by Alicia Di Rado

Something fishy is going on in the world of medicine, and human health may be the better for it.

Across the world, researchers are uncovering the benefits of omega-3 fatty acids, the dietary fats abundant in mackerel, salmon, sardines and other oily ocean fish, as well as walnuts and avocados. Already touted for protecting against potentially fatal irregular heartbeats, these fatty acids might also help boost immunity, maintain mental health and prevent diabetes complications, among other health concerns.

At the Keck School of Medicine of USC, researcher James Dwyer, Ph.D., and his colleagues are examining how omega-3 polyunsaturated fatty acids from foods might help the circulatory system. Dwyer’s research shows that fatty acids seems to protect people who are vulnerable to atherosclerotic disease, a dangerous build-up of fats along the inner walls of arteries. Atherosclerosis sets the stage for most heart attacks and strokes.

But there is more, says Dwyer, professor of preventive medicine. The studies provide much-needed evidence that links genes, inflammation and diet as intertwined instigators for atherosclerosis.

If science proves the links true, not only might new heart-protecting medications result, but individuals might also have better clues than ever before about the specific foods they should chew—and eschew—to keep themselves healthy.

Dwyer and his fellow medical researchers from USC and the David Geffen School of Medicine at UCLA kicked off 2004 with a high-profile start: In its Jan. 1 issue, the New England Journal of Medicine published the team’s atherosclerosis study, spurring media coverage across the globe.

For the first time in humans, the researchers discovered that those who possess a common gene are at greater risk for atherosclerosis that progresses at a rapid clip. And, interestingly, that risk can be curbed or exaggerated through diet.

The story, though, begins not with humans, but with the modest mouse.

Study co-author Margarete Meh-rabian, UCLA assistant professor of human genetics, studied the 5-lipoxygenase gene (or ALOX5) in the tiny rodents. She found that when researchers eliminated ALOX5 from the mouse genome, the rodents were protected against atherosclerosis, even when they ate a diet high in fat. Researchers surmised that ALOX5 might be important in human atherosclerosis, too, and merited some detective work—even though attempts to link alterations in other genes to atherosclerotic disease in humans generally have not panned out.

The scientists delved into the Los Angeles Atherosclerosis Study to investigate ALOX5’s importance. The ongoing study, spearheaded by Dwyer, follows 470 healthy, middle-aged Southern California utility workers, both male and female.

Researchers recorded each participant’s diet over 18 months and used ultrasound to measure the wall thickness of arteries in the neck of each participant—a gauge of atherosclerosis and heart disease risk.

Scientists examined the ALOX5 gene in DNA sampled from each participant. All human beings have the ALOX5 gene, but the gene can be found in a few different varieties within the population, in addition to the common form of the gene.

Among participants who had ALOX5 variations, artery walls were an average 18 percent thicker. Researchers found the ALOX5 variations in about 20 percent of African Americans and Asian Americans and nearly 5 percent of Latinos and non-Latino whites.

Interestingly, among those with a variant form of ALOX5, artery walls thickened either faster or slower depending on consumption of dietary fats.

For those with a high-risk form of ALOX5, the “bad” fats are two omega-6 polyunsaturated fats called arachidonic acid and linoleic acid. Arachidonic acid is found in some meats, while linoleic acid is found in many vegetable oils. The “good” fats for this group are omega-3 fatty acids.

This diet-gene interaction makes scientific sense, says Dwyer.

“The function of ALOX5 is to convert fatty acids into molecules involved in inflammation,” Dwyer says. “Since atherosclerosis is an inflammation of the arteries, our findings suggest that persons with this ALOX5 variation could reduce their risk of heart disease by modifying their diet.”

In the rest of the population, eating these fatty acids seems to have little impact on atherosclerosis, Dwyer adds, although omega-3 fatty acid consumption has been linked to lower risk of potentially fatal arrhythmias.

Inflammatory Cause

Dwyer is particularly interested in the study’s implications for the mysterious roots of atherosclerosis.

As far back as 1852, some scientists proposed that inflammation helped cause atherosclerosis, but conclusive evidence has been elusive. In an editorial accompanying the study in the New England Journal of Medicine, though, two other physicians commented that the study findings “contribute to the untangling of the intricate connections between inflammation and atherosclerosis in humans, and might actually provide the first proof of a causal link between the two.”

Because inflammation accompanies almost all injury and disease, it is often the result, rather than a cause, of a problem, Dwyer explained. Scientists have had a hard time figuring out which comes first in atherosclerosis—the disease or the inflammation.

But in Dwyer’s study, results indicate that altering a pathway of inflammation (through genetics) actually can cause atherosclerosis. For carriers of the variant ALOX5 genes, the body’s attempts to fix injury to artery walls from normal wear and tear actually seem to cause new injury to artery walls.

And after years of this vicious circle of inflammation and buildup, the resulting atherosclerotic plaques finally rupture and produce heart attacks and strokes, he adds.

Dwyer says that large studies involving hundreds of thousands of participants will be needed to completely determine the genetic causes of atherosclerotic disease. But there may be a few genes, such as ALOX5, in which alteration of a single gene will wield a hefty impact on risk of the disease.

“It is also likely that most genes with forms that increase the risk of atherosclerotic disease will have a greater impact among persons with certain diets, lifestyle patterns or exposures,” he adds. “At some point in the future, dietary advice for disease prevention will probably be tailored to a person’s genetic makeup.”