Genetics of Pulmonary Arterial Hypertension

Abstract

Tremendous progress has been made in understanding the genetics of pulmonary arterial hypertension (PAH) since its description in the 1950s as a primary disorder of the pulmonary vasculature. Heterozygous germline mutations in the gene coding bone morphogenetic receptor type 2 (BMPR2) are detectable in the majority of cases of heritable PAH, and in approximately 20% of cases of idiopathic pulmonary arterial hypertension (IPAH). However, recent advances in gene discovery methods have facilitated the discovery of additional genes with mutations among those with and without familial PAH. Heritable PAH is an autosomal dominant disease characterized by reduced penetrance, variable expressivity, and female predominance. Biallelic germline mutations in the gene EIF2AK4 are now associated with pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis. Growing genetic knowledge enhances our capacity to pursue and provide genetic counseling, although the issue remains complex given that the majority of carriers of PAH-related mutations will never be diagnosed with the disease.

Anaemia, iron homeostasis and pulmonary hypertension: a review

“…Second, heritable forms of PAH are associated with variants in the TGFbeta receptor family and have revealed an important role of bone morphogenetic protein receptor type 2 (BMPR2) mediated signalling in the pathophysiology of PH [42][43][44]. For instance, treatment with TGF-BRII-Fc, a selective TGF-beta1/3 ligand trap, mitigates pulmonary vascular remodelling and PH in monocrotalinetreated rats, SU5416/hypoxia-treated rats, and SU5416/ hypoxia-treated mice [45].…”

Expression of serum miR‑27b and miR‑451 in patients with congenital heart disease associated pulmonary artery hypertension and risk factor analysis

“…Pulmonary arterial hypertension (PAH) is a disease mainly characterized by pulmonary vascular remodeling and elevated pulmonary arterial pressure (PAP) ( 1 ). The abnormal cardiac structure in patients with congenital heart disease (CHD), a common cardiac disease in clinical practice, may cause aggravation of the cardiac load, resulting in elevated blood flow in the pulmonary circulation and increased pulmonary pressure, leading to the development of PAH ( 2 , 3 ).…”

Evolution in PH Care: 3 Decades of Milestones

“…Since then, at least 7 more genetic mutations associated with PAH have been identified. 11 Unfortunately, to date there are still no approved PAH therapies that have resulted from the BMPR-II discovery nor from other, more recent genetic discoveries. Nevertheless, the time may soon come when individually targeted PAH therapies based on a patient's specific genetic makeup become available.…”