NEW YORK – Researchers have tied rare variants in the PTGIS gene to susceptibility to idiopathic pulmonary arterial hypertension.
Pulmonary arterial hypertension is rare, with about 1,000 new diagnoses in the US each year, according to the National Institutes of Health. About 17 genes have been linked to PAH risk, but these risk genes only account for a small portion of idiopathic PAH (IPAH). Variants in BMPR2 — the most common causal gene — only explain about 17 percent of idiopathic PAH cases.
Researchers from Peking Union Medical College Hospital and their colleagues conducted a two-stage, case-control genetic association study to tease out additional genes that might affect IPAH risk. Through this, they homed in on variants in the PTGIS gene, which they found to alter prostaglandin production and increase lung cell death, as they reported in JAMA Cardiology Wednesday.
"This study identified three rare loss-of-function variants in the PTGIS gene from two independent cohorts with IPAH," PUMCH's Zhi-Cheng Jing and his colleagues wrote in their paper, adding that their results "suggest that PTGIS variants may be involved in the pathogenesis of IPAH."
For their study, they sequenced the genomes of 42 patients with IPAH, none of whom had BMPR2 variants. After filtering, the researchers uncovered 1,986 rare variants affecting 1,772 candidate genes.
Most of these alterations were present only in a single person, but 15 genes were altered in three or more people. Of those, PTGIS, MACF1, GTF3C1, and ABCA3 are expressed in the lung, and as PTGIS encodes prostaglandin synthase, which is involved in prostaglandin production, the researchers suspected it might be the most relevant of those 15 genes.
In a replication cohort of 188 patients with IPAH, the researchers uncovered additional patients with PTGIS variants. In all, 14 patients harbored one of three rare PTGIS variants.
They also sequenced the PTGIS gene in a control cohort of 968 individuals. Using that data, they calculated that the patient group had a rare variant frequency of 6.1 percent, while the control group had a rare variant frequency of 0.8 percent, indicating that people with rare PTGIS gene variants have increased odds of developing IPAH, with an odds ratio of 7.8. This suggests PTGIS influences the pathogenesis and pathophysiology of IPAH, the researchers noted.
The three rare PTGIS variants — A447T, R252Q, and c.521 +1G>A — are all located in conserved regions of the gene and are predicted by in silico analysis to be deleterious. Functional studies found that the PTGIS splicing variant affects the gene's transcription, as it led to exon skipping and an in-frame deletion. The two missense variants, meanwhile, led to impaired enzyme activity, decreased prostaglandin production, and increased cell death of pulmonary microvascular endothelial cells.
Compared to age-matched IPAH patients without PTGIS variants, patients with PTGIS variants had decreased pulmonary vascular resistance and an increased cardiac index following testing with iloprost, a synthetic prostacyclin analog. This indicated to the researchers that targeting the prostaglandin pathway could uncover tailored therapies to manage PAH in patients with PTGIS variants.
The researchers noted, though, that their sample was small and limited to patients of Han Chinese ancestry.
Still, as they excluded patients with BMPR2 variants, they said they have uncovered rare variants that independently may affect IPAH development.
"Using data from WGS of patients with IPAH, we demonstrated that PTGIS might be a PAH susceptibility gene," they wrote. "Importantly, these patients lacked any BMPR2 variants, which suggests that the IPAH susceptibility of PTGIS variants is independent of BMPR2."