Troublemakers. Leukotrienes, inflammatory molecules made by the enzyme 5-lipoxygenase (visible here as brown spots in a carotid artery lesion), have been implicated in heart attack and stroke.

Gene Links Heart Attack, Stroke

For the first time, researchers have found a gene associated with a higher risk of both heart attacks and strokes. The gene codes for a protein required for the synthesis of anti-inflammatory molecules called leukotrienes.

Leukotrienes, which contribute to asthma in part by constricting airways, are the target of some asthma drugs. But a flurry of recent papers has suggested that they also may play a central role in cardiovascular disease. The compounds are secreted by several types of inflammatory cells that cluster at injured sites in blood vessels. The molecules are thought to attract white blood cells, which gobble up fat, creating more plaque, and trigger chemical reactions that lead to dangerous clots.

Even so, human geneticist Kari Stefansson of deCODE Genetics in Reykjavik, Iceland, and his colleagues did not have leukotrienes in mind when they set out to isolate a heart attack gene among Icelanders. By sifting through the genomes of 700 heart attack patients and their unaffected relatives, they located a broad band of DNA on chromosome 13. A second set of 1600 patients narrowed the search to two genes, one of which was FLAP, short for 5-lipoxygenase activating protein. FLAP brings starting material to the enzyme that makes leukotrienes.

The deCODE researchers hypothesized that some heart attack patients have an overactive version of FLAP, boosting production of leukotrienes. They buttressed this idea by pinpointing a variation that nearly doubles the risk of heart attacks in about 30% of heart attack patients. They also found that it confers a similar risk of stroke and that a different FLAP variant doubles the risk of heart attacks in a British population. Moreover, cells from patients with the first risky FLAP gene produced significantly more leukotrienes than controls, the researchers report in the March 2004 issue of Nature Genetics.

The new paper points to "an important target for interrupting the inflammatory cascade involved in atherosclerosis," says Robert Aiello, an atherosclerosis researcher at Pfizer in Groton, Connecticut. Indeed, the deCODE team is gearing up for a 200-person clinical trial in Iceland of an experimental asthma pill developed by Bayer that inhibits FLAP. The study will test whether the drug lowers the levels of certain molecular markers of cardiovascular disease.

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