What can we learn from pathophysiology and therapeutic targetable pathways from all genetic causes and associations in PH?

Abstract

Pulmonary hypertension (PH) encompasses a group of conditions which ultimately lead to elevated pulmonary arterial pressure. PH is classified into five subgroups, of which Group 1 pulmonary arterial hypertension (PAH), is the most extensively studied. Numerous causal genes have been identified in PAH, most notably germline mutations in bone morphogenetic protein receptor type 2 (BMPR2) and the wider BMP pathway. Often when considering the genetics of PH, sporadic idiopathic and heritable PAH dominates the discussion. There are a number of reviews that elegantly describe the ‘state of the art’ in respect to group 1 PAH, however this focus misses the wider context of genetic conditions where PH is a feature, but outside of the framework of classical ‘idiopathic or heritable’ PAH. In addition to variants in genes within the TGF-β/BMP signaling pathway, genes which regulate ion channels, the extracellular matrix, inflammation, angiogenesis, and mitochondrial dysfunction have been shown to play a significant role in PH pathogenesis across different PH groups. In this review, we aim to cast the net wider to understand what we can learn from the spectrum of genetic conditions where PH is an acknowledged feature or complication, and what this tells us about the important cellular, molecular and systems physiology features that predispose to PH and consequently might be treatment targets.

Keywords

• Genetics
• PH