The genetics of pulmonary arterial hypertension

Abstract

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.

Figure 1. Legend: Major factors in the development of PAH

Heterozygosity for the presence of a rare variant (mutation) in a gene known to associate with PAH is a major risk factor (e.g. BMPR2 gene mutation). However, subjects with these mutations do not always develop PAH, suggesting that the mutations are generally not sufficient to cause PAH in isolation. Additional factors are likely to contribute to disease penetrance in the genetically-susceptible individual. Some of the potential factors, which may also contribute to other forms of PAH, are noted.

Figure 2. Legend: Simplified schematic of the proteins encoded by the genes with mutations known to associate with PAH, with a focus upon the BMP signaling pathway but addition of recently described mutations

Genes with mutations known to associate with PAH are shown in red, with possible resultant effects of the actions briefly listed. Of note, Smad-independent effects of BMP signaling abnormalities are not shown but may contribute to PAH pathogenesis, such as alterations in cytoskeletal dynamics, cell survival, and mitochondrial metabolism.