Phenomic and genomic study to subphenotype Hispanics with pulmonary hypertension

项目概述/摘要肺动脉高压（Pulmonary hypertension， PH）是一种使人衰弱且常常致命的疾病，目前尚无治愈方法。驱动PH易感性发展和对治疗反应的环境和遗传因素尚不清楚。在特定的人口统计学（如男性）和临床（如硬皮病）人群中，这一观察结果尤其正确，这些人群经历了更高的PH风险和严重程度。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、组织病理学实体和对治疗的反应的复杂分类而加剧，这些分类构成了当前世界研讨会PH患者分类中的5类。目前的分类虽然为诊断和治疗提供了框架，但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、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。我们的项目在所有5个组中都有拉丁裔PH过高的代表（25%的拉丁裔与1-PH组的高印第安人混合）。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）患者中发表的非常强大的亚表型研究，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对5种PH类别的拉丁裔和非拉丁裔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、超声心动图和导管检查，可靠地测量心室-血管耦合（VVC）和肺血管阻抗，以及心肺运动测试，对所有1-5组PH表型的拉丁裔和非拉丁裔PH患者进行生理表型。sa# 2将在外周血单个核细胞（PBMCs）中生成全基因组遗传/表观遗传分子特征，以对所有5种WHO PH类别的PH患者进行亚表型分析。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）患者的全基因组关联研究（GWAS）的基础上扩展先前的研究，并利用全基因组测序来鉴定新的单核苷酸多态性（snp），这些多态性在特定类型ph的拉丁美洲人中过度代表。我们将进一步研究SA #1-3与临床重要复合变量的关系。到临床恶化时间（TTCW）。总之，大量不同PH患者的UA库，大量的PH转诊基础，全面的UA BioBank倡议，以及先前使用这些表型工具的经验，都有助于增加我们专注于拉丁裔PH患者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，并有望确定PH发展的高风险群体；b)个性化PH治疗（联合治疗，移植或外科转诊），以及c)为新的PH分类范式提供基本原理。

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.