Using Patient Genes to Further Understand Pulmonary Arterial Hypertension

by Amanda Chase, PhD
June 15, 2021

Blood pressure is the force that your blood exerts against the wall of your arteries. High blood pressure (hypertension) indicates that there is greater pressure due to narrowed or blocked blood vessels. Unfortunately, this also increases how hard the heart works, ultimately leading to damage to your heart. Pulmonary arterial hypertension (PAH) is a rare, progressive disorder in which the blood vessels in the lung are narrowed or blocked, slowing blood flow through the lungs and making the heart work harder. This, in turn, leads to weakened heart muscle that can ultimately fail. The exact cause of PAH is unknown, although it is known that 15-20% are inherited, due to a change or mutation in a gene. Of those, 20% are a result of an unknown gene mutation. Understanding what mutations contribute to PAH has the potential to significantly impact patient care.

A team from Stanford University, including Cardiovascular Institute affiliated senior author Vinicio de Jesus Perez, and from Spain, let by Dr. Jair Tenorio, collaborated to identify two novel variants that cause PAH. Their findings were recently published in Frontiers in Medicine. The team was able to use whole-exome sequencing (WES) on two unrelated families with PAH. WES can be imagined to be similar to allowing one to watch only the game highlights across a season to understand the final team record. In this case, genes are the recipe for making proteins and are made up of parts that are used to make the protein (exons; game highlights) and other information. WES specifically reads the exons of most genes at once to find any gene changes, or variants. By comparing families with PAH, the researchers were able to identify two novel variants that contributed to PAH: TNIP2 and TRAF2. Both genes are involved with inflammation and immunity, and the team was able to show that the variants likely increased susceptibility to PAH by their ability to change immune responses and to drive abnormal cell growth in the vasculature of the lungs, ultimately leading to narrowing of the arteries.  

Figure. Families affected by PAH were subjected to whole exome sequencing to find any genetic variants causing their disease. A custom variant prioritization pipeline found candidate variants: TNIP2 and TRAF2. Knockdown of TNIP2 and TRAF2 suggested that they increased susceptibility to PAH by changing the immune response and driving abnormal cell growth in the vasculature of the lungs.

This the first report to document a potential link between TNIP2 or TRAF2 loss of function and PAH in humans. They also showed that WES can be used to determine variants causing PAH that cannot be identified. Identifying gene variants related to PAH holds the potential for the development of personalized treatments and the potential for tremendous impact on patient care.

Other Stanford affiliated author are Shaun Pienkos, David Condon, Stuti Agarwal, Hiral Patel, and Ananya Chakraborty.

Dr. Vinicio de Jesus Perez