Novel IPAH Mutations Found in Chinese Patients, Study Reports 

Newly identified mutations that contribute to a higher susceptibility of idiopathic pulmonary arterial hypertension (IPAH) in people from China, were found in a pathway commonly targeted by therapies that dilate blood vessels (vasodilators), a new study reports. 

The authors suggested that screening for these mutations may improve personalized treatments for patients taking these medications.

The study, “Association of Rare PTGIS Variants With Susceptibility and Pulmonary Vascular Response in Patients With Idiopathic Pulmonary Arterial Hypertension,” was published in the journal JAMA Cardiology. 

Research has identified mutations in at least 17 genes linked to the development of PAH. However, these mutations explain only a small proportion of the cases. For example, mutations in the gene most associated with IPAH, known as BMPR2, are responsible for about 17% of IPAH cases. 

Despite this knowledge, current therapies do not target pathways involving these genes. Instead, therapies that open (dilate) blood vessels, called vasodilators, are commonly prescribed to replace the naturally occurring vasodilator prostacyclin, because prostacyclin production is significantly decreased during PAH development.

Despite these advances, little is known about genetic mutations (variants) in genes that are part of the prostacyclin pathway that may influence the development and treatment of IPAH. 

Thus, to identify unknown prostacyclin pathway genes associated with IPAH, a team led by researchers based at the Chinese Academy of Medical Sciences and Peking Union Medical College in China conducted an extensive genetic analysis of people with IPAH without BMPR2 variants. 

A total of 230 IPAH patients without BMPR2 mutations (average age 34 years, 164 females and 66 males) were identified and recruited for the study. Of these, 42 patients were selected for a discovery phase (including 10 pediatric patients) to identify genes linked to IPAH.

The remaining 188 patients, along with 968 healthy controls, were part of a replication group used to validate findings of the discovery phase. 

DNA analysis in the discovery group revealed that only 15 genes harbored rare variants shared by three or more people with IPAH, and four of these genes were abundantly active in the lung. Of these, mutations were identified in the PTGIS gene that contains the instructions for making an enzyme called prostacyclin synthase, which has a key role in prostacyclin production. That’s why this gene was chosen for further study.

When looking at the replication group, researchers identified a total of 14 patients (6.1%, 14 of 230 patients), including two pediatric cases, who carried mostly one of three rare PTGIS mutations that were predicted by computer analysis to affect prostacyclin synthase function.

A clinical assessment of these 14 patients found that most were diagnosed with IPAH at a young age (median of 26 years), and a significant sex bias was observed with a female-to-male ratio of 6-to-1.

Further analysis of 12 of these 14 patients found that, compared to those without PTGIS mutations, treatment with the synthetic version of prostacyclin, inhaled Ventavis (iloprost, marketed by Actelion), significantly decreased the pulmonary vascular resistance — how hard the heart works to pump blood through pulmonary vessels — and increased the cardiac index, a measure of heart performance.

“Thus, genetic variants of PTGIS predisposed pulmonary vascular responses to the iloprost stimulation,” researchers wrote. “Patients carrying rare PTGIS variants were more responsive to iloprost stimulation than those without such variants.”

Cell-based tests showed that these three PTGIS mutations were “loss-of-function” mutations that led to either a lack of prostacyclin synthase production or lower enzyme activity.

Overall, the team “identified 3 rare loss-of-function variants in the PTGIS gene from 2 independent cohorts with IPAH,” the researchers wrote.

“The rare variants of the PTGIS gene appear to contribute [to a] higher susceptibility to idiopathic pulmonary arterial hypertension, and screening of PTGIS variants may help improve personalized treatment of these patients,” the team concluded.