The genomic complexity underlying pulmonary arterial hypertension: from mendel to networks.

Pulmonary arterial hypertension (PAH) is a life-threatening condition characterized by remodeling of pulmonary muscular arterioles and pulmonary vascular obstruction and vasoconstriction, leading to increased pulmonary vascular resistance (PVR), a mean pulmonary artery pressure of at least 25 mm Hg at rest, and right heart failure. PAH in the absence of an obvious cause is classified as heritable (HPAH) in the 6% of cases with a positive family history and in an additional 10–40% of cases previously classified as idiopathic PAH who are found to have an underlying genetic mutation despite a negative family history. Mutations have been found most commonly in bone morphogenetic protein receptor 2 (BMPR2), a member of the transforming growth factor β (TGFβ) superfamily of receptors; less commonly in genes encoding other members of the TGFβ signaling pathway, such as ALK-1, ENG, SMAD4, SMAD8, and CAV1; and rarely in KCNK3, which encodes a member of the two-pore domain potassium channels expressed in pulmonary artery smooth muscle cells (1). However, there is considerable phenotype heterogeneity, including incomplete penetrance, so that only a fraction of individuals with the same mutation develop PAH. This phenotype heterogeneity is likely related to environmental factors and to variants in other genes (“modifiers”) that attenuate or exacerbate the pathophysiology of PAH. It has been proposed that the development of PAH requires multiple hits (2, 3). Genetic modifiers have proved challenging to investigate. In the May 1 issue of the Journal, Stearman and colleagues (4) report an elegant study that identifies functionally relevant noncoding variants in prostacyclin synthase (PGIS).