Rheumatoid Arthritis and the Risk of Cardiovascular Disease: Biomarkers Risk Prediction and Underlying Mechanisms

类风湿关节炎和心血管疾病的风险：生物标志物风险预测和潜在机制

• 批准号: 10643971
• 负责人: Daniel Hal Solomon
• 金额: $ 74.63万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10643971
• 关键词: Aftercare; Atherosclerosis; Basic Science; Biological Markers; Blood Coagulation Factor; Blood Vessels; Calibration; Cardiovascular Diseases; Cells; Cellular Immunology; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Characteristics; Clinical; Clinical Sciences; Cohort Studies; Complement; Cross-Sectional Studies; Data; Data Set; Discrimination; Disease; Epidemiology; Equation; Event; Funding; Gene Expression; General Population; Goals; Image; Immune; Individual; Inflammation; Inflammatory; Ligands; Link; Lipids; Literature; Longevity; Measurable; Measures; Methods; Modeling; Morbidity - disease rate; Myocardial Infarction; National Institute of Arthritis, and Musculoskeletal, and Skin Diseases; Outcome; PET/CT scan; Pathway interactions; Patient Care; Patients; Performance; Peripheral Blood Mononuclear Cell; Phenotype; Population; Proteins; Proteomics; Randomized, Controlled Trials; Reporting; Research Personnel; Rheumatoid Arthritis; Risk; Running; Sampling; Source; Stroke; Structure; Surface; Testing; Translating; United States National Institutes of Health; Visit; arthritis registry; biobank; biomarker discovery; biomarker panel; biomarker selection; biomarker validation; cardiovascular disorder risk; cell type; cohort; cytokine; experience; fluorodeoxyglucose positron emission tomography; high dimensionality; improved; insight; longitudinal analysis; patient subsets; programs; prospective; protein biomarkers; randomized, clinical trials; receptor; responders and non-responders; risk prediction; risk stratification; single-cell RNA sequencing; tool; transcriptomics; treatment arm; uptake; vascular inflammation

PROJECT ABSTRACT Inflammation contributes substantially to atherosclerotic cardiovascular disease (CVD) in the general population. Epidemiology, basic science and randomized clinical trial data support the importance of this relationship. Patients with systemic inflammatory conditions, such as rheumatoid arthritis (RA), can provide important insights into this relationship because of their more extreme systemic inflammatory phenotype. Investigators have appreciated the elevated risk of CVD experienced by RA patients: the risk of MI and stroke are both elevated in RA compared with the general population, contributing to a shortened lifespan. CVD risk stratification in RA is imprecise and general population tools are not accurate. Most attempts at improving CVD risk stratification have added clinical RA factors to existing population risk tools. Easily assessed protein biomarkers would likely enhance CVD risk prediction. The literature strongly suggests relationships between > 20 biomarkers shared by RA and CVD. These relationships have never been studied systematically across diseases. The overarching goal of this proposal is to identify protein biomarkers for CVD in RA patients, leveraging the structure of a controlled trial and rigorous methods for deriving and validating a risk score. We complement the robust biomarker analyses with high-dimensional cellular immuneprofiling, which has the potential to link specific cell types mechanistically to protein biomarkers and to identify new cellular biomarkers. We conducted a randomized controlled trial, the TARGET trial, to examine whether specific treatments for RA produce reductions in CV risk as measured by FDG PET/CT. This trial, funded by NIH (U01 AR068043) allowed us to prospectively characterize RA patients, collect biospecimens before and after treatment, and conduct baseline and 24-week FDG PET/CT scans to assess vascular inflammation. Analyses are still ongoing to determine whether different RA treatments translate into differential changes in CV risk. We propose to leverage the TARGET study cohort, dataset and biorepository for the following aims. Aim 1: To use a comprehensive biomarker panel to derive and validate a CV risk score for patients with RA. The TARGET trial provides biospecimens, patient phenotypes, and a broad biomarker discovery panel that will have been run as an in-kind donation. We hypothesize that adding biomarkers to the Pooled Cohort Equation and variables related to RA disease activity will significantly improve prediction of CV outcomes in RA patients. Aim 2: To elucidate cellular immune mechanisms linking RA and CVD through scRNA-seq profiling. We will use single cell transcriptomic and surface proteomics (CITE-seq) to study PBMCs from a subset of TARGET patients, including both responders and non-responders based on FDG PET/CT, to identify circulating immune cell populations associated with CV risk and CV biomarkers. We hypothesize that specific immune cell populations will associate with CV risk at baseline and will decrease in abundance or activation state after treatment in parallel with CV risk. Further, these treatments will differ in their effects on relevant cell populations.

项目摘要 一般来说，炎症在很大程度上导致动脉粥样硬化性心血管疾病（CVD） 人口。流行病学、基础科学和随机临床试验数据支持了这一点的重要性 关系。患有系统性炎症（例如类风湿性关节炎 (RA)）的患者可以提供 由于它们具有更极端的全身炎症表型，因此对这种关系有重要的见解。 研究人员已经认识到 RA 患者罹患 CVD 的风险较高：心肌梗死和中风的风险 与一般人群相比，RA 中的这两项指标均升高，从而导致寿命缩短。心血管疾病风险 RA 的分层不精确，一般人群工具也不准确。大多数改善CVD的尝试 风险分层将临床 RA 因素添加到现有的人群风险工具中。易于评估的蛋白质 生物标志物可能会增强 CVD 风险预测。文献强烈表明>之间的关系 RA 和 CVD 共有 20 个生物标志物。这些关系从未被系统地研究过 疾病。该提案的总体目标是确定 RA 患者 CVD 的蛋白质生物标志物， 利用对照试验的结构和严格的方法来推导和验证风险评分。我们 通过高维细胞免疫分析补充稳健的生物标志物分析，该分析具有 将特定细胞类型与蛋白质生物标志物机械地联系起来并识别新的细胞生物标志物的潜力。 我们进行了一项随机对照试验，即 TARGET 试验，以检验特定治疗是否有效 通过 FDG PET/CT 测量，治疗 RA 可降低心血管风险。该试验由 NIH (U01 AR068043) 资助 使我们能够前瞻性地描述 RA 患者的特征，在治疗前后收集生物样本，以及 进行基线和 24 周 FDG PET/CT 扫描以评估血管炎症。分析仍在进行中 以确定不同的 RA 治疗是否会导致 CV 风险的差异变化。我们建议 利用 TARGET 研究队列、数据集和生物样本库来实现以下目标。目标 1：使用 综合生物标志物组，用于得出并验证 RA 患者的 CV 风险评分。 TARGET 试验 提供生物样本、患者表型和广泛的生物标志物发现小组，该小组将作为 实物捐赠。我们假设将生物标志物添加到合并队列方程和变量中 与 RA 疾病活动相关的研究将显着改善 RA 患者心血管结局的预测。目标 2： 通过 scRNA-seq 分析阐明关联 RA 和 CVD 的细胞免疫机制。我们将使用单 细胞转录组学和表面蛋白质组学 (CITE-seq) 用于研究 TARGET 患者子集的 PBMC， 包括基于 FDG PET/CT 的应答者和无应答者，以识别循环免疫细胞 与心血管风险和心血管生物标志物相关的人群。我们假设特定的免疫细胞群 与基线时的心血管风险相关，并且在治疗后丰度或激活状态会降低 与心血管风险平行。此外，这些治疗对相关细胞群的影响也有所不同。