Mutation in the gene for 5-lipoxygenase can raise the levels of inflammatory mediators called leukotrienes, resulting in accelerated development of atherosclerosis in affected people, according to an article in the January 1st issue of the New England Journal of Medicine. Researchers are currently investigating whether a blood test for variant forms of the enzyme can serve as a marker for cardiovascular disease risk.

"We discovered that the arteries of a 40-year-old with modified 5-lipoxygenase look like those of a 50-year-old with the normal version of the gene," explained Hooman Allayee, Ph.D., a coauthor of the article. "Our findings suggest that this form of 5-lipoxygenase speeds the development of atherosclerosis in 5 percent of the population, intensifying a person's risk for heart attack and stroke."

Because research has long linked enzyme-mediated leukotriene activity with asthma, drugs derived from that work may be useful in preventing or treating atherosclerosis in the roughly 6 percent of the population with a mutant enzyme.
"This opens up a new market for existing asthma drugs that already target 5-lipoxygenase," noted Allayee. "Our conclusions suggest that modified 5-lipoxygenase could be used as a genetic marker for heart disease and lead to improved diagnosis, prevention, and treatment for atherosclerosis."

Findings from the current study also indicate that diet may play a key role in controlling heart disease risk related to the enzyme and leukotriene-mediated inflammation." We found that 5-lipoxygenase’s adverse effect is increased by the consumption of certain polyunsaturated fats contained in meat, yet blocked by the intake of some polyunsaturated fats found in oily fish, such as salmon," said James Dwyer, PhD, lead author of the article.

"The function of 5-lipoxygenase is to convert fatty acids into molecules involved in inflammation," added Dwyer. "Since atherosclerosis is an inflammation of the arteries, our findings suggest that persons with this [enzyme] variation could reduce their risk of heart disease by modifying their diet."

The team's research was driven by a mouse model developed by Margarete Mehrabian, PhD, the article’s senior author. She was the first to show that eliminating the gene for the enzyme from the mouse genome helps protect against atherosclerosis. In that work, Mehrabian fed a high-fat diet to mice engineered without the 5-lipoxygenase gene. After 4 months, she compared the knockout mice's coronary arteries with those of normal mice on the same diet.

"Though both mice ate the same diet, the normal mice's arteries were full of fatty deposits, while the knockout mice's arteries contained none," said Mehrabian. "This confirmed our suspicion that 5-lipoxygenase could make a significant difference in cardiovascular health."

In the current work, the investigators studied blood samples from 470 healthy middle-aged women and men in an atherosclerosis study at the same university. The researchers recorded diet information for participants and evaluated them for atherosclerosis with carotid ultrasound. When the participants’ DNA was analyzed, researchers found 6 different mutations.

When 5-lipoxygenase genotype was compared with ultrasound data, the team discovered that people possessing a mutation had more advanced atherosclerosis than peers with normal genotype. In fact, their carotid arteries measured up to 120 microns more in thickness than the average depth of 650 microns.

As Allayee explained, "Even after we adjusted for all the variables that could affect carotid artery thickness, such as smoking, age, high cholesterol and blood pressure, the arteries of persons with the 5-lipoxygenase variation were still 50 microns thicker. This equals a disease progression of 5 to 10 years. We realized that modified 5-lipoxygenase could be used as a marker for heart disease."

The researchers' next step will be to replicate their findings in other populations. If the team learns that 5-LO is also implicated in the rupture of hardened fatty deposits in the artery -- the leading cause of heart attacks -- the findings could lead to early detection of individuals at high risk for coronary heart disease.