The genetics of pulmonary arterial hypertension

Circ Res. 2014 Jun 20;115(1):189-202. doi: 10.1161/CIRCRESAHA.115.303404.


Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. Many germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 (BMPR2) and related genes. Recent advanced gene-sequencing methods have facilitated the discovery of additional genes with mutations among those with and those without familial forms of PAH (CAV1, KCNK3, EIF2AK4). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic, and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacological intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biological variations now associated with PAH. Ultimately, an in-depth understanding of the genetic factors relevant to PAH provides the opportunity for improved patient and family counseling about this devastating disease.

Keywords: bone morphogenetic protein receptor, type II; genetics; hypertension; pulmonary.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Alleles
  • Animals
  • Bone Morphogenetic Protein Receptors, Type II / genetics
  • Caveolin 1 / genetics
  • Epigenesis, Genetic
  • Familial Primary Pulmonary Hypertension
  • Genetic Testing
  • Gonadal Steroid Hormones / metabolism
  • Humans
  • Hypertension, Pulmonary / genetics*
  • Mutation
  • Nerve Tissue Proteins / genetics
  • Potassium Channels, Tandem Pore Domain / genetics
  • Protein Precursors / genetics
  • Protein-Serine-Threonine Kinases / genetics


  • CAV1 protein, human
  • Caveolin 1
  • Cbln2 protein, mouse
  • Gonadal Steroid Hormones
  • Nerve Tissue Proteins
  • Potassium Channels, Tandem Pore Domain
  • Protein Precursors
  • potassium channel subfamily K member 3
  • EIF2AK4 protein, human
  • Protein-Serine-Threonine Kinases
  • Bone Morphogenetic Protein Receptors, Type II