Whether genes responsible for a rare disorder that dramatically elevates blood pressure holds clues for identifying many people at risk for hypertension is the focus of a new study.

The rare disorder is Liddle syndrome, first reported in 1963 in a 15-year-old Alabama girl diagnosed with a blood pressure of 180/110 mmHg, says Dr. Yanbin Dong, molecular geneticist and cardiologist at the Medical College of Georgia.

Interestingly, an inexpensive diuretic worked best to manage her problem. Tests years later found the reason was that genes involved in the channel that recycles sodium from food into the body were drastically mutated. "This mutation enables sodium to come back into the body like a flood," says Dr. Dong.

Today he is looking at sodium channel genes implicated in Liddle syndrome to identify less severe changes that could be used to screen for hypertension risk in the general population.

"My hypothesis is if Liddle syndrome is caused by these nasty, drastic mutations, maybe the majority of hypertension can be caused by milder, less nasty polymorphisms or variations in the same genes," says Dr. Dong who received a $1.43 million grant from the National Heart, Lung and Blood Institute to see if he is correct.

He's recruiting 300 healthy blacks ages 15 to 19 with normal blood pressure to a Georgia Prevention Institute study that first measures sodium-handling following environmental stress, then analyzes the genes of those who don't handle it well.

Dr. Dong is exploring findings by Dr. Gregory A. Harshfield, director of the Georgia Prevention Institute, showing that some healthy youths, particularly black youths, continue to retain sodium after the stress that drove up their blood pressure is gone. This impaired stress-induced pressure natriuresis occurs in about 36 percent of healthy black youths and 25 percent of healthy white youths, according to Dr. Harshfield's studies.

The body naturally increases blood pressure during stress, immediately by constricting blood vessels and longer term by directing the kidneys to retain more sodium and so increase blood volume, says Dr. Harshfield, a co-investigator on Dr. Dong's latest grant. His own studies have shown the importance of the interaction between salt and stress in regulating blood pressure.

The new study should provide additional insight into the relationship between salt and stress as well as diet and genetics, Dr. Dong says.

Study participants will be on a salt-restricted diet for four days, then come to the GPI on the fifth day to rest for an hour, play competitive video games and rest again. Blood pressure and sodium excretion will be measured before games are played, immediately afterward, then two hours later.

The five genes - alphaENaC, betaENaC, gamma ENaC, SGK-1 and Nedd4-2 - taken from blood samples will be analyzed so specific variations can be correlated with variations in a youth's ability to excrete sodium after stress has passed. Gene-to-gene interactions also will be studied.

Researchers say poor sodium-handling is a major player in hypertension and that a youth's reduced ability to excrete salt following stress is a sign of what's to come.

If Dr. Dong's hypothesis holds, young people with risky genetic variations could have advance warning of their increased hypertension risk and make changes such as salt intake restriction and stress reduction management to ideally avoid the problem.

The body needs sodium but doesn't produce it, Dr. Dong notes. Still most people get adequate sodium in their diets without adding salt to food.



Other co-investigators are Dr. Haidong Zhu, molecular geneticist; Dr. Harold Snieder, genetic epidemiologist; and Dr. David Ludwig, biostatistician.

Contact: Toni Baker
Medical College of Georgia