Phenomic and genomic study to subphenotype Hispanics with pulmonary hypertension

描述(由申请人提供)：项目摘要/摘要肺动脉高压(PH)是一种使人虚弱且通常是致命的疾病，目前还没有治愈的方法。环境和遗传因素使人对PH的易感性和对治疗的反应知之甚少。这一观察结果在特定人群(即男性)和临床(即硬皮病)队列中尤其如此，这些人群被认为经历了更大的PH风险和严重程度。此外，关于种族对疾病严重性的影响知之甚少，这些信息差距因错综复杂的临床特征、组织病理学实体和治疗反应的分类而加剧，这些分类构成了当前世界研讨会对PH患者的5类分类。虽然目前的分类为诊断和治疗提供了一个框架，但在临床实践中存在严重的局限性。部分源于预测能力有限的功能测量，需要更多针对疾病的测量来预测生存、生活质量、进展和对治疗的反应。亚利桑那大学(UA)医学中心是一个主要的地区性转诊中心，用于治疗PH患者，包括大量的拉丁裔PH患者。我们的计划在所有5个群体中都有过多的拉丁裔和PH(25%的拉丁裔和高美洲原住民混杂在1-PH组)。基于我们在明确的PH亚组(CTEPH、与镰状细胞疾病相关的PH)和复杂肺部疾病(结节病、IPF、肺移植)患者中发表的特别强大的亚表型研究，我们建议使用最先进的生理学、基因组和表观遗传学策略来对5个PH类别的拉丁裔和非拉丁裔PH患者进行亚型分型。SA#1将利用我们先进的诊断临床算法，结合心脏MRI、超声心动图和导管术，可靠地测量生理表型拉丁裔和非拉丁裔PH患者所有组1-5 PH表型的室血管耦合(VVC)和肺血管阻抗和心肺运动试验。SA#2将在所有5个世卫组织PH类别的亚表型PH患者的外周血单个核细胞(PBMC)中生成全基因组、遗传/表观遗传学分子签名。这些研究将包括全基因组的基因表达、miRNA阵列和DNA甲基化阵列。SA#3将扩展先前在特发性肺动脉高压(IPAH)和慢性血栓栓塞性肺动脉高压(CTEPH)患者中利用全基因组关联研究(GWAS)的研究，并利用全基因组测序来识别在类别特定的PH的拉丁裔人中过度出现的新的单核苷酸多态(SNPs)。我们将进一步研究SA#1-3与临床重要的复合变量--临床恶化时间(TTCW)的关系。总而言之，庞大的不同PH患者的UA池，庞大的PH转诊基数，全面的UA Biobank倡议，以及这些表型工具的先前经验，都有助于增加我们以患有PH的拉丁裔人为重点的新型亚表型策略的可行性。这些高度翻译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记物，并有望a)识别PH发展的高风险组，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分类范例提供理论基础。

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.