deCODE Describes Genetic Risk Factor for Heart Attack

A paper by a deCODE-led team of scientists has been published to present the discovery of a gene variant conferring increased risk of myocardial infarction, or heart attack.

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 United States.

In Icelanders and in Americans of European origin the at-risk version of the gene is quite common and confers a moderate increase in risk of the disease.

The variant occurs less frequently in African Americans but triples the risk of heart attack.

The paper, entitled ‘A variant of the gene encoding leukotriene A4 hydrolase confers ethnic-specific risk of myocardial infarction,’ is published 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. 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,” said Kari Stefansson, CEO of deCODE and senior author on the study.

“We are now preparing a Phase III clinical trial of a compound aimed at reducing the risk of heart attack by correcting the biological perturbation caused by the gene variants we have discovered.”

“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.”

“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 study builds upon deCODE's 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.

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, in the gene encoding the LTA4H in 2000 patients and controls in Iceland.

The haplotype, or version of the gene, defined by these 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 United States, HapK was analyzed in 3000 individuals in study cohorts at the Cleveland Clinic in Ohio, Emory University in Atlanta, and the University of Pennsylvania in Philadelphia.

In its drug development programs for the prevention of heart attack, deCODE is currently preparing a Phase III clinical trial for DG031, an inhibitor of FLAP.

At its medicinal chemistry group in Chicago, the company has developed an inhibitor of LTA4H.