Jan. 1, 2004 UCLA/USC researchers have linked a variation of a gene called 5-lipoxygenase (5-LO) to an increased risk for atherosclerosis, or thickening of the arteries. Published Jan. 1, 2004 in the New England Journal of Medicine, the discovery may soon enable physicians to test for modified 5-LO as a marker for cardiovascular disease.
"We discovered that the arteries of a 40-year-old with modified 5-LO look like those of a 50-year-old with the normal version of the gene," explained Hooman Allayee, Ph.D., co-principal investigator and human genetics researcher at the David Geffen School of Medicine at UCLA. "Our findings suggest that this form of 5-LO speeds the development of atherosclerosis in 5 percent of the population, intensifying a person's risk for heart attack and stroke."
Because earlier research links 5-LO to asthma, cardiologists may now be able to prescribe current asthma medications to prevent and control atherosclerosis in persons who are at greater risk for heart disease.
"This opens up a new market for existing asthma drugs that already target 5-LO," noted Allayee. "Our conclusions suggest that modified 5-LO could be used as a genetic marker for heart disease and lead to improved diagnosis, prevention, and treatment for atherosclerosis."
The findings also indicate that diet may play a key role in controlling heart disease risk.
"We found that 5-LO'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, Ph.D., co-principal investigator and professor of preventive medicine at the USC Keck School of Medicine.
"The function of 5-LO 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 5-LO 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, Ph.D., senior author and assistant professor of human genetics at the David Geffen School of Medicine at UCLA. She was the first to show that eliminating 5-LO from the mouse genome helps protect against atherosclerosis, even when the animal ate a fatty diet.
Mehrabian fed a high-fat diet to mice engineered without the 5-LO gene. After four months, she compared the knockout mice's cardiac arteries to 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-LO could make a significant difference in cardiovascular health."
Allayee applied Mehrabian's findings to blood samples that Dwyer had collected from 470 healthy middle-aged women and men in USC's Los Angeles Atherosclerosis Study. The researchers had recorded each participant's diet and used ultrasound to measure the thickness of each subject's carotid arteries - a primary target for atherosclerosis.
"Doctors often use an ultrasound of the carotid artery as a surrogate marker for heart disease," said Dwyer. "There is a strong link between artery thickness and heart attack risk."
Allayee analyzed the DNA in the blood samples and discovered six different versions of 5-LO. The modified versions had missing or extra DNA sequences.
Dwyer grouped the DNA samples by 5-LO type and compared the carotid artery thickness of people with the modified gene to those with the normal version. The team discovered that people possessing the 5-LO variation showed more advanced atherosclerosis. In fact, their carotid arteries measured up to 120 microns more than the average size of 650 microns. (A micron equals one millionth of a meter.)
"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-LO variation were still 50 microns thicker," said Allayee. "This equals a disease progression of five to 10 years. We realized that modified 5-LO 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.
The UCLA/USC study was funded by grants from the American Heart Association and the National Institutes Health. Co-authors included Huiyan Wu, Rebecca Mar and Aldons J. Lusis of UCLA, and Kathleen Dwyer and Jing Fan of USC.
CITATION: "Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis," New England Journal of Medicine, 2004. Vol.350, No. 1, pp. 29-37.
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