Researchers Highlight Progress, Remaining Unknowns in Genetics of PAH

As up to 1 in 3 patients with pulmonary arterial hypertension (PAH) have unknown explanations for their disease and its pathobiology, a team of researchers is exploring the genetic architecture that goes beyond BMPR2 mutations, which has been established in up to 80% of patients with familial PAH and up to 20% of patients with idiopathic PAH.

The identification of new genes of interest has been a goal of many, including 3 consortia that have initiated large-scale genomic and multi-omics programs. Through these programs, several new PAH risk genes have been identified, including tissue kallikrein 1 (KLK1) and gamma-glutamyl carboxylase (GGCX). Within a sample of patients with Group 1 PAH, researchers identified 12 cases that harbored KLK1 variants and 28 that carried GGCX variants.

This particular group of researchers who authored the paper identified KDR as a PAH candidate gene after deploying a novel Bayesian comparison method in deeply phenotyped patients.

“We found that protein-truncating variants (PTV) in KDR were strongly associated with significantly reduced KCO and older age of onset,” wrote the researchers. “In addition to statistical evidence accompanied by biological plausibility, we also identified one case with a family history, which together with a recently published case report of two families, in which PTVs in KDR segregated with the phenotype of PAH and significantly reduced KCO, amounts to three reported cases with familial segregation.”

With more known genes playing a role in PAH, there also comes a need for genetic testing, although the researchers of the study note that almost 80% of provider never or rarely offer genetic testing for their patients. Interestingly, the most reported reason for offering testing stems from patient inquiry, according to the researchers.

There’s also been research into factors influencing disease penetrance and expressivity, which has established mutation type, individual variation in gene expression, epigenetic and environmental factors, and age and sex as factors.

“Variable gene expression was also found to impact on PAH penetrance; the expression levels of wild-type BMPR2 from the unaffected allele transcript were higher in healthy carriers than in affected individuals,” wrote the researchers. “Additionally, analysis of genetic variants affecting alternative splicing of BMPR2 showed that patients have a higher isoform B/A ratio than carriers. Moreover, in vitro study on patient-specific induced pluripotent stem cells derived endothelial cells, it was shown that downregulation of endogenous receptor antagonists and upregulation of receptor activators might compensate for impaired BMPR2 signalling in unaffected BMPR2 mutation carriers.”

Meanwhile, the impact of environmental factors on PAH penetrance still remains largely unknown, although some literature has suggested that BMPR2 expression and degradation can be impacted by viral proteins and cocaine.

Reference

Swietlik E, Gräf S, Morrell N. The role of genomics and genetics in pulmonary arterial hypertension. Glob Cardiol Sci Pract. 2020; 2020(1): e202013.