Rare Mutations Can Keep Blood Pressure Low

Scientists have identified rare variations in 3 genes that can protect against hypertension and its consequences, such as stroke, kidney disease and heart failure.

High blood pressure, or hypertension, affects about 1 in 3 adults nationwide and about 1 billion people across the globe. It can cause significant damage to the heart, blood vessels, kidneys and other parts of the body. Scientists have tried—but so far failed—to find common genetic variations that affect blood pressure or lead to hypertension.

Rather than looking for genetic variations across the entire genome, a research team, led by Dr. Richard P. Lifton of Yale University School of Medicine and including Dr. Daniel Levy of NIH's National Heart, Lung and Blood Institute (NHLBI), focused on rare variations in 3 genes that are known to cause severe inherited blood pressure disorders. All 3 genes affect how the kidneys process salt, which in turn influences blood pressure.

In earlier research, the team found that people who inherit 2 defective copies of any of these salt-regulating genes develop a rare disease—such as Gitelman or Bartter syndrome—marked by dangerously low blood pressure. In the new study, which appeared in the April 6, 2008, online edition of Nature Genetics, the scientists hypothesized that inheriting a single defective copy of 1 of these salt-regulating genes might lead to a less severe, perhaps even beneficial, reduction in blood pressure.

The researchers analyzed DNA from 3,125 participants in the NHLBI-funded Framingham Heart Study, which has been monitoring the cardiovascular health of thousands of people and their offspring for more than 5 decades. They carefully sequenced the DNA of the 3 genes, looking for tiny variations that would affect the functions of the resulting protein.

The researchers found that 2% of the tested participants had a single defective copy of 1 of the 3 genes. These individuals had significantly reduced blood pressure compared to their counterparts who had the normal variants. They also had a 60% lower risk of developing hypertension by the time they were 60 years old.

Because these 3 genes represent just a portion of those already known to affect blood pressure, and because many more are likely to be discovered, Lifton and his colleagues conclude that rare variants could have a powerful combined effect on blood pressure in the general population. Their findings are just the latest in a recent spate of papers suggesting that rare genetic variations may be significant contributors to widespread and complex diseases, including schizophrenia, autism and certain cancers.

"Collectively, common variants have explained a small fraction of the risk of most diseases in the population, as we would expect from the effects of natural selection," Lifton says. "The question this leaves open is whether many rare variations in genes will collectively account for a large influence on common disease."

—by Vicki Contie