|February 9, 2006|
|Uva Researchers Demonstrate Value for the First Genetic Test for High Blood Pressure and Sensitivity to Salt
Charlottesville, Va., Feb. 6, 2006 -- 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 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."
Researchers at the University of Virginia and Georgetown University Medical Center have discovered and characterized a set of gene polymorphisms that may be used to determine a persons predisposition to essential hypertension (high blood pressure) and salt sensitivity. With this discovery, a Charlottesville, Virginia startup, Hypogen, Inc., has developed a proprietary diagnostic test that provides a 70 percent prediction of the hypertensive phenotype, a rate significantly better than competing tests. This new test, called the Hypogen Test, will be available in early 2003 through the University of Virginia Health System and can be taken at any doctors office. This technology may also be used to facilitate ongoing research into the cause of high blood pressure.
An estimated 50 million American adults, one in four, suffers from high blood pressure, which is known as the Silent Killer because it shows no external symptoms. If undiagnosed and left untreated, high blood pressure can lead to heart attack, stroke, kidney failure and blindness. Recent research has shown that people who are sensitive to salt, but who do not otherwise exhibit high blood pressure, are just as likely to develop these complications as people with hypertension. In fact, complications arising from high blood pressure and salt sensitivity are the leading causes of death in America today. Unfortunately, by the time hypertension is diagnosed, irreversible damage to vital internal organs may have already taken place. By taking a quick and easy, non-invasive test, people can now find out whether they are sensitive to salt in their diet or at risk for developing hypertension. Information revealed by the Hypogen Test will also help doctors determine the most appropriate course of treatment, saving money and reducing unnecessary side effects.
Hypogen also plans to use these findings to search for novel drug targets to treat hypertension without the side effects associated with existing medications. Because the Hypogen gene polymorphisms are the first to be associated with essential hypertension that are located exclusively in the kidneys, Hypogen anticipates that this research may lead to an entirely new class of antihypertensive therapies.
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. This finding is allowing development of the first predictive medical test for high blood pressure, according to an article in the March 12 issue of Proceedings of the National Academy of Sciences.
The research team's results show that the presence of these gene variants, also called polymorphisms, can be determined by a simple genetic test used to assess an individuals risk of developing high blood pressure (hypertension). The test detects inherited gene variants by encoding for a protein called G protein when it is coupled with receptor kinase type 4 (GRK4). This gene in turn regulates a receptor in the kidney that is important in ridding the body of excess salt.
"This new genetic information will allow physicians to provide guidance to patients with a family history of hypertension, so they can modify their lifestyles to help prevent kidney failure, heart failure, stroke and blindness that can result from high blood pressure," said Robin A. Felder, principal investigator and professor of pathology at the U.Va. Health System, where the test was developed as part of the study.
"This discovery will lead to a new test for hypertension that will offer the same high quality diagnostic aid to physicians as the test created to diagnose genetic forms of breast cancer," he said. It will be suitable for screening a large number of patients based on a fluorescent molecular beacon assay.
During an 18-year collaboration between U.Va. and Georgetown University, the researchers found that variants in GRK4 lead to a reduced ability of individuals to excrete excess sodium and water from their bodies. When expressed in mice, this abnormal protein also produced high blood pressure. The presence of even a single GRK4 variant in tested subjects indicated a significantly increased the risk of developing hypertension later in life.
In other recent studies, these gene variants by themselves, or in interaction with other genes, were associated with essential hypertension in Caucasians, Ghanaians and Japanese populations. 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.
Hypertensive individuals have a delayed and inappropriate sodium excretory mechanism, said Dr. Pedro A. Jose, professor of pediatrics (TITLE) and senior author of the journal article. "This discovery is expected to provide a major breakthrough in the care of individuals at increased risk for hypertension, because hypertension is a treatable disease in almost 100 percent of cases. This is one disease in which lifestyle modification yields positive and predictable results."
The researchers' discovery also may lead to improved medical treatments for the disease. In another part of the study, U.Va. and Georgetown, in collaboration with Hironobu Sanada at Fukujima University in Japan, reported the use of an experimental drug (antisense technology) (????) to correct the biochemical error in human kidney cells that leads to high blood pressure. This treatment also corrects the high blood pressure in genetically hypertensive rats. Furthermore, the research teams have produced human cell lines that may lead to development of additional treatments for high blood pressure.
The findings in this study were submitted for patent protection in January of 1999, and now assigned to Hypogen, Inc., in Charlottesville. The research 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.
USA Weekend, July 19 - 21, 2002
"One-quarter of adults have hypertension (high blood pressure), a major risk factor for stroke, heart attack, heart failure and kidney failure. Doctors think it's hereditary in half of all cases, but until now they had no test to identify who caried the gene. A new patented test, developed by Georgetown University and University of Virginia researchers, identifies three abnormalities in a singe gene linked to hypertension . The so-called GRK4 variation identifies people with significant lifetime risk for developing hypertension; those people then can make early lifestyle changes to delay or prevent its onset."
UVA Press Release, September 24, 1999
University of Virginia Researcher Receives Award to Examining Genetic Causes for High Blood Pressure
The National Heart, Lung, Blood Institute (NHLBI) of the National Institutes of Health (NIH) has awarded more than $1.2 million to University of Virginia pathologist Robin A. Felder and his colleagues to study genetic causes of essential hypertension, or high blood pressure of unknown causes.
The research is looking for a genetic cause for high blood pressure or the propensity to develop high blood pressure. In addition, Felder will study salt-sensitive hypertension to determine why, in some people, a high salt diet causes elevated blood pressure or exacerbates blood pressure that is already high, while in others, there is no relationship between salt intake and blood pressure levels.
"Along with Dr. Pedro Jose at Georgetown University, I recently discovered FJ1, a mutated protein that may provide insight into the cause of this elusive disease," Felder said. "We will use the NHLBI grant to study the role FJ1 plays in the development or maintenance of high blood pressure. In addition, we hope to generate a genetic blood test that may yield predictive information for those with a family history of high blood pressure. This research could have a significant impact on reducing cardiovascular disease."
At least 25 percent of the adult population has high blood pressure. As much as 30 percent of blood pressure variability is thought to be a result of genetic factors. Left untreated, high blood pressure can lead to cardiovascular disease, stroke, heart attack and end-stage kidney disease. Because people with high blood pressure generally feel well, it often goes undiagnosed and untreated until a serious medical problem develops. As a result, high blood pressure is the leading cause of cardiovascular morbidity and mortality in this country.
In the last decade, the death rate from cardiovascular disease fell significantly, but the actual number of individuals who died from cardiovascular diseases declined only slightly, according to the American Heart Association's 2001 Heart and Stroke Statistical Update, an annual report released today.
From 1988 to 1998, the age-adjusted death rate from cardiovascular diseases (CVD) per 100,000 people fell 20 percent. For coronary heart disease alone, the death rate in that same 10-year period declined by 26 percent. However, the actual numbers of deaths fell by just 3 percent and about 10 percent, respectively.
Age-adjusted death rates are used to compare death rates per 100,000 people in the nation over time. These rates use a standard population so they aren't affected by changes in the age composition of the population. However, when actual numbers of deaths are considered, the numbers are likely to be affected by factors such as an aging population.
Though the lower death rate and fewer deaths are good news, cardiovascular diseases still claimed almost 950,000 lives in the United States in 1998, the most recent year for which data are available. That includes 459,841 from coronary heart disease and 158,448 from stroke. Cardiovascular diseases include high blood pressure, coronary heart disease (including heart attack and angina), stroke, congenital cardiovascular defects and congestive heart failure among others.
President of the American Heart Association Rose Marie Robertson, M.D., emphasizes that there's still a lot of work to be done to meet the goal of reducing death and disability from heart disease and stroke by 25 percent in the year 2010. "Cardiovascular diseases still cause more deaths in both men and women in the United States than the next six causes of death combined, the prevalence of hypertension is still very high, and minorities with CVD are still underserved and undertreated from slower 9-1-1 response times in minority neighborhoods to a lower likelihood of minorities receiving lifesaving treatments or devices," she says.
The expected price tag for CVD in 2001 is nearly $300 billion. This amount covers the price of health spending (such as the direct costs of physicians and other professionals, hospital and nursing home services, the cost of medications, home health and other medical durables) and indirect costs such as lost productivity resulting from death and disability.
High blood pressure toll rising
About 50 million Americans age 6 and older have high blood pressure, or hypertension. From 1988-1998, the death rate from high blood pressure increased 16 percent. Of those with high blood pressure, 32 percent are unaware they have it, 54 percent are on medication (about half of whom have their blood pressure controlled), and 15 percent are aware they have the condition, but still not on medication. High blood pressure directly increases the risk of coronary heart disease (which leads to heart attack) and stroke, especially when other risk factors are present, and it is a major cause of congestive heart failure.
"High blood pressure is easily identified and often easily controlled," says Robertson. "It usually has no specific symptoms or early warning signs so it truly is a silent killer."
Stroke still burdensome
The report includes an update on stroke statistics. From 1988-1998, the stroke death rate per 100,000 individuals fell 15 percent, but the actual number of stroke deaths increased more than 5 percent. Stroke remains the third leading cause of death in the United States, and a major cause of disability, and is particularly burdensome in minorities.
The American Heart Association established the American Stroke Association in Nov. 1998, launching Operation Stroke to raise awareness for risk factors and warning signs of stroke, and to improve quality of care in medical facilities nationwide.
"We are still seeing large numbers of people dying from stroke and suffering major disabilities," says Edgar Kenton, M.D., chair of the American Stroke Association advisory committee. "It is important for us to continue our focus on prevention as a way to reduce the toll of this disease, as well as to make the public aware that we have much more effective treatments for stroke if patients come to the hospital within the first three hours of experiencing symptoms."
Women and minorities still fare worse
Though there were fewer total deaths due to cardiovascular diseases in 1998 compared to 1997 - and CVD deaths among men seem to be decreasing CVD deaths among women increased by about 1,000 individuals to a total of nearly 504,000. CVD continues to claim over 58,000 more women than men each year.
The 2001 update also includes more information and statistics on minorities with heart disease (see Figure A). These statistics shed new light on the striking differences in risk factors and disease rates among minority populations, especially minority women.
"The striking differences by both ethnicity and socioeconomic status underscore the critical need to improve screening, early detection and treatment of CVD-related conditions for black and Mexican-American women, as well as for women of lower socioeconomic status in all ethnic groups," the report says. Among blacks in general, the risk of death from both stroke and high blood pressure remain significantly higher than for whites. This, too, highlights a need for more effective outreach to these groups.