New Gene Signals Likely Blood Pressure Drug Targets

The list of genes affecting blood pressure is expanding, as researchers pursue likely targets for therapeutics already in existence or in development. A Children's Hospital researcher collaborated with an international study team that discovered 11 novel genetic signals associated with blood pressure levels and confirmed 27 previously discovered genetic signals.

High blood pressure, or hypertension, is a complex condition and a well-known risk factor for heart disease, stroke, peripheral artery disease, and chronic kidney disease. A substantial need for improved blood pressure medicines exists because not all patients respond well to current treatments, and other patients require combinations of three or more drugs.

Most of the new genetic signals that Brendan J. Keating, DPhil, a geneticist with The Center for Applied Genomics (CAG) at The Children’s Hospital of Philadelphia, and the study’s co-authors identified are “druggable” targets that offer the possibility of expedited pharmaceutical development of therapeutics for high blood pressure.

“Some of the protein targets already are targets of existing drugs for other diseases, while others are the focus of drugs currently in early-phase clinical trials or under preclinical development,” Dr. Keating said.

In the study that appeared online in the American Journal of Human Genetics, the researchers performed a discovery analysis of DNA from more than 87,000 individuals of European ancestry. They assessed their initial findings in a replication test, using an independent set of another 68,000 individuals.

Then the researchers used pharmacological databases to analyze potential targets in the discovered genetic region. They found that gene products associated with 10 of the genes were predicted to be targets for small-molecule drugs. In fact, two genes — KCNJ11 and NQO1 — are currently targeted by existing approved drugs.

“If clinicians can reposition existing drugs to treat some patients with hypertension, this will save significant time in drug development, as they won’t be starting development from scratch,” Dr. Keating said.

He added that even with possible repositioning, more research is needed to determine which drug candidates are effective against hypertension, possibly in personalized treatments based on patients’ genetic makeup.

Dr. Keating is the lead clinical data analyst at CAG, one of the world’s largest programs for detecting gene variations and linking them to particular illnesses, and the only such program entirely based at a pediatric hospital. In addition to his position at CHOP, Dr. Keating is a faculty member of the Department of Pediatrics and the Division of Transplantation in the Department of Surgery in the Perelman School of Medicine at the University of Pennsylvania.

For this study, Dr. Keating collaborated with two senior co-authors, Folkert W. Asselbergs, MD, PhD, of University Medical Center Utrecht, the Netherlands, and Patricia B. Munroe, PhD, of Queen Mary University, London, U.K. Other study co-authors were from the U.S., the U.K., the Netherlands, Canada, Germany, Sweden, and Ireland.

Study funders included the National Heart, Lung and Blood Institute; the British Heart Foundation; and the Netherlands Organisation for Health Research and Development.