A rare genetic variant that occurs more commonly in families of patients with atrial fibrillation (AF) may be a key to better understanding this common and potentially life threatening condition, Vanderbilt University researchers reported this week.
The finding, published Dec. 7 in the journal Disease Models & Mechanisms, could lead to more successful treatments for AF, which is associated with an increased risk for stroke and heart failure, the researchers said.
“Atrial fibrillation is becoming an increasingly prevalent disease, yet our understanding of its mechanisms remains limited, offering patients few therapeutic options,” said Ela Knapik, M.D., a corresponding author of the study with Antonis Hatzopoulos, Ph.D.
Previous studies have linked AF to mutations in genes that control the electrical activation of the heart, but few mutations in genes that regulate heart development have been identified.
The researchers investigated whether bone morphogenetic proteins (BMPs), which regulate heart development, and Grem2, which blocks BMP signaling, may play a role in the development of AF. In two families that submitted genetic material for research purposes through the Vanderbilt AF Registry, they discovered a variation in GREM2 gene that increases its inhibitory activity.
In zebrafish, a common animal model for studying heart disease, the researchers found that the GREM2 variant alters heart development and slows heart contraction rates. In mouse embryonic stem cells, it also induces genes that have been linked to AF in humans.
These results implicate for the first time the role that altered BMP signaling may play in AF, and suggest potential new therapeutic targets that could lead to better treatments.
“Genomic studies have identified numerous genetic variants in human genes, but we have little knowledge about how these variants lead to disease in individual patients,” Hatzopoulos said.
“Our work provides an original approach to functionally model human disease genes in zebrafish and stem cells.”
During the past decade, Vanderbilt researchers led by Dawood Darbar, M.D., Ph.D., have helped advance understanding of the role that genetic variations play in the development of AF.
Other co-authors were Iris Müller, M.D., David Melville, Ph.D., Vineeta Tanwar, Ph.D., Witold Rybski, M.S., Amrita Mukherjee, M.S., Benjamin Shoemaker, M.D., Wan-Der Wang, Ph.D., John Schoenhard, M.D., Ph.D., and Dan Roden, M.D.
The research was supported in part by the National Institutes of Health (grants R01 DE018477, HL083958, U01HL100398, T32GM008554, HL65962 and HL09221).
