First link found in humans between common gene and artery-clogging disease

Study in NEJM indicates dietary fatty acids may influence atherosclerosis in a segment of the population genetically at risk

Scientists have found the first strong link in humans between a common gene and risk for the disease that leads to most heart attacks and strokes, according to results of a study by researchers at the Keck School of Medicine of the University of Southern California and the David Geffen School of Medicine at UCLA.

People with a variant form of a gene called 5-lipoxygenase (ALOX5) have a greater risk of atherosclerosis, a build-up of cholesterol in artery walls that contributes to heart disease, scientists report in the Jan. 1 issue of the New England Journal of Medicine. The high-risk form of ALOX5 occurred in about 5 percent of participants in the Los Angeles Atherosclerosis Study, which follows the cardiovascular health of 470 utility workers in Southern California.

Researchers have known for many years that atherosclerosis risk may run in families, yet the genetic markers known to increase risk for atherosclerosis either were rare or made only a slight difference. This new finding, however, indicates that a substantial proportion of people carry a form of ALOX5 that may wield potent effects on cardiovascular disease.

“One of the most interesting aspects of this new finding is that the effect of the ALOX5 gene on atherosclerosis depends upon diet,” says co-author James Dwyer, Ph.D., professor of preventive medicine at the Keck School of Medicine of USC and the Los Angeles Atherosclerosis Study’s principal investigator. “The adverse effect of this gene is increased by dietary intake of certain n-6 polyunsaturated fats, while the adverse effect is blocked by intake of fish oils containing n-3 polyunsaturated fatty acids.”

For those who carry a high-risk form of ALOX5, the “bad” fats are two n-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 n-3 (or omega-3) fatty acids, found mainly in oily fish such as salmon.

This diet-gene interaction makes scientific sense, since the ALOX5 protein serves to convert fatty acids into molecules involved in inflammation, and scientists believe atherosclerosis is an inflammatory process.

Results also suggest that people with a high-risk form of ALOX5 could reduce their risk by eating less n-6 polyunsaturated fats and more n-3 polyunsaturated fatty acids. In the rest of the population, eating these fatty acids seems to have little impact on atherosclerosis, Dwyer adds-although there is substantial evidence that consuming a lot of n-3 fatty acids from fish oils prevents arrhythmias involved in sudden cardiac death.

Co-author Hooman Allayee, Ph.D., human genetics researcher at the David Geffen School of Medicine at UCLA, noted that earlier research links ALOX5 to asthma, so physicians might potentially prescribe existing asthma medications to prevent and control atherosclerosis in those genetically at high risk.

“Our conclusions suggest that 5-lipoxygenase could be used as a genetic marker for heart disease, and should lead to improved diagnosis, prevention and treatment for atherosclerosis,” Allayee says.

The team’s work was driven by a mouse model developed by Margarete Mehrabian, Ph.D., senior author and UCLA assistant professor of human genetics. She was the first to show that eliminating the gene from the mouse genome helps protect against atherosclerosis, even when the rodent ate a fat-heavy diet. Other researchers have shown that knocking out other inflammatory genes can protect mice against atherosclerosis, but attempts to link alterations in inflammatory genes to atherosclerotic disease in humans generally has been disappointing.

For this study, the team examined 470 healthy middle-aged women and men. Researchers recorded each participant’s diet over 18 months and used ultrasound to measure the thickness of carotid artery walls in each participant-a gauge of atherosclerosis and heart disease risk.

Scientists also examined the ALOX5 gene in DNA sampled from each participant. The ALOX5 gene can be found in a few different varieties, or polymorphisms, within the population, in addition to the common form of the gene.

The scientists found that artery walls were as much as 18 percent thicker among participants who did not have the common form of ALOX5. And walls thickened faster among those with a high-risk version of ALOX5 who ate more food containing n-6 polyunsaturated fatty acids, while a diet abundant in n-3 polyunsaturated fatty acids seemed to protect them.

Researchers found the ALOX5 variations more frequently in certain ethnic groups. About 20 percent of African Americans and Asian Americans had the genetic variant, compared to less than 5 percent of Latinos and non-Latino whites.

A grant from the National Institutes of Health supports the Los Angeles Atherosclerosis Study. The American Heart Association also sponsored the research.

James H. Dwyer, Hooman Allayee, Kathleen M. Dwyer, Jing Fan, Huiyun Wu, Rebecca Mar, Aldons J. Lusis, Margarete Mehrabian, “Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. The Los Angeles Atherosclerosis Study,” New England Journal of Medicine. 2004, Vol.350, No. 1, pp. 29-37.