Pankaj Arora, M.D., and Naman Shetty, M.D.Researchers from the University of Alabama at Birmingham Marnix E. Heersink School of Medicine have published a study in Circulation: Genomic and Precision Medicine that maps the genetic blueprint of NT-proBNP, a hormone produced by the heart that plays a central role in regulating blood pressure, metabolism and cardiovascular health.
NT-proBNP is one of the most widely used tested biomarkers in medicine. Doctors rely on it to diagnose and monitor heart failure, and it is used as a key measure in major clinical trials of heart failure therapies. The genetic factors that determine how much of this hormone a person naturally produces have remained largely unknown.
By analyzing genetic data from more than 81,000 individuals across the Trans-Omics for Precision Medicine initiative, the UK Biobank, the All of Us Research Program and the REGARDS study, the team identified 12 genomic regions linked to NT-proBNP levels, nine of which had never been reported before. This makes it the largest, most diverse genetic study of NT-proBNP ever conducted.
“This study gives us the most comprehensive genetic map of NT-proBNP to date,” said Pankaj Arora, M.D., senior author and director of the UAB Cardiogenomics Clinic. “By studying people from different ancestries and both sexes, we found that the genetic signals influencing this critical heart hormone are remarkably consistent. We also uncovered new biology that could change how we think about cardiovascular disease.”
Several of these newly identified genes have well-established roles in heart muscle function. For example, BAG3 helps maintain the structural integrity of heart muscle cells and has been linked to heart failure. FLNC is essential for the function of the protein that allows the heart muscle to contract. NEDD4L plays a role in regulating sodium balance, a key driver of blood pressure. These discoveries suggest that NT-proBNP levels are not a passive marker of heart stress but are actively shaped by the same biological pathways that cause heart disease.
The study also examined rare genetic variants and structural changes in DNA, such as deletions and duplications of genetic material. The results suggest that these variants and changes also influence NT-proBNP levels.
Rare variants in stretches of DNA that act as “switches” controlling when and how much of a gene is turned on were strongly associated with NT-proBNP, pointing to a layer of overlooked genetic control.
Co-author Garima Arora, M.D., co-director of the UAB Cardiogenomics Clinic, highlighted the quality of the study sample.
“It is well known that NT-proBNP levels differ by race and sex, and those differences have real consequences for how patients are diagnosed and treated,” Garima Arora said. “By including individuals of European and African ancestry, and by analyzing men and women separately, we showed that the genetic effects are consistent across these groups, which strengthens the case for using these findings to improve care for everyone.”
Naman Shetty, M.D., first author of the study and alumnus of Arora’s lab, says the collaboration between multiple institutions and populations catalyzed the study.
“Looking beyond the usual suspects in the genome and incorporating rare variants and structural changes enabled us to uncover genetic signals that had been missed in smaller, less diverse studies,” Shetty said. “These findings lay the groundwork for understanding why some individuals are more vulnerable to heart disease than others.”
According to Pankaj Arora, these findings open the door to precision approaches for preventing and treating heart disease.
“Understanding why some people naturally have lower levels of this protective hormone will help us identify those at risk earlier and develop targeted therapies,” Pankaj Arora said.
The authors push for more genetic research in diverse groups and suggest that gene editing and new drugs could eventually help personalize care by targeting specific variants found in this study.