Genetic evidence to support an inherited tendency to retain salt

Researchers at the University of Chicago have found genetic evidence to support the sodium-retention hypothesis, a controversial 30-year-old theory that the high rate of hypertension in certain ethnic groups is caused, in part, by an inherited tendency to retain salt.

In the December issue of the American Journal of Human Genetics, (available now on-line) the researchers show that the frequency of one version of a gene that plays a crucial role in salt retention correlates with distance from the equator. Populations that live in hot, humid climates near the equator tend to have the normal version of that gene, which produces a very effective protein. Populations adapted to cooler climates tend to have a mutant gene that codes for a totally dysfunctional protein.

"The surprise," said study author Anna Di Rienzo, Ph.D., associate professor of human genetics at the University of Chicago, "was finding that as populations moved away from the tropics the original or normal version of the gene became less and less common and the 'broken' version more frequent, which suggests it is protective. There seems to be a strong selective advantage conferred by the non-functioning protein, and that advantage increases with latitude."

"This could change the way we look for disease genes," she added. "Historically, we have searched for mutations, altered or damaged versions of genes that cause rare disorders, like cystic fibrosis or phenylketonuria. Now, we are starting to look for common genes that may have been beneficial in an environment of scarcity, but have become harmful in a world of plenty. In the modern setting, it may often be the genes that aren't damaged that predispose to disease, such as the "thrifty genes" associated with type 2 diabetes."

Humans need salt, sodium chloride, to transport nutrients, transmit nerve impulses or contract muscles, such as the beating heart. The average adult contains about 250 grams of salt, enough to fill three small saltshakers. This salt is constantly lost through sweat and urine and replaced through the diet.

Salt is now "so common, so easy to obtain and so inexpensive," according to Mark Kurlansky, author of a recent history of salt, "that we have forgotten that from the beginning of civilization until about 100 years ago, salt was one of the most sought-after commodities in human history."

In the sub-Saharan African regions where humans first appeared, available salt must have been limited and quickly lost through sweat. People who were better at retaining salt may have had a significant survival advantage.

This advantage decreased as humans spread to cooler climates. The first suggestion that too much salt, rather than too little, may be harmful appeared in a Chinese text on herbal medicines, which linked dietary salt to high blood pressure. "Too much salt in food endangers the heart," notes the Yellow Emperor's Classic of Internal Medicine, "the pulse hardens, tears make their appearance and the complexion changes."

About two thousand years later, too much salt has become the norm. Despite a recommended daily allowance of less than six grams of salt, the average American consumes about 10 grams daily.

Since 1972, a series of studies has attempted to connect excess salt intake to high blood pressure, but that connection remains uncertain. After three decades of ecologic studies, intrapopulation studies and clinical trials of salt reduction, the controversy over the benefits of lowering salt intake "constitutes one of the longest running, most vitriolic, and surreal disputes in all of medicine," wrote journalist Gary Taubes in Science Magazine in 1998.

Di Rienzo's team of evolutionary biologists took a different approach, looking at the genetics of salt processing. They focused on a gene called CYP3A5, part of a family known as cytochrome P450 genes, which help the body break down and eliminate a wide range of compounds, including many drugs and salt. In the kidney, CYP3A5 acts to retain salt. One version of this gene, however, a mutation known as "CYP3A5 *3," produces a truncated, non-functional protein.

The researchers looked at variations of this gene in 1,064 individuals drawn from 52 populations scattered around the world. The mutation was least common in some natives of sub-Saharan Africa, ranging from a low of only six percent of Yorubans in Nigeria (Latitude 8°N) to 31 percent among the Mandenka of Senegal (12°N). Rates were higher among populations in East Asia, ranging from 55 percent among the Dai of China (21°N) to 75 percent among Han Chinese (32°N) to 77 percent among Japanese (38°N) and 95 percent among the Uygur of China (44°N). Rates in Europe are uniformly high, ranging from 80 to 95 percent in Italy, France and Russia. The highest rate, 96 percent, was found among the Basque, an isolated ethnic group of uncertain origins now concentrated in the Pyrenees mountains (43°N).

The correlation between distance from the equator and CYP3A5 *3 was maintained when the focus was narrowed to 18 East Asian populations spread out over 51 degrees of latitude.

The researchers found one other gene, for a hormone called angiotensin (AGT), that followed a similar distribution pattern with different versions that correlated with distance from the equator. AGT is also involved in salt retention and has been associated with hypertension and pre-eclampsia, a complication of pregnancy. One variation of this gene, known as AGT M235, was closely correlated with CYP3A5 *3.

This correlation of two unlinked gene variants with similar effects, "is remarkable," the authors note, "and suggests a shared selective pressure."

The National Institutes of Health funded this study through the Pharmacogenetics Research Network. Additional authors include E. E. Thompson, H. Kuttab-Boulos and D. Witonsky of the University of Chicago, and L. Yang and B. A. Roe of the University of Oklahoma.