skin; Small Interfering RNA; T-Lymphocyte; TNFSF15 gene; TYK2; Testing; Transcript; United States; Untranslated RNA; Variant; arthropathies; biomarker development; biomarker identification; causal variant; clinically relevant; cohort; comorbidity; differential expression; exome; follow-up; genetic variant; genome wide association study; high risk; innovation; insight; memory CD4 T lymphocyte; metabolome; metabolomics; novel; osteoblast differentiation; predictive marker; rare variant; recruit; systemic autoimmunity; tool; tool development; transcriptome; transcriptome sequencing

Psoriatic arthritis (PsA) is distinctive amongst the inflammatory/autoimmune joint diseases in that its onset is commonly preceded by cutaneous psoriasis (PsC). This provides an unparalleled opportunity for the identification of predictive biomarkers to determine which of the approximately 25% of psoriasis vulgaris (PsV) patients will develop PsA. Over the past decade, we have expanded our genetic study of PsV to focus on PsA, resulting in the collection of 1,279 PsA patients at Michigan, 743 of whom have already been subjected to GWAS. Initiated in 2007, the International Psoriatic Arthritis Research Team (IPART) has accumulated 1,919 Canadian PsA patients, of whom 1,370 have already been subjected to GWAS. In 2015, we completed a meta- GWAS of PsC and PsA involving a discovery cohort of 1,430 PsA cases and 1,417 controls, with 9,293 additional PsV replication samples (3,061 PsA, 3,110 PsC) and 13,670 controls. We detected 10 associations for PsA and 11 for PsC, as well as a new association for PsV. Utilizing an innovative core exome array to genotype additional cases and controls, we carried out the largest meta-GWAS of PsV to date (~40,000 subjects) and found 16 more susceptibility regions, highlighting the roles of interferon signaling and the NFB cascade, and demonstrating strong enrichment for psoriasis genetic signals in T-cell regulatory elements. Using machine learning to model ~200 genetic variants in our PsA vs. PsC GWAS, we achieved 82% area under receiver operator curve for distinguishing PsA vs PsC, with 98% accuracy among the top 10% of patients with the highest genetic load. We also carried out RNA-seq on mRNA and miRNA from 65 pairs of pre- and post-conversion samples from PsC patients who developed PsA. Suggestive of a shift from skin- focused to systemic autoimmunity, we found significant post-conversion enrichment for central memory CD4+ T-cell (CD4-Tcm) transcripts among the up-regulated genes. We also observed highly correlated pre- and post- conversion behaviors of 54 differentially-expressed miRNAs and their mRNA targets, as well as multiple serum miRNAs that are significantly differentially expressed in PsA vs. PsC. A metabolomic study of 50 paired converter sera revealed 293 biochemicals with significant alterations, 275 of which were increased. Finally, we identified noncoding eQTLs for IL23R that correlate strikingly with a region of selective PsA association. Based on these results, we hypothesize that PsA and PsC have pathogenetic mechanisms that are T-cell, osteoblast and osteoclast-driven and progress from skin to systemic during transition to PsA. We propose that this paradigm can be used to develop a useful test to predict PsA in PsC patients, while increasing our basic understanding of PsA. To test this hypothesis, we propose four aims: (1) to maintain and grow our longitudinal clinical resource; (2) To identify biomarkers for the development of PsA in PsC patients; (3) To integrate the biomarkers identified in Aim 2 into a clinically-useful tool for PsA identification using machine learning ; and (4) to explore the mechanisms by which the IL23R gene contributes to PsA pathogenesis.

银屑病关节炎 (PsA) 在炎症/自身免疫性关节疾病中具有独特性，因为它的发病 通常先有皮肤牛皮癣（PsC）。这为 识别预测生物​​标志物，以确定大约 25% 的寻常型银屑病 (PsV) 中的哪一种 患者会发展为银屑病关节炎（PsA）。在过去的十年中，我们扩大了 PsV 的基因研究，重点关注 PsA， 密歇根州收集了 1,279 名 PsA 患者，其中 743 人已经接受过治疗 GWAS。国际银屑病关节炎研究小组 (IPART) 自 2007 年发起以来，已累计 1,919 加拿大银屑病关节炎患者，其中 1,370 名患者已经接受了 GWAS。 2015年，我们完成了元 PsC 和 PsA 的 GWAS 涉及 1,430 例 PsA 病例和 1,417 例对照的发现队列，其中 9,293 例 额外的 PsV 复制样本（3,061 个 PsA、3,110 个 PsC）和 13,670 个对照。我们检测到 10 个关联 针对 PsA 的关联和针对 PsC 的 11 关联，以及针对 PsV 的新关联。利用创新的核心外显子组阵列 对其他病例和对照进行基因分型，我们进行了迄今为止最大规模的 PsV 元 GWAS（约 40,000 受试者）并发现了另外 16 个易感区域，强调了干扰素信号传导和 NF+B 的作用 级联反应，并证明 T 细胞调节元件中银屑病遗传信号的强烈富集。 使用机器学习对 PsA 与 PsC GWAS 中的约 200 个遗传变异进行建模，我们获得了 82% 的面积 在接受者操作曲线下区分 PsA 与 PsC，准确率在前 10% 中达到 98% 遗传负荷最高的患者。我们还对 65 对 mRNA 和 miRNA 进行了 RNA-seq 来自患有 PsA 的 PsC 患者的转化前和转化后样本。暗示从皮肤的转变- 专注于系统性自身免疫，我们发现中央记忆 CD4+ 转换后显着富集 T 细胞 (CD4-Tcm) 在上调基因中转录。我们还观察到前后高度相关 54个差异表达的miRNA及其mRNA靶标以及多种血清的转化行为 PsA 与 PsC 中表达显着差异的 miRNA。 50对配对的代谢组学研究 转化者血清显示 293 种生化物质发生显着改变，其中 275 种生化物质有所增加。最后，我们 鉴定出 IL23R 的非编码 eQTL 与选择性 PsA 关联区域显着相关。 基于这些结果，我们假设 PsA 和 PsC 的发病机制是 T 细胞、 成骨细胞和破骨细胞驱动，并在向 PsA 转变期间从皮肤进展到全身。我们建议 该范式可用于开发一种有用的测试来预测 PsC 患者的 PsA，同时增加我们的基础知识 对 PSA 的了解。为了检验这一假设，我们提出四个目标：（1）维持和发展我们的纵向 临床资源； (2) 确定 PsC 患者发生 PsA 的生物标志物； (3) 整合 将目标 2 中确定的生物标志物转化为使用机器学习识别 PsA 的临床有用工具；和（4） 探讨 IL23R 基因促进 PsA 发病的机制。

项目成果

MicroRNA-155 Controls iNKT Cell Development and Lineage Differentiation by Coordinating Multiple Regulating Pathways.

• DOI: 10.3389/fcell.2020.619220
• 发表时间: 2020
• 期刊: Frontiers in cell and developmental biology
• 影响因子: 5.5
• 作者: Wang J;Li K;Zhang X;Li G;Liu T;Wu X;Brown SL;Zhou L;Mi QS
• 通讯作者: Mi QS

Dual Role of Act1 in Keratinocyte Differentiation and Host Defense: TRAF3IP2 Silencing Alters Keratinocyte Differentiation and Inhibits IL-17 Responses.

• DOI: 10.1016/j.jid.2016.12.032
• 发表时间: 2017-07
• 期刊: The Journal of investigative dermatology
• 作者: Lambert S;Swindell WR;Tsoi LC;Stoll SW;Elder JT
• 通讯作者: Elder JT

RNA-Seq Analysis of IL-1B and IL-36 Responses in Epidermal Keratinocytes Identifies a Shared MyD88-Dependent Gene Signature.

• DOI: 10.3389/fimmu.2018.00080
• 发表时间: 2018
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Swindell WR;Beamer MA;Sarkar MK;Loftus S;Fullmer J;Xing X;Ward NL;Tsoi LC;Kahlenberg MJ;Liang Y;Gudjonsson JE
• 通讯作者: Gudjonsson JE

Endogenous Glucocorticoid Deficiency in Psoriasis Promotes Inflammation and Abnormal Differentiation.

• DOI: 10.1016/j.jid.2017.02.972
• 发表时间: 2017-07
• 期刊: The Journal of investigative dermatology
• 作者: Sarkar MK;Kaplan N;Tsoi LC;Xing X;Liang Y;Swindell WR;Hoover P;Aravind M;Baida G;Clark M;Voorhees JJ;Nair RP;Elder JT;Budunova I;Getsios S;Gudjonsson JE
• 通讯作者: Gudjonsson JE

Proprotein convertase subtilisin/kexin type 9 is a psoriasis-susceptibility locus that is negatively related to IL36G.

普罗蛋白转化酶枯草蛋白/KEXIN 9型是牛皮癣敏感性基因座，与IL36G负相关。

• DOI: 10.1172/jci.insight.141193
• 发表时间: 2022-08-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Merleev, Alexander;Ji-Xu, Antonio;Toussi, Atrin;Tsoi, Lam C.;Le, Stephanie T.;Luxardi, Guillaume;Xing, Xianying;Wasikowski, Rachael;Liakos, William;Brueggen, Marie-Charlotte;Elder, James T.;Adamopoulos, Iannis E.;Izumiya, Yoshihiro;Leal, Annie R.;Li, Qinyuan;Kuzminykh, Nikolay Y.;Kirane, Amanda;Marusina, Alina, I;Gudjonsson, Johann E.;Maverakis, Emanual
• 通讯作者: Maverakis, Emanual