Rare genetic mutations protect against hypertension

Howard Hughes Medical Institute (HHMI) researchers have found that rare mutations in three genes contribute to blood pressure variation in the general population.

The scientists had previously shown that mutations in the three “salt handling” genes cause several rare diseases that are characterized by low blood pressure. By sequencing DNA samples obtained from 3,125 people who are participating in the Framingham Heart Study, the researchers identified new functional mutations in these three genes that are likely to be carried by an estimated 100 million people worldwide.

The Framingham Heart Study was begun in 1948 in an effort to identify common factors or characteristics that contribute to cardiovascular disease by following its development over a long period of time in a large group of participants who had not yet developed overt symptoms of cardiovascular disease or suffered a heart attack or stroke.

“We find that about two percent of the population has mutations in at least one of these three genes – although all of the identified mutations are individually very rare,” said senior author Richard P. Lifton, a Howard Hughes Medical Institute researcher at Yale University School of Medicine. “Mutation carriers have reduced blood pressure, with a 60 percent reduction in the risk of hypertension at age 60.”

The findings, reported in the April 6, 2008, edition of the journal Nature Genetics, are important because they yield tantalizing new evidence about why some people seem to be less susceptible to developing high blood pressure, a condition that affects a billion people worldwide and contributes significantly to heart and kidney disease, and stroke.

What's more, by identifying the role played by rare genetic mutations in governing how the kidney regulates salt, the researchers have devised a general approach that may be broadly applicable to uncovering the genetic architecture of common conditions such as hypertension.

“This new study, for the first time, extends the findings from patients with rare Mendelian traits to the general population. The findings suggest that independently rare mutations that alter salt handling by the kidneys collectively account for a substantial fraction of the general population's variability in disease susceptibility,” said Lifton.

Lifton noted that there are probably about 100 million people worldwide who carry the mutations and are thus protected from hypertension. “The mutations we have identified have clinically meaningful effects to individual patients and suggest that independently rare mutations will collectively account for a substantial fraction of the population's variability in disease susceptibility,” he said.

The researchers started by examining variations in three genes known to cause rare recessive diseases characterized by large reductions in blood pressure. The analysis was conducted on “salt handling” genes isolated from people involved in the Framingham Heart Study (FHS), which is directed by Daniel Levy of the National Heart, Lung and Blood Institute. Levy is a co-author of the Nature Genetics report. Co-first authors Weizhen Ji and Jia Ni Foo are at Yale University School of Medicine.