Genetic studies in patients with PAH
Insight into the genetic basis of PAH was first provided through studies of families and identified mutations in BMPR2 , bone morphogenetic protein type 2 (Deng et al., 2000; International et al., 2000). More recent studies of carefully curated cohorts of patients with idiopathic PAH have confirmed that BMPR2 is the most commonly affected gene associated with PAH but identified rare variants in a number of other genes that appear to be pathogenic (Southgate, Machado, Graf & Morrell, 2020; Zhu et al., 2019). Several converge on the TGF-B signalling pathway but other novel pathways are also implicated, including deleterious changes in genes encoding potassium channels (KCNK3and ABCC8 ) and transcription factors (TBX4 andSOX17 ) (Southgate, Machado, Graf & Morrell, 2020). These genetic insights are informing drug development, and studies to evaluate restoring BMPR2 signalling or the imbalance in BMP-TGF-b signalling are in progress.
Aside from Chuvash polycythaemia, where arguably the main impact is on haematocrit, the rare variants identified in PAH families and cohorts do not affect genes that have emerged from genetic studies in high-altitude subjects and animals. This might reflect the different underlying pathology; remodelling is severe in PAH than HAPH. It might reflect the heterogeneity of clinical pulmonary hypertension; that it is the end stage of a number of pathological processes that converge on this phenotype. Nonetheless, comparison of the genetically driven pathways that emerge from studies in PAH and high-altitude subjects remains a potentially fruitful strategy, as one may inform the other, as work to exploit pharmacologically the HIF signalling pathway exemplifies.