Plasma Proteomic and Metabolomic Predictors of Vascular Disease in Treated HIV

HIV治疗者血管疾病的血浆蛋白质组学和代谢组学预测因子

• 批准号: 10331583
• 负责人: PETER W HUNT
• 金额: $ 78.89万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10331583
• 关键词: Address; Age; Basic Science; Bioinformatics; Biological; Biological Assay; Biological Markers; Blood; Blood Vessels; Blood coagulation; Carnitine; Catabolism; Clinical; Clinical Trials; Cohort Studies; Consensus; Cytomegalovirus; Data; Disease; Disease Outcome; Educational workshop; Enzyme-Linked Immunosorbent Assay; Epidemiology; Etiology; Event; Gender; General Population; Goals; Gonadal Steroid Hormones; HIV; HIV Infections; Health behavior; Heart failure; Immunoglobulin G; Immunologics; Immunology; Incidence; Inflammation; Inflammatory; Intervention; Intervention Trial; Ischemic Stroke; Kynurenine; Link; Malignant Neoplasms; Mediating; Menopausal Status; Metabolic Pathway; Morbidity - disease rate; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathogenesis; Pathway interactions; Pattern; Phenotype; Plasma; Postmenopause; Proteins; Proteome; Proteomics; Recurrence; Research Personnel; Resources; Risk; Sampling; Smoking; Stroke; Surrogate Markers; System; Systems Biology; Time; Tryptophan; United States National Institutes of Health; Validation; Vascular Diseases; Veins; Viral; Woman; adjudicate; advanced disease; antiretroviral therapy; cis-male; cohort; comorbidity; demographics; design; experience; high risk; hormone therapy; immune activation; immunoregulation; inflammatory marker; injection drug use; interest; men; metabolome; metabolomics; microbial; mortality; multidisciplinary; multiple chronic conditions; new therapeutic target; novel; predictive marker; protein metabolite; sex; systemic inflammatory response; transgender women; trend; venous thromboembolism

PROJECT SUMMARY/ABSTRACT People with HIV (PWH) remain at higher risk for Type 1 myocardial infarction (T1MI), ischemic stroke, and venous thromboembolism (VTE) than the general population despite antiretroviral therapy (ART)-mediated viral suppression. Systemic inflammation persists in many PWH despite ART and predicts each of these vascular events, but the optimal interventional targets remain unclear. To begin to address these issues, we performed an initial case-cohort study of nearly 1,200 PWH within the CFAR Network of Integrated Clinical Systems (CNICS) who were maintaining at least 1 year of ART-mediated viral suppression and identified several plasma inflammatory markers – including surrogate markers of microbial translocation, CMV, and the kynurenine pathway of tryptophan catabolism - that predicted increased risk of subsequent vascular events. We also observed that women (particularly at post-menopausal ages) had higher levels of most inflammatory markers than men, and trends suggesting that sex may modify the association between inflammation and vascular events. This proposal will build upon these findings by nearly doubling the adjudicated vascular event cases in our study (n=135 T1MI, n=74 ischemic strokes, and n=135 VTE). We will also assess the plasma proteomic and metabolomic pathways most strongly predictive of each event type and explore the associations between sex and plasma sex hormone levels and the pathways that predict vascular disease. Aim 1 will assess the plasma proteomic pathways that most strongly predict T1MI, ischemic stroke, and VTE using the most comprehensive plasma proteomic platform (SomaScan, targeting 7,000 proteins), and validating the top hits with commercial ELISAs and by cross-validation in the VACS BC cohort. Aim 2 will assess the plasma metabolomic predictors of these vascular events using an untargeted metabolomic approach, confirming top hits with quantitative assays, and quantitative assessments of metabolites previously linked to vascular disease (e.g., kynurenine and carnitine metabolic pathways). For both Aims 1 and 2, we will assess whether the top immunologic hits that predict vascular disease outcomes are also increased in treated HIV compared to HIV-uninfected controls matched for demographics and health-related behaviors in the SCOPE cohort. Aim 3 will assess the degree to which sex and plasma sex hormone levels are associated with the immunologic pathways that predict vascular disease and whether these pathways vary by menopausal status and between transgender women on gender-affirming hormonal therapy and cis-men. Lastly, we will explore whether sex modifies the relationship between inflammatory pathways and vascular disease. These studies leverage a multidisciplinary team with expertise in translational immunology, HIV pathogenesis, vascular disease, metabolomics, epidemiology, and bioinformatics and will create a resource that can be leveraged by others to assess predictors of other disease outcomes and/or add additional analytes. Collectively, these studies will accelerate the identification of novel interventional targets to reduce multi-morbidity in treated HIV infection.

项目摘要/摘要 艾滋病毒（PWH）的患者仍然面临1型心肌梗塞（T1MI），缺血性中风和 静脉血栓栓塞（VTE）比一般人口目的地抗逆转录病毒疗法（ART）介导的 病毒抑制。在许多PWH目的地艺术和预测中，系统性炎症持续存在 血管事件，但最佳的介入目标尚不清楚。为了开始解决这些问题，我们 在集成临床的CFAR网络中对近1200 PWH进行了初步的病例研究 维持至少1年艺术介导的病毒抑制并确定的系统（CNIC） 几种血浆炎症标记 - 包括微生物易位的替代标记，CMV和 色氨酸分解代谢的Kynurenine途径 - 预测随后的血管事件的风险增加。 我们还观察到妇女（部分在绝经后年龄）的炎症水平较高 标记比男性，趋势表明性别可能会改变炎症与 血管事件。该提案将通过几乎加倍调整后的血管事件来建立这些发现的基础 在我们的研究中，病例（n = 135 t1mi，n = 74缺血性中风，n = 135 VTE）。我们还将评估血浆 蛋白质组学和代谢组途径最有力地预测每种事件类型，并探索关联 性别激素水平和预测血管疾病的途径之间。目标1意志 使用最强烈预测T1MI，缺血性中风和VTE的血浆蛋白质组学途径 最全面的等离子体蛋白质组学平台（Somascan，目标7,000蛋白），并验证顶部 与商业ELISA和VACS BC队列中的交叉验证进行命中。 AIM 2将评估血浆 使用非靶向代谢组方法对这些血管事件的代谢组预测指标，确认顶部 通过定量评估进行命中，以及对先前与血管相关的代谢物的定量评估 疾病（例如，kynurenine和Carnitine代谢途径）。对于两个目标1和2，我们将评估是否 与治疗的HIV相比，预测血管疾病结局的最高免疫学家也会增加 HIV未感染的控件匹配范围队列中人口统计学和与健康相关的行为。目标3 将评估性别和血浆性激素水平与免疫学相关的程度 预测血管疾病的途径以及这些途径是否因更年期状态而有所不同 跨性别妇女进行性别良好的荷尔蒙治疗和顺式妇女。最后，我们将探讨性是否 修改炎症途径与血管疾病之间的关系。这些研究利用 多学科团队具有转化免疫学，HIV发病机理，血管疾病， 代谢组学，流行病学和生物信息学，将创建一种可以利用他人来利用的资源 评估其他疾病结果的预测因素和/或添加其他分析物。这些研究总的来说 加速鉴定新的介入靶标，以降低治疗的HIV感染中的多物种。