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: 8795928
• 负责人: Franz P Rischard
• 金额: $ 22.89万
• 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/8795928
• 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; Genes; Genetic; Genomics; Graft Rejection; Hamman-Rich syndrome; Heart Diseases; Hispanics; Hypoxemia; Incidence; Latino; Left; Lung; 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; genome sequencing; genome wide association study; genome-wide; high risk; improved; male; mortality; novel; outcome forecast; phenomics; pressure; programs; pulmonary arterial hypertension; response; symposium; tool; translational approach; translational study; treatment center; vasoconstriction

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）是一种使人衰弱且通常致命的疾病，目前尚无治愈方法。环境和遗传因素，驱动易感性的PH的发展和对治疗的反应知之甚少。这一观察在特定的人口统计学中尤其如此。（即男性）和临床此外，关于种族对疾病严重程度的影响知之甚少。这些信息差距因临床特征的复杂分类而加剧，组织病理学实体和对治疗的反应构成了PH患者当前世界研讨会分类中的5个类别。虽然为诊断和治疗提供了一个框架，但目前的分类在临床实践中存在严重的局限性。部分来源于预测能力有限的功能测量，需要更多的疾病特异性测量来预测生存率，生活质量，进展和对治疗的反应。亚利桑那大学（UA）医学中心是治疗PH患者的主要区域转诊中心，包括大量拉丁裔PH患者。我们的计划有一个在所有5个组与PH的拉丁美洲人的过度代表性（25%的拉丁美洲人与组1-PH的高美洲原住民混合）。基于我们在明确定义的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）患者中发表的非常强的亚表型研究，我们建议采用最先进的生理学，基因组学和表观遗传学策略，在5个PH类别中对拉丁裔和非拉丁裔PH患者进行亚表型。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，以可靠地测量心室-血管耦合（VVC）和肺血管阻抗以及心肺运动试验，以在所有第1-5组PH表型中对拉丁裔和非拉丁裔PH患者进行生理表型检测。SA #2将在外周血单核细胞（PBMC）中生成全基因组、遗传/表观遗传分子特征，用于所有5种WHO PH类别的亚表型PH患者。这些研究将包括全基因组的基因表达、微RNA阵列和DNA甲基化阵列。SA #3将在特发性肺动脉高压（IPAH）和慢性血栓栓塞性肺动脉高压（CTEPH）患者中扩展利用全基因组关联研究（GWAS）的先前研究，并利用全基因组测序来鉴定在拉丁美洲人中过度代表的新型单核苷酸多态性（SNP）与类别特异性PH的关系。临床重要复合变量，至临床恶化时间（TTCW）。总之，各种PH患者的大型UA池，大型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，这些高度转化的研究将在这种毁灭性的肺血管疾病中产生新的类别特异性生物标志物，并有望a）识别高-PH发展风险，B）个性化PH治疗（联合治疗、移植或手术转诊），以及c）提供新PH分类范例的基本原理。