Germline and Somatic Genetic Changes in Pulmonary Arterial Hypertension

描述（由申请人提供）：肺动脉高压（PAH）是一种严重的肺部疾病，其特征为小肺动脉进行性狭窄和肺动脉压升高，可导致右心衰竭。在约75%的家族性PAH病例和20-25%的散发性特发性病例中可识别BMPR 2基因突变。然而，这些突变的发生率较低，导致PAH病因的其他遗传或环境因素尚未得到充分了解。有一些先前的证据表明，肺中的增殖性病变类似于瘤形成，具有单克隆扩增和遗传不稳定性。扩展这种与癌症的类比，我们假设遗传或表观遗传突变存在于PAH肺组织中，并通过异常细胞增殖和信号传导促进PAH的发展或进展。这项研究的目的是：（1）表征PAH肺中体细胞遗传和表观遗传变化的作用;（2）研究可能导致基因组不稳定性的机制;（3）检验基因内多态性通过影响肺中BMPR 2的表达来改变PAH易感性的假设。总体目标是了解家族性PAH的发病率降低，确定BMPR 2在PAH病例中发挥作用的程度（未检测到生殖系突变），并开始研究可能提供不同类型PAH之间常见致病联系的其他（epi）遗传事件。 公共卫生相关性：肺动脉高压是一种严重的、可能危及生命的肺部疾病，病因复杂。本研究旨在描述导致肺动脉高压发病机制的遗传和获得性遗传变化。长期目标是更好地了解导致肺动脉高压的原因以及风险最大的人，以便改进治疗干预措施并努力预防该疾病。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) is a serious lung disease characterized by progressive narrowing of the small pulmonary arteries and elevated pulmonary artery pressure, which can lead to right heart failure. Mutations of the BMPR2 gene are identifiable in about 75% of familial PAH cases and 20-25% of sporadic idiopathic cases. However, the penetrance of these mutations is low and the additional genetic or environmental factors that contribute to the etiology of PAH are not well understood. There is some prior evidence that proliferative lesions in the lung are akin to neoplasia, with monoclonal expansion and genetic instability. Extending this analogy with cancer, we hypothesize that genetic or epigenetic mutations are present in PAH lung tissues and contribute to the development or progression of PAH through abnormal cell proliferation and signaling. The aims of the study are: (1) to characterize the role of somatic genetic and epigenetic changes in PAH lungs; (2) to investigate the mechanisms that could predispose to genomic instability; and (3) to test the hypothesis that intragenic polymorphisms modify susceptibility to PAH by affecting expression of BMPR2 in the lung. The overall goals are to understand reduced penetrance in familial PAH, to determine to what extent BMPR2 plays a role in PAH cases with no detectable germline mutation and to begin investigating other (epi)genetic events that may offer common pathogenic links between different types of PAH. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension is a serious, potentially life-threatening lung disorder with a complex etiology. This study seeks to characterize inherited and acquired genetic changes that contribute to the pathogenesis of pulmonary hypertension. The long term aims are to better understand what causes pulmonary hypertension and who is most at risk, in order to refine therapeutic interventions and work towards prevention of the disease.