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，其特征是小肺动脉进行性狭窄和肺动脉压力升高，可导致右心衰竭。BMPR2基因突变在大约75%的家族性PAH病例和20%-25%的散发性特发性病例中可被识别。然而，这些突变的外显率很低，而且导致PAH病因的其他遗传或环境因素还没有很好地了解。先前有一些证据表明，肺内的增生性病变类似于肿瘤，具有单克隆性扩张和遗传不稳定性。将这种类比延伸到癌症，我们假设PAH肺组织中存在基因或表观遗传突变，并通过异常细胞增殖和信号转导促进PAH的发展或进展。本研究的目的是：(1)研究体细胞遗传和表观遗传改变在PAH肺中的作用；(2)研究可能导致基因组不稳定的机制；(3)验证基因内多态通过影响肺中BMPR2的表达来改变PAH易感性的假设。总体目标是了解家族性PAH外显性降低，确定BMPR2在没有可检测到胚系突变的PAH病例中的作用程度，并开始研究可能在不同类型PAH之间提供共同致病联系的其他(Epi)遗传事件。 公共卫生相关性：肺动脉高压是一种严重的、潜在威胁生命的肺部疾病，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性和获得性遗传改变。长期目标是更好地了解是什么导致了肺动脉高压，以及谁面临的风险最大，以便完善治疗干预措施，并努力预防这种疾病。

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.