Phenomic and genomic study to subphenotype Hispanics with pulmonary hypertension

西班牙裔肺动脉高压亚表型的表型和基因组研究

• 批准号: 9119052
• 负责人: Franz P Rischard
• 金额: $ 30.7万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9119052
• 关键词: Admixture; African American; Algorithms; Arizona; Arts; Biological Markers; Blood Vessels; Cardiac; Cardiopulmonary; Categories; Catheterization; Cessation of life; Characteristics; Chronic; Classification; Clinical; Clinical assessments; Combined Modality Therapy; Complex; Coupling; DNA Methylation; Deterioration; Development; Diagnosis; Diagnostic; Disease; Echocardiography; Epigenetic Process; Ethnic Origin; Evaluation; Exercise; Failure; Gene Expression; Generations; Genetic; Genomics; Graft Rejection; Hamman-Rich syndrome; Heart Diseases; Hispanics; Hypoxemia; Incidence; Latino; Left; Lung; Lung Transplantation; Lung diseases; Magnetic Resonance Imaging; Measurement; Measures; Medical center; MicroRNAs; Molecular Profiling; Morbidity - disease rate; Native Americans; Operative Surgical Procedures; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Physiological; Population; Predisposition; Process; Publishing; Pulmonary Hypertension; Pulmonary Vascular Resistance; Quality of life; Risk; Sarcoidosis; Scleroderma; Severities; Severity of illness; Sickle Cell Anemia; Single Nucleotide Polymorphism; Subgroup; Time; Transplantation; Universities; Vascular Diseases; Vascular remodeling; Ventricular; Workload; abstracting; base; biobank; clinical phenotype; clinical practice; cohort; electric impedance; experience; genetic signature; genome sequencing; genome wide association study; genome-wide; genomic signature; high risk; improved; male; mortality; novel; outcome forecast; phenomics; pressure; primary pulmonary hypertension; programs; pulmonary arterial hypertension; response; specific biomarkers; survival prediction; symposium; tool; translational approach; translational study; treatment center; vasoconstriction; whole genome

DESCRIPTION (provided by applicant): Project Summary/Abstract Pulmonary hypertension (PH) is a debilitating and often fatal disease for which there is currently no cure. The environmental and genetic factors that drive susceptibility to the development of PH and responses to therapy are poorly understood. This observation is particularly true in specific demograghic (i.e. male) and clinical (i.e. scleroderma) cohorts noted to experience greater risk and severity of PH. Additionally, little is known about the impact of ethnicity on disease severity These information gaps are exacerbated by the perplexing assortment of clinical characteristics, histopathological entities and responses to therapy that constitute the 5 categories within the current World Symposium classification of PH patients. While providing a framework for the diagnosis and treatment, the current classification has serious limitations in clinical practice. Derived in part from functional measurements with limited predictive ability, more disease-specific measurements are needed that predict survival, quality of life, progression and response to therapy. The University of Arizona (UA) Medical Center is a major regional referral center for treatment of patients with PH, including a large population of Latino PH patients. Our program has an over-representation of Latinos with PH across all 5 Groups (25% Latinos with high Native American admixture with Group 1-PH). Based on our exceptionally strong published sub-phenotyping studies in well-defined PH subgroups (CTEPH, PH-associated with sickle cell disease) and patients with complex lung disorders (sarcoidosis, IPF, lung transplant), we propose to employ the state-of-the-art physiologic, genomic and epigenetic strategies to sub-phenotype Latino and non-Latino PH patients across the 5 PH categories. SA #1 will leverage our advanced diagnostics clinical algorithm, incorporating cardiac MRI, echocardiography, and catheterization to reliably measure ventriculo- vascular coupling (VVC) and pulmonary vascular impedance and cardiopulmonary exercise tesing to physiologically phenotype Latino and non-Latino PH patients across all Group 1-5 PH phenotypes. SA #2 will generate genome-wide, genetic/epigenetic molecular signatures in peripheral blood mononuclear cells (PBMCs) to sub-phenotype PH patients across all 5 WHO PH categories. These studies will include genome- wide gene expression, miRNA arrays, and DNA methylation arrays. SA #3 will extend out prior studies utilizing genome-wide association studies (GWAS) in patients with idiopathic pulmonary arterial hypertension (IPAH) and chronic thromboembolic pulmonary hypertension (CTEPH) and utilize whole-genome sequencing to identify novel single nucleotide polymorphisms (SNPs) that are over-represented in Latinos with category- specific PH. We will further examine the relationship of SA #1-3 to the clinically important composite variable, time to clinical worsening (TTCW). Together, the large UA pool of diverse PH patients, large PH referral base, comprehensive UA BioBank initiative, and prior experience with these phenotyping tools, all serve to increase the feasibility of our novel sub-phenotyping strategy focusing on Latinos with PH. These highly translational studies will generate novel category-specific biomarkers in this devastating pulmonary vascular disease and hold promise for a) identifying groups at high-risk for development of PH, b) personalizing PH therapies (combination therapy, transplant or surgical referral), and c) providing the rationale for novel PH classification paradigms.

描述（由申请人提供）： 项目摘要/摘要 肺动脉高压（PH）是一种使人衰弱且常常致命的疾病，目前尚无治愈方法。人们对导致 PH 发展易感性和治疗反应的环境和遗传因素知之甚少。这一观察结果在特定人口群体（即男性）和临床群体（即硬皮病）中尤其如此，这些群体注意到 PH 的风险和严重程度更高。此外，人们对种族对疾病严重程度的影响知之甚少。临床特征、组织病理学实体和对治疗的反应构成了当前世界PH患者研讨会分类中的5个类别，这些令人困惑的分类加剧了这些信息差距。目前的分类在为诊断和治疗提供框架的同时，在临床实践中存在严重的局限性。部分源自预测能力有限的功能测量，需要更多针对疾病的特异性测量来预测生存、生活质量、进展和治疗反应。亚利桑那大学 (UA) 医疗中心是治疗 PH 患者的主要区域转诊中心，其中包括大量拉丁裔 PH 患者。我们的计划在所有 5 个组中具有 PH 的拉丁裔人数过多（25% 的拉丁裔与 1-PH 组有大量美洲原住民混合）。基于我们在明确的 PH 亚组（CTEPH、与镰状细胞病相关的 PH）和复杂肺部疾病（结节病、IPF、肺移植）患者中发表的非常有力的亚表型研究，我们建议采用最先进的生理学、基因组和表观遗传学策略对 5 个 PH 类别中的拉丁裔和非拉丁裔 PH 患者进行亚表型分析。 SA #1 将利用我们先进的诊断临床算法，结合心脏 MRI、超声心动图和导管插入术，对所有 1-5 组 PH 表型的拉丁裔和非拉丁裔 PH 患者的生理表型进行可靠测量心室血管耦合 (VVC) 和肺血管阻抗以及心肺运动测试。 SA #2 将在外周血单核细胞 (PBMC) 中为所有 5 个 WHO PH 类别的亚表型 PH 患者生成全基因组遗传/表观遗传分子特征。这些研究将包括全基因组基因表达、miRNA 阵列和 DNA 甲基化阵列。 SA #3 将利用全基因组关联研究 (GWAS) 对特发性肺动脉高压 (IPAH) 和慢性血栓栓塞性肺动脉高压 (CTEPH) 患者进行先前的研究，并利用全基因组测序来识别新的单核苷酸多态性 (SNP)，这些单核苷酸多态性 (SNP) 在具有特定类别 PH 的拉丁裔中过多。我们将进一步检查 SA #1-3 与临床重要的复合变量、临床恶化时间 (TTCW) 的关系。总之，由不同 PH 患者组成的大型 UA 库、庞大的 PH 转诊基础、全面的 UA BioBank 计划以及这些表型分析工具的先前经验，所有这些都有助于提高我们专注于患有 PH 的拉丁裔的新型亚表型策略的可行性。这些高度转化的研究将在这种破坏性肺血管疾病中产生新的类别特异性生物标志物，并有望a)识别肺动脉高压高危人群，b)个性化肺动脉高压治疗（联合治疗、移植或手术转诊），以及c)为新的肺动脉高压分类范例提供理论基础。