Germline and Somatic Genetic Changes in Pulmonary Arterial Hypertension

描述（申请人提供）：肺动脉高压（PAH）是一种严重的肺部疾病，以小肺动脉进行性狭窄和肺动脉压升高为特征，可导致右心衰。在大约75%的家族性多环芳烃病例和20-25%的散发性特发性病例中可发现BMPR2基因突变。然而，这些突变的外显率很低，导致多环芳烃病因的其他遗传或环境因素尚不清楚。有一些先前的证据表明，肺增生性病变与肿瘤类似，具有单克隆扩张和遗传不稳定性。将这种类比扩展到癌症，我们假设PAH肺组织中存在遗传或表观遗传突变，并通过异常的细胞增殖和信号传导促进PAH的发生或进展。本研究的目的是：(1)表征多环芳烃肺中体细胞遗传和表观遗传变化的作用；(2)研究基因组不稳定性的易感性机制；(3)验证基因内多态性通过影响肺组织中BMPR2的表达来改变PAH易感性的假设。总体目标是了解家族性多环芳烃外显率的降低，确定BMPR2在未检测到种系突变的多环芳烃病例中起多大作用，并开始研究其他（epi）遗传事件，这些遗传事件可能提供不同类型多环芳烃之间的共同致病联系。

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.