A team of scientists led by deCode Genetics (Reykjavik, Iceland) has discovered a gene variant they say confers increased risk of heart attack, moderately in those of European descent, but most particularly in African-Americans.

The link between the variant of the gene encoding the leukotriene A4 hydrolase (LTA4H) and increased risk of heart attack, first made in Iceland, was confirmed in studies of three cohorts in the U.S. – Atlanta, Cleveland and Philadelphia.

In Icelanders and in Americans of European origin, the at-risk version of the gene is "quite common," the company said, and confers a moderate increase in risk of heart disease. However, the variant, which occurs much less frequently in African-Americans, still more than triples that group's risk of heart attack, raising it by as much as 250%, the company said.

A paper on the findings by a deCode-led team of scientists was published Thursday in the online edition of Nature Genetics and will appear in the January print edition.

"This is an important discovery with immediate relevance to improving health," said Kari Stefansson, CEO of deCODE and senior author on the study. "It confirms the importance of the leukotriene pathway in mediating susceptibility to heart attack and provides a means of directing new medicine to those at particularly elevated risk."

The company said it is preparing a Phase III clinical trial of a compound called DG301, which is aimed at reducing the risk of heart attack by correcting the biological perturbation caused by the gene variants it has discovered, he said.

"By weaving these findings into the design of our Phase III trial, we may be able to swiftly translate this discovery into benefit for patients," Stefansson said. "At the same time, we are looking at how to make available to African-Americans a diagnostic test for the at-risk variant. This could be used to help people at risk to work with their doctors to develop prevention strategies aimed at minimizing the likelihood of suffering a heart attack."

The company said the study builds upon its previously published work linking variants of the gene encoding the five lipoxygenase activating protein (FLAP) to increased risk of heart attack. The at-risk variants of the FLAP gene appear to contribute to the risk of heart attack by upregulating the production of leukotriene B4 (LTB4). Higher production of LTB4, an important modulator of inflammatory response, may increase the propensity of atherosclerotic plaques to rupture, the event directly preceding most heart attacks."

The LTA4H enzyme acts downstream in the leukotriene pathway from FLAP, and is directly involved in the synthesis of LTB4. At its medicinal chemistry group in Chicago, the company has developed an inhibitor of LTA4H.

To search for variants in the LTA4H gene that might confer risk of heart attack, the deCode team analyzed a set of single-base variations, or SNPs (single nucleotide polymorphisms) in the gene encoding the LTA4H in more than 2,000 patients and controls in Iceland.

The haplotype, or version of the gene, defined by those markers and referred to as HapK, was found to correlate with a 40% greater risk of heart attack in Icelandic patients with a history of other cardiovascular disease such as stroke or peripheral artery disease.

To study the significance of this variant in the U.S., HapK was analyzed in more than 3,000 persons in study cohorts at the Cleveland Clinic, Emory University (Atlanta), and the University of Pennsylvania (Philadel-phia).

Overall, among participants self-identified as being of European ancestry, 27% of control subjects carried one or more copies of HapK, compared to 31% of heart attack patients, corresponding to a 16% increase in risk. Among participants self-identified as African-American, HapK was carried by 6% of controls and 20% of patients, representing a more than 250% increase in risk.

The authors note that the higher relative risk conferred by HapK in African- Americans is likely due to interaction between HapK and other genetic or environmental risk factors for heart attack which are not yet well understood.

An analysis of the prevalence of HapK and other genetic markers in Icelanders, Nigerian Yorubans and in the U.S. study cohorts points to the likelihood that its occurrence in African-Americans is due to European admixture.

The company said that if so, HapK would be relatively new in the African-American population, reducing time for the evolution of other genetic factors that might mitigate the risk conferred by HapK, as may well have occurred in European populations in which HapK has been present long enough to have become very common.