A fundamental mechanism that controls the body’s response to limited oxygen

A shared genetic trait that could predict a higher risk of small lung vessel disease.


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Pulmonary hypertension is a serious health problem where the blood vessels in the lungs and the right side of the heart have high blood pressure. This condition can be caused by various issues, leading to a decreased oxygen supply to the lungs and the blood. It’s a chronic and life-threatening disease, and we don’t fully understand its molecular and genetic roots.

Researchers at the University of Pittsburgh School of Medicine used a mix of genetic studies (looking at all the genes in the body) and biochemistry (studying the chemicals in the body) to discover a critical process that controls how the body responds to low oxygen. This process also plays a role in regulating diseases of the blood vessels in the lungs. Understanding these mechanisms could be a big step toward finding new ways to treat pulmonary hypertension.

The scientists examined the genetic information of over 20,000 people from the United States, France, England, and Japan. They also did experiments in the lab to understand the molecules in the body. What they found was a common genetic feature that could tell if someone is more likely to get a type of lung disease called pulmonary hypertension.

It could also help make medicines targeting how the body deals with low oxygen.

Senior author Dr. Stephen Chan, a cardiologist who serves as the Vitalant Chair in Vascular Medicine and director of the Vascular Medicine Institute at Pitt, said, “This new level of knowledge will help identify people who may be at a higher genetic risk of pulmonary hypertension and jump-start precision medicine practices to offer customized treatments.”

Importantly, scientists found a gene pair with an essential function in regulating blood vessel metabolism and disease. This gene pair consists of a long non-coding RNA (a messenger) and a protein that works together. They found that these two molecules interact more often in cells that are not getting enough oxygen compared to healthy cells.

Digging deeper into their findings, the team noticed that a tiny change in one letter of the DNA code could make these genes produce more of the RNA and protein pair when oxygen levels are low. This specific DNA change is linked to a higher chance of having pulmonary hypertension. Importantly, this connection was observed across different groups, showing that it could be a significant factor in the genetic risk for pulmonary hypertension in diverse populations.

Chan said“Pulmonary hypertension is a borderline orphan disease, and the limited number of patients with pulmonary hypertension makes it challenging to find genetic variations that are rare but still impactful enough to eclipse individual differences.”

“These findings will spur the development of targeted therapies relevant to oxygen sensitivity in blood vessel lining, and their pending patent application will contribute to the growth of an entirely new field of epigenetic and RNA drug therapeutics that work not by manipulating the genome but by changing how it is being read.”

Journal Reference:

  1. Yi-Yin Tai, Qiujun Yu et al. Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension. Science Translational Medicine. DOI: 10.1126/scitranslmed.add2029


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