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.