Genes That Control Body's Salt Levels Are Identified
MONDAY Feb. 16, 2009 -- The largest study of the effects of genetics on blood pressure in humans has linked variant versions of genes that control levels of salt in the body with high blood pressure, a major risk factor for heart disease and stroke.
"There have been hundreds of genes and gene variants reported to be related to blood pressure," said Dr. Christopher Newton-Cheh, assistant professor of medicine at Harvard Medical School and the Center for Human Genetic Research at Massachusetts General Hospital and lead author of a report in Nature Genetics. "What distinguishes this study is the ability to genotype 30,000 people to establish a relationship that these gene variants cause higher levels of natriuretic peptides and therefore are related to blood pressure." Natriuretic peptides are compounds that help the body get rid of salt.
It's not yet clear that the finding will be of use in medical practice, Newton-Cheh said. Drugs aimed at the genes might be no more effective at keeping high blood pressure under control than existing medications, such as diuretics, he said. But the study does offer valuable insight into a basic physiological cause of high blood pressure.
The researchers looked at variants of two genes for these peptides -- atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). They found three variants clearly related to higher levels of the peptides and, therefore, to lower blood pressure. Higher peptide levels lead to lower blood pressure because "these are molecules designed to let the body get rid of salt and relax blood vessels," Newton-Cheh explained.
"What's exciting about this study is that it proves that in human beings, natriuretic peptides are important in blood pressure," he said. "Until now, the finding has been limited to animals -- that if you take away the ANP gene in mice, you get hypertension [high blood pressure]."
The medical implication of the study is that "there are people out there who do not have enough natriuretic peptide, and they can be targeted to increase those peptides," Newton-Cheh said.
But that may be easier said than done, he added. For one thing, genetics might not be the only reason why people have low peptide levels. Other factors, such as obesity, might be involved.
And natriuretic peptides are essentially simple proteins that are quickly broken down once they enter the body. It might be possible to make a peptide-targeted drug that would be kept active by tying it to another molecule, but that remains to be seen, Newton-Cheh said.
Also, existing blood pressure medications work quite well if taken as prescribed, so the value of proposed newer drugs is not clear, he said.
Dr. John C. Burnett, professor of cardiovascular research at the Mayo Clinic, said that such drugs could be valuable because of the central role of the natriuretic peptides in controlling blood pressure.
"What we are doing at Mayo is developing what you might call designer peptides," Burnett said. "We change the amino acid sequence so that the body's usual system of getting rid of these peptides is diminished. We are engineering the body's own peptides to create super peptides."
The U.S Food and Drug Administration has approved a human trial of the first of those molecules, one aimed at heart failure, Burnett said. There is a parallel effort to develop molecules that would help control blood pressure.
The current generation of experimental peptides must be given in the same way as insulin, by injection under the skin, "but our plan is to modify these peptides so they can be given orally," he said. "That would be a massive breakthrough."
Another gene variant that might make people more likely to develop hypertension was reported in December by University of Maryland researchers. Their discovery was of a mutation that seems to reduce blood levels of fats called triglycerides and thus lower the risk of heart disease.
First identified in an Amish community in Pennsylvania, the gene variant is present in about one of every five white Americans, according to their report, published in the Proceedings of the National Academy of Sciences.
The U.S. National Heart, Lung, and Blood Institute has more on lowering blood pressure.
Posted: February 2009
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