Genetics and the Molecular Pathogenesis of Pulmonary Arterial Hypertension

Mutations in the bone morphogenetic protein type II receptor (BMPR-II) gene (BMPR2) have been recognized to cause heritable PAH (HPAH). Recent studies focused on novel BMPR2 mutations in the Asian population and provided evidence for genotype-phenotype correlations. A candidate gene strategy has suggested additional mutations in SMAD, TBX4 and TSP1 in PAH. A genome-wide association study (GWAS) identified an association at the CBLN2 locus with PAH. Studies have addressed the role of additional factors required for disease penetrance. The unbalance between TGF β1 and BMPRII signaling may stimulate inflammatory cytokine expression and leukocyte extravasation. Epigenetics, including DNA methylation and microRNAs, appear to play a role in the development of PAH. Next-generation sequencing with advances in bioinformatics will provide further insights into the underlying genetic and epigenetic architecture underlying the pathobiology of PAH.