Study Identifies Individuals at Higher Genetic Risk for Pulmonary Hypertension

University of Pittsburgh Schools of Medicine researchers have made a significant breakthrough in understanding the body’s response to limited oxygen and its role in regulating blood vessel diseases of the lung. The team, led by senior author Stephen Chan, M.D., Ph.D., discovered a shared genetic trait among more than 20,000 individuals in the U.S., France, England, and Japan, which could predict a higher risk of small lung vessel diseases such as pulmonary hypertension and its more severe form, pulmonary arterial hypertension. 

The findings, published in Science Translational Medicine, provide a fundamental mechanism for understanding pulmonary hypertension, a group of conditions characterized by high blood pressure in the arteries of the lung and the right side of the heart. This chronic and deadly disease is associated with decreased oxygen supply to lung tissue and blood, and its molecular origins and genetic background have been elusive. 

The researchers employed a comprehensive approach, combining genomics and biochemistry, to uncover a gene pair that plays a crucial role in regulating blood vessel metabolism and disease. This gene pair consists of a long non-coding RNA molecule—a messenger facilitating the transformation of genetic code into protein products—and a protein binding partner. Their interaction was found to be frequently active in cells exposed to low oxygen, compared to normal cells. 

Taking their investigation further, the team identified a single DNA letter change directing the expression of this RNA-protein pair under low oxygen conditions, which was associated with a higher genetic risk of pulmonary hypertension across diverse patient populations. 

Pulmonary hypertension is considered a borderline orphan disease, with a limited number of patients, making it challenging to identify rare but impactful genetic variations. To address this, the Pitt scientists collaborated with researchers worldwide and utilized public research datasets, such as All of Us—a nationwide health registry—to ensure the relevance of their findings across a diverse global population. 

The researchers hope that this newfound knowledge will facilitate the identification of individuals at a higher genetic risk of pulmonary hypertension, paving the way for precision medicine practices and customized treatments. According to Chan, the findings could lead to the development of targeted therapies focused on oxygen sensitivity in blood vessel linings.

Additionally, the team has a pending patent application that they believe could contribute to the growth of a novel field in epigenetic and RNA drug therapeutics. Unlike traditional approaches that manipulate the genome, these therapies would work by altering how the genetic code is read. 

In summary, the study has unveiled a critical genetic trait associated with pulmonary hypertension, offering insights into the disease’s molecular origins. The global collaboration and integration of diverse datasets ensure the broad applicability of these findings, potentially advancing the field of precision medicine and opening avenues for the development of innovative therapies targeting oxygen sensitivity in blood vessels.

The pending patent application underscores the potential for novel epigenetic and RNA drug therapeutics, presenting a new frontier in medical research and treatment strategies for pulmonary hypertension. 

Journal Reference  

Yi Yin Tai et al, Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.add2029. www.science.org/doi/10.1126/scitranslmed.add2029.