Germline and Somatic Genetic Changes in Pulmonary Arterial Hypertension

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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.