Mixed Blessing: Unusual gene helps heart, hurts immunity

Molecules called toll-like receptors sit on the surface of human cells, always ready to start a reaction against bacteria and other invaders. When activated, the receptors call in a posse of immune system cells and proteins that take a shoot-first-and-ask-questions-later approach to strangers (SN: 9/8/01, p. 152: Immunity’s Eyes). Researchers now report that in certain people, one of these signaling molecules, toll-like receptor 4, is not so trigger-happy.

The scientists report in the July 18 New England Journal of Medicine that people carrying the gene for this version of the receptor seem to generate less inflammation as they rev up an immune response than do people who harbor the garden-variety gene for toll-like receptor 4.

The upshot is both bad and good news for the people with the gene variant. They appear to have a weaker front-line defense against infection but seem less prone to heart disease than people with the normal gene are.

A team of researchers in the United States, Austria, and Italy discovered this oddity as part of a study of atherosclerosis–the buildup of fatty plaques in arteries–and other health problems in randomly chosen volunteers in Italy.

Blood samples from 810 study volunteers taken between 1990 and 2000 showed that 55 of the people carry the variant of the gene for toll-like receptor 4. These people had significantly lower concentrations of several inflammatory proteins in their blood than the others did and were more likely to develop a severe infection during the study.

To evaluate heart health, the scientists performed ultrasound examinations of plaque buildup in the participants’ carotid artery, the large Y-shaped vessel that supplies blood to the head. Carotid atherosclerosis is a reliable indicator of plaque buildup in arteries of the heart. People with the low-inflammation gene had about half as much atherosclerosis in the carotid artery as did those with the common gene form, says study coauthor David A. Schwartz, a pulmonologist at Duke University Medical Center and the Veterans Affairs Medical Center in Durham, N.C.

The researchers weren’t surprised to find a link between atherosclerosis and toll-like receptor 4. They knew that this receptor is routinely activated by Chlamydia pneumoniae and Helicobacter pylori, two bacteria that have been implicated in heart disease.

Because inflammation aggravates atherosclerosis, a muted inflammatory response in people with the variant form of the toll-like receptor 4 gene may limit plaque accumulation, Schwartz says.

“This is an interesting phenomenon that immunologically makes a lot of sense,” comments immunologist Scott E. Plevy of the University of Pittsburgh School of Medicine.

“Many diseases we get are the function of these very subtle [variations] that don’t disable a gene but allow it to function somewhat differently,” Schwartz says.

Scientists may someday use such information to create genetic profiles of high-risk heart patients, he says.

Researchers haven’t yet tried suppressing toll-like receptors as therapy for atherosclerosis. Altering them would carry a risk because they belong to an ancient part of the immune system. “It’s our first line of defense against the external environment,” Plevy says. Nevertheless, there may be a way to mute toll-like receptors safely. The idea “is now more than fantasy,” he says.