Clinical Challenges: Genetic Insights Into Pulmonary Arterial Hypertension

The past two decades have brought major advances in the understanding of the genetics of pulmonary arterial hypertension (PAH), and it is now believed that close to one-third of cases have a family link and should be classified as heritable PAH.

Advances in DNA sequencing technology have dramatically expanded the ability to perform large-scale genetic studies, even in rare diseases like PAH.

Those studies are bringing into clearer focus the genetics and genomics of both heritable PAH and idiopathic PAH, which occurs in people without any family history of the disease or predisposing conditions.

PAH is a rare progressive disease that occurs in adults as well as children, with an estimated prevalence of 15 to 50 cases per million adults and 2.1 to 4.4 cases per million children.

The disease is characterized by remodeling of the small pulmonary vessels leading to extremely elevated blood pressure in the pulmonary artery, progressing to right heart failure; the average life expectancy with treatment is approximately 10 years.

A significant percentage of heritable PAH cases are now known to be associated with mutations identified in the bone morphogenetic protein receptor 2 (BMPR2) gene, leading to gene function loss.

More than 600 variants in the BMPR2 gene have been identified, and these pathogenic variants are believed to account for around 70%-80% of heritable PAH cases and 10-20% of idiopathic PAH cases; non-BMPR2 mutations so far account for less than 5% of PAH cases.

Patients with BMPR2 gene variants often have earlier onset of disease and decreased survival compared with patients without a known genetic predisposition.

At least 17 PAH risk genes have been reported in recent decades. In addition to BMPR2, other identified genes that predispose for PAH include CAV1, which encodes caveolin; KCNK3; and TBX4, which is a gene that has also been linked to small patella syndrome, a rare bone malformation disease.

TBX4 mutations are a common genetic cause of PAH in children, suggesting “that PAH is at least in part a developmental lung disease when it presents early in life,” wrote James Loyd, MD, of Vanderbilt University Medical Center in Nashville, and colleagues, writing in a 2018 review exploring the genetics and genomics of PAH.

The authors noted that the observation that PAH can occur in families segregating hereditary hemorrhagic telangiectasia (HHT) also implicates activin receptor-like kinase 1 (ACVRL1) and endoglin (ENG) gene mutations in PAH.

A large study conducted in Europe, published in 2018, involving more than 1,000 adults with PAH (idiopathic, familial, and anorexigen-associated) confirmed the presence of causal mutations in BMPR2 (15.3%), TBX4 (1.3%), ACVRL1 (0.9%), ENG (0.6%), SMAD9 (0.4%), and KCNK3 (0.4%). No pathogenic coding variants in CAV1, SMAD1, or SMAD4 were identified, possibly due to the rarity of mutations in these genes in adults, wrote Stefan Graf, PhD, of the University of Cambridge in England, and colleagues.

Search for Novel Therapeutics Underway

So far, the identification of gene variants linked to PAH has not influenced the treatment or clinical course of the disease, but that could soon change.

Currently approved PAH treatments target pathways that promote dilation of the pulmonary vessels with the goal of reducing destructive pulmonary vascular resistance and slowing PAH progression.

But the investigational drug sotatercept is a novel fusion protein designed as a selective ligand trap that targets BMRP2. Results from the company’s phase II PULSAR study, presented in June at the American Thoracic Society virtual meeting, showed that the drug significantly improved pulmonary vascular resistance and 6-minute walk distance in patients with PAH.

PULSAR was designed to evaluate the efficacy and safety of sotatercept in PAH, with the primary endpoint being change from baseline pulmonary vascular resistance over 24 weeks of treatment. In his presentation of the results, David Badesch, MD, of the University of Colorado in Aurora, said that echocardiographic data still being analyzed suggested a possible improvement in right ventricular function associated with sotatercept use over time.

“The study was 6 months in duration, and we were using a drug that affects vascular structure as opposed to vasodilatation,” he said. “It is possible that we will see an effect on cardiac output later, but I think the principal effect is within the small vessels and pulmonary vasculature.”

Large Databases for a Rare Disease

Eric Austin, MD, director of the pediatric PAH program at Vanderbilt University Medical Center in Nashville, told MedPage Today that large-scale international efforts like the International Consortium for Genetic Studies in PAH (PAH ICON) are making it possible to gain the statistical power needed to understand the complete genetic picture of the rare disease, by generating thousands of samples from patients with idiopathic and heritable PAH.

The PAH Biobank in the U.S. is a registry, funded by the National Heart, Lung, and Blood Institute, that is generating genetic data (targeted DNA sequencing, whole exome sequencing, and genome-wide single nucleotide polymorphisms) on 3,000 group 1 PAH patients — i.e., those with PAH caused when arteries in the lungs become narrowed, thickened, or stiff.

The National Institutes of Health and the Pulmonary Hypertension Association are also sponsoring the Pulmonary Vascular Disease Phenomics (PVDOMICS) initiative, with the goal of defining new molecular classifications for the disease.

The BRIDGE Project in the U.K. includes more than 1,250 idiopathic PAH/familial PAH patients from Europe being studied to investigate the underlying genetic variation.

Austin said the goals of genetic research are ambitious, and include the identification of targeted therapies to modify the course of disease or even prevent it.

“When these mutations were first identified a lot of people thought [the mutations] were just an esoteric component of an esoteric disease,” he said. “But we quickly realized, and it is now widely accepted, that even people with PAH not caused by a known mutation may have irregularities in the pathways those [identified] genes represent.”

The identified genetic irregularities may be highlighting molecular pathways “we don’t yet understand, which may represent possible therapeutic approaches for other forms of the disease,” he explained.

Austin and colleagues at Vanderbilt as well as researchers at Columbia University Irving Medical Center in New York City have been following PAH families for years, including those with BMPR2 mutations who have not developed the disease.

The research has led to significant discoveries regarding the presentation of familial PAH, including the fact that many people with the mutations do not develop the disease.

“Around 14% of males and 42% of females will develop PAH during their lifetime if they have a BMPR2 mutation,” Austin said. “It is not a death sentence. That is what is so interesting about it, but also so confusing.”

The team’s research, published in 2012, also led to the recognition that in heritable PAH families, having the genetic risk does not lead to earlier diagnosis and earlier disease progression as the gene is passed down through generations.

Austin said the investigators are now following about 225 families who have at least two members with PAH or known mutations for the disease, and the team is seeking funding to conduct a large study that will follow healthy family members with known genetic risk.