Scientists recently published in Genome Medicine the identification of two more genes potentially associated with pulmonary arterial hypertension (PAH), through the work of the PAH Biobank, a National Institutes of Health-funded resource of blood and cell samples, genetic data and clinical data for those researching PAH.

A rare disease characterized by high blood pressure of the lungs, PAH frequently develops because the pulmonary arteries of people with PAH become thicker and stiffer than normal. Scientists still do not fully understand why this happens in people with PAH. However, many scientists and doctors are working together to learn more about who develops PAH, why they develop PAH, and who might be at risk for PAH. This knowledge will allow doctors to diagnose PAH earlier and perhaps even develop new and more effective therapies.

Since the 1950s, doctors have noticed that PAH appears more frequently than they would expect in some families. In 1954, doctors in New York City discussed in a paper a possible familial connection to what is now called heritable PAH (HPAH), describing a mother, her sister and her son who all died from the disease. In 1984, doctors—including James Loyd, M.D., and John Newman, M.D., from Vanderbilt University, who are still involved in pulmonary hypertension (PH)—wrote a paper trying to better understand families they knew who develop PAH and whether they could find new people with PAH in these families. They did identify a significant number of new PAH cases from screening family members of PAH patients and hypothesized that some cases of what is now known as idiopathic PAH (IPAH, where the cause of PAH is unknown) might actually be more properly characterized as “familial” PAH if a better family history was taken. When diseases run in families, doctors frequently wonder if there could be a genetic cause or causes to the disease.

Since this time, scientists and doctors studying PAH have discovered a number of genes that are associated with developing PAH. At the 2018 World Symposium on Pulmonary Hypertension, the Genetics and Genomics Task Force identified 12 genes with a high level of evidence of a causal role in PAH. The National Biological Sample and Data Repository for PAH, or “PAH Biobank,” is a large research study funded by NIH in the U.S. that seeks to better understand the genetics of PAH. Housed at the Cincinnati Children’s Hospital Medical Center in Cincinnati, Ohio—a PHA-accredited Center of Comprehensive Care (PHCC)—the PAH Biobank collected and stored blood from 2,900 PAH patients in 38 North American PH centers. They also collected clinical information on these patients through a survey and medical record review. This effort helped the Biobank team to identify potential new genes associated with PAH and confirm the findings of other scientists about already-known genes that are likely to have a causal role in PAH. The NIH-funded Biobank is designed to be a resource for the entire PH community; scientists with a new idea about genetic relationships in PAH can apply to request samples and/or analyze genetic data obtained from the blood samples in the PAH Biobank to conduct their own research.

In November, scientists from the PAH Biobank reported on their genetic study evaluating more than 2,500 people with PAH, and more than 50 people related to someone with PAH and not diagnosed with PAH. In their analysis, they identified two new potential genes associated with PAH. The first, KLK1, is a gene that acts as the “blueprint” for a protein our bodies make called tissue kallikrein. Tissue kallikrein has been identified and studied in systemic blood pressure and blood vessel disease, but never PH. The scientists additionally discovered mutations in a gene called GGCX. This gene is the blueprint for a protein our bodies make called gamma glutamyl carboxylase. This protein has previously been studied in problems with blood clotting and vascular calcification, but, again, never PAH. They found that about 0.4% (or 4 in 1,000 people with PAH) of the participants in the PAH Biobank had a mutation in their KLK1 gene and about 0.9% (or 9 in 1,000 people with PAH) had a mutation in their GGCX gene. For a disease like PAH that only affects one-two per million persons worldwide, this was a significant discovery.

The PAH Biobank scientists next studied whether PAH was more severe in people with these two different genes (KLK1 and GGCX). When they compared people with these genetic mutations to people with IPAH, they looked overall similar when studying their basic features such as age at diagnosis and right heart catheterization values. However, they found that people with these genetic mutations might have less severe PAH than those HPAH patients that have the first discovered gene associated with PAH, BMPR2, in their DNA.

The authors of this study noted that though this was an exciting observation, more research needs to be completed to better understand this new knowledge. First, scientists need to study a different group of people with PAH to confirm whether changes in KLK1 and GGCX are present in other groups of people with PAH, or just those in the PAH Biobank (“prospective validation”). Next, not everyone who has abnormalities in a gene known to be associated with PAH will develop PAH. This is known as “incomplete penetrance.” Scientists need to better understand why some people with these genetic mutations develop the disease and why others do not. By continuing to study which genes are associated with PAH, scientists hope to better understand how and why some people get PAH, which hopefully will lead to earlier diagnosis and new, improved therapies.