Genetic variations help predict risk for salt-induced high blood pressure

Researchers led by UVa Health System pathologist Robin Felder, Ph.D., have demonstrated that looking for several variations of genes that control blood pressure can predict the risk for high blood pressure caused by high levels of salt.

Once it is fully developed, this effective diagnostic test will be the first of its kind, says Dr. Felder, whose work will be published in the Feb. 23 issue of the journal Clinical Chemistry. When a subject had three or more variations in these genes, the new genetic test correctly predicted risk for salt-induced high blood pressure in 94 percent of cases. Health is adversely affected by high salt intake in up to half of Americans.

In a separate finding, two genes at most were necessary to predict with a 78 percent accuracy which people with high blood pressure (hypertension) had a low renin levels, a substance that is currently measured to help establish the diagnosis of salt (sodium chloride) sensitivity. Thus, the researchers found different genetic bases for low renin in the blood and for salt sensitivity. Salt sensitivity is defined as a greater than 10 percent increase in blood pressure following a high-salt meal.

The researchers also determined that the increase in subjects' blood pressure and inability to eliminate excess salt from their systems was directly related to how many variations were found in the participants' salt regulating genes, a phenomenon called a gene dosing effect. The more gene variants, the bigger the health problems.

"A genetic test for high blood pressure and/or salt sensitivity will be instrumental in motivating Americans to adopt heart healthy lifestyles and help to improve their overall health and quality of life," Dr. Felder said. "In addition, because the treatment of hypertension costs the U.S. health system more than $13 billion per year, this test could result in significant cost savings as well."

"Diagnostic genetic tests with this high level of predictive value for hypertension simply don't exist at this time," said Dr. Hironobu Sanada, M.D., Ph.D., Fukushima Medical University, who led the clinical trials of the diagnostic genetic panel with Japanese subjects. Dr. Sanada is a former UVa pathology fellow who studied and worked with Dr. Felder.

Performing extended studies among people with different ethnic origins, the research group hopes to demonstrate the effectiveness of this test in particular among African Americans, who have a higher incidence of salt-sensitive hypertension than other races. While 98 million Americans suffer from either high blood pressure or sensitivity to dietary salt (or both), until now no genetic test had been created that could predict who may develop these diseases. Salt sensitivity, with or without high blood pressure, has the same deleterious consequences as high blood pressure. Left undiagnosed, high blood pressure and/or salt sensitivity can lead to devastating consequences such as stroke, blindness, heart attack and kidney failure.

The studies were conducted by a team of collaborators including Pedro A. Jose, M.D., Ph.D., at Georgetown University School of Medicine (Washington D.C.), Hironobu Sanada, M.D., Ph.D., Fukushima Medical University (Fukushima, Japan), and Scott Williams, Ph.D., Vanderbilt University (Nashville, TN). Funding for these studies was provided in part by a $10.2 million grant from the National Heart, Lung and Blood Institute.

The grant will allow this group of collaborating investigators, including Dr. Robert M. Carey, M.D. (University of Virginia) to extend their studies on the genetic bases for high blood pressure and salt sensitivity and their mechanisms in subjects from many different ethnic backgrounds, which could influence the predictive value of the diagnostic test. The team's work will examine the normal mechanisms associated with sodium (salt) management by the kidney and how the failure of these mechanisms contributes to high blood pressure.

Dr. Carey will recruit an additional 3,000 volunteers who will receive genetic screens to identify gene variants that contribute to elevated blood pressure. Dr. Jose's research will determine how dopamine receptors and angiotensin II receptors regulate each other. The information from these studies will provide new insights into how hypertension develops, how it can be tested and how it can be treated.

Right now, no definitive diagnostic test exists for salt sensitivity, except for a protocol in which diet is controlled rigorously over a two-week period. "Through these grant funds, we wish to stimulate broader research in the area of cardiovascular disease, hypertension and salt sensitivity," said Dr. Felder. "It's important because cardiovascular diseases, including stroke, account for more disability and death than the next top five causes combined."