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）是一种令人衰弱的疾病，通常无法治愈。众所周知，促使人们对pH发展和对治疗反应的反应的易感性的环境和遗传因素知之甚少。在特定的Demogroghic（即雄性）和临床（即硬皮病）同类中，该观察结果尤为正确，pH值更大的风险和严重程度。此外，对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，组织病理学实体和对治疗的反应而加剧，这些信息构成了当前世界pH患者的当前世界研讨会分类中的5个类别。在提供诊断和治疗框架的同时，当前的分类在临床实践中存在严重的局限性。需要以有限的预测能力的功能测量结果得出，需要进行更多的疾病特异性测量，以预测生存，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。我们的计划在所有5个组中具有pH值的拉丁美洲人（Latinos）的代表性过高（25％的拉丁美洲人具有高度的美国原住民混合物为1-PH）。基于我们在明确定义的pH亚组（CTEPH，与镰状细胞疾病相关）和复杂肺部疾病（Sycoidosis，IPF，肺移植）的患者中，我们建议采用最新的物理学，氏族和表观phlino phlino phlino phlino，我们建议我们在定义明确的pH亚组（CTEPH，与镰状细胞疾病相关）和患有复杂肺部疾病的患者（结节症，IPF，肺移植）中，基于我们异常强烈的亚表型研究。 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来可靠地测量心室 - 血管耦合（VVC）（VVC），肺血管渗透和心populopulmonory锻炼与物理学上的现象性现象型Latino和非电视pH患者以及各个组的pH患者。 SA＃2将在所有5个pH pH类别的所有5个pH类别中生成周围血液单核细胞（PBMC）的全基因组，遗传/表观遗传学分子特征（PBMC）。这些研究将包括基因组表达，miRNA阵列和DNA甲基化阵列。 SA＃3将扩展利用全基因组关联研究（GWAS）的先前研究（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）的患者，并使用全基因组测序识别新单核苷酸多酶（SNPS），并识别出lat-per per per-per-repersensentsentsentersensentsentsentersensentersens per。我们将进一步研究SA＃1-3与临床上重要的复合变量的关系，即临床恶化的时间（TTCW）。共同，大型的UA池库，大量的pH转介基础，全面的UA生物银行计划以及这些表型工具的先前经验，都可以提高我们新型的子表型策略的可行性，该策略专注于Latinos，ph。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）a）在pH发展的高风险中识别基团，b）个性化pH疗法（组合疗法，移植或手术转诊），以及c）为新型的pH分类范式提供了理由。