"Salt Gene" Determines Benefit Of Low-Salt Diet

September 17, 1998

DALLAS, Sept. 18--Researchers have identified a "salt gene" that helps explain the variation in an individual's response to a low-salt diet for reducing high blood pressure. The research is reported in this month's Hypertension: Journal of the American Heart Association.

The gene--called the angiotensinogen gene -- is thought to influence the effect of dietary salt on blood pressure. Increased blood levels of angiotensinogen, the hormone that the gene encodes, have been correlated with high blood pressure.

Researchers studied three forms or variations of the gene, referred to as AA, AG and GG. A person's sensitivity to salt -- meaning that they may fare better in lowering their blood pressure through salt restriction -- was associated with the type of gene variation.

"This is a first step in defining who is salt sensitive and who is not," says lead author Steven C. Hunt, Ph.D., professor of medicine at the University of Utah School of Medicine in Salt Lake City. "However, we are not to the point yet where we can say on an individual basis: If you have one particular form of the gene, the AA form, you are salt sensitive."

The researchers obtained blood samples from 1,894 people in a three-year study called the Trials of Hypertension Prevention (TOHP). Hunt's team studied a specific section of the angiotensinogen gene to determine which of three gene variations each person carried.

Because only 10 of 323 African Americans in the study carried the GG and only 62 participants represented other nonwhite races, the team could only do a meaningful analysis on the 1,509 Caucasians in the study.

TOHP participants were moderately overweight and had borderline high blood pressure. That is, their diastolic blood pressure -- the force pressing on blood vessels between heart contractions -- was between 83 and 89 millimeters of mercury (mm/Hg). This is below the level of 90 mm/Hg that doctors normally regard as high blood pressure.

The TOHP participants, men and women ranging in age from 30 to 54, were divided into four groups to determine whether sodium reduction and weight loss would significantly reduce blood pressure.

One group ate a low-salt diet; another followed a weight-loss diet; a third was put on a combination of the two diets; and the fourth, the "usual care" group, was not given a special diet. Participants were examined at six, 18, and 36 months after beginning the study.

Hunt and his colleagues found a significant difference in diastolic blood pressures among people in the low-salt group, depending on which form of the angiotensinogen gene they had.

At the end of the study, people in the low-salt group who carried the AA form had an average diastolic pressure 2.2 mm/Hg lower than those in the usual care group with this gene type. Their diastolic pressure was also 3.3 mm/Hg lower than those with GG, whose blood pressure had actually risen an average of 1.1 mm/Hg compared to the usual care group.

Those with the AA form maintained their blood pressure drop at all three visits. "The GGs started out with about the same amount of blood pressure decrease at six months as AAs and AGs, but they lost their ability to maintain a lower blood pressure over time," says Hunt.

The positive results seen with the AA group is considered particularly interesting, says Hunt, because among people in the usual care group, those with the AA were more likely to develop high blood pressure.

Surprisingly, the statistically significant differences among the three gene types did not appear until late in TOHP. "We didn't see it at the six-month visit or at the 18-month visit," Hunt explains. "We don't know quite what to make of it."

Participants in the weight-loss group had similar blood pressure reductions to those seen in the sodium-reduction group for each angiotensinogen gene type. Individuals who carried the AA or AG did lower their blood pressures on the weight-loss diet, but individuals with GG did not. The results were less clear among people who were in the combination sodium-reduction and weight-loss group, says Hunt.

"The results would be more credible if they had been consistent over time and if an effect of angiotensinogen gene type had also been observed in the combination intervention group," writes Theodore A. Kotchen, M.D., professor and chairman of the department of medicine, of the Medical College of Wisconsin, Milwaukee, in an accompanying editorial.

Additional studies are needed to determine what casual role, if any, the different angiotensinogen variations play in the sensitivity of blood pressure to sodium, Kotchen adds.

Co-authors of the paper are Nancy R. Cook, D.Sc.; Albert Oberman, M.D.; Jeffrey A. Cutler, M.D.; Charles H. Hennekens, M.D.; P. Scott Allender, M.D.; W. Gordon Walker, M.D.; Paul K. Whelton, M.D.; and Roger R. Williams, M.D.

American Heart Association

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