University of Virginia Health System

RESEARCHERS IDENTIFY GENETIC CAUSES OF HYPERTENSION

Scientists at the University of Virginia and Georgetown University in Washington, D.C., have discovered three variants in a kidney gene that indicate the most common type of hypertension. Their findings, the result of an 18-year collaboration between the two schools, are allowing development of the first predictive medical test for high blood pressure, according to an article in the March 19 issue of Proceedings of the National Academy of Sciences (PNAS).

The researchers report that these gene variations, either by themselves or through interaction with variations of other genes, are associated with essential hypertension in several populations: Caucasian American, Ghanaian and Japanese. The presence of these gene variants, also called polymorphisms, can be determined by a simple genetic test used to assess an individual's risk of developing high blood pressure (hypertension). The test is based on detection of inherited gene variations that encode for a protein called G protein coupled receptor kinase type 4 (GRK4). GRK4 variations are associated with an inability to eliminate sodium from the body.

This discovery has led to a high quality test that should be suitable for screening a large number of patients based on a fluorescent molecular beacon assay, and will aid physicians in their diagnosis of genetic forms of hypertension, said Robin A. Felder, professor of pathology and director of the U.Va. Medical Automation Research Center, the lead author on the paper.

The genetic information disclosed by the new test will allow physicians to provide guidance to patients with a family history of hypertension who wish to know if they should modify their lifestyles to help prevent the debilitating consequences such as kidney failure, heart failure, stroke, blindness or high blood pressure, Felder said.

Essential hypertension - a type that classifies 50 percent of hypertension - affects 25 percent of the world's adult population and is a major risk factor for stroke, myocardial infarction and heart and kidney failure. Although scientists have believed this condition to be hereditary, determining the genetic cause of essential hypertension was previously difficult because blood pressure level results from a combination of hereditary and environmental factors.

Patients with even a single GRK4 variation have a significant lifetime risk for developing hypertension, said Dr. Pedro A. Jose, professor of pediatrics and of physiology and biophysics at Georgetown University, and senior author of the journal article. We have now identified the genetic abnormalities that cause this error and so we have a better idea of the impact of these gene variations in the development of hypertension in three distinct racial groups.

Identification of this leading cause of hypertension should lead to improved medical treatments for the disease. The U.Va. and Georgetown teams, in collaboration with Dr. Hironobu Sanada at Fukushima University in Japan, also have reported the use of antisense technology to correct the biochemical error in human kidney cells that leads to high blood pressure. Antisense drugs work at the genetic level to interrupt the process by which disease-causing proteins (in this case, GRK4-containing changes in the DNA that may cause disease, called single nucleotide polymorphisms) are produced. The research teams have produced human kidney cell lines that may be useful in discovering other therapeutic methods to treat high blood pressure.

Drs. Felder and Jose submitted their discoveries for patent protection in January 1999. The resulting patents have been recently assigned to Hypogen, Inc., in Charlottesville. The research reported in the PNAS article was funded in part by the National Institutes of Health's National Institute of Diabetes and Digestive and Kidney Diseases, the National Heart, Lung and Blood Institute, and the National Center for Research Resources.

March 18, 2002