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By Kevin Davies

March 17, 2004 | The search for complex disease genes has taken another tantalizing step forward with the publication last month of a study from deCODE Genetics linking discrete gene variations to increased risk of heart attacks and stroke. But at least two of the scientific experts who reviewed the report for the journal Nature Genetics have questioned whether the data merited such a high-profile publication.

DeCODE CEO Kari Stefansson and colleagues reported in the study that the gene encoding 5-lipoxygenase activating protein (FLAP) increases the risk of myocardial infarction and stroke. Performing a genome-wide scan on almost 300 families including 713 affected individuals, they found that a group of inherited variants in the ALOX5AP gene, which encodes FLAP, on chromosome 13 is present in almost one third of heart attack victims in Iceland, and doubles the risk of both heart attack and stroke. This variant haplotype, hapA, is associated with increased FLAP activity, which is involved in activating the white blood cells involved in inflammation.

In an effort to replicate these findings, deCODE also studied the gene in some 750 British heart disease patients. They found evidence implicating the same gene, but surprisingly a different group of variants – dubbed hapB.

The decision of Nature Genetics to publish the report was not unanimously approved by the experts consulted to review the manuscript. It is, of course, an editor’s prerogative to overrule the advice of the journal’s peer reviewers, but it is unusual for those concerns to be aired in the New York Times.

Heartbroken
Yale University geneticist Richard Lifton recommended against publication¸ saying the data were “actually rather weak.” The Broad Institute’s David Altshuler said the most favorable interpretation was merely that the paper’s “hypothesis might be true.”

However, Nature Genetics editor Myles Axton told Bio-IT World he decided in favor of publishing the deCODE article “because I am convinced that it will stimulate important discoveries in the genetic underpinning of common complex disease.” In a letter to Lifton, Axton defended his decision to publish: “On balance, the work is a

state-of-the art attempt to analyze the genetic basis of two highly important and very prevalent diseases, and its perceived shortcomings will stimulate discussion and attempts at replication.”

Axton acknowledges that the paper’s conclusions would have been stronger had deCODE documented the hapA association in the British patients. However, he says, “It is at least as likely that there are many variants on many genetic backgrounds” associated with heart attacks.

DeCODE is about to commence clinical trials in Iceland with a FLAP inhibitor codenamed DG-031, which it has licensed from Bayer. The drug was originally developed to treat asthma, but Bayer dropped the project after evaluating more than 1,000 patients in Phase I trials.

“Big Pharma doesn’t get it,” says Eric Topol, provost of the Cleveland Clinic Lerner College of Medicine at Case Western Reserve University and a co-author of the Nature Genetics study. “All of the large firms are committed to developing drugs without genotyping of any kind, and for large unrestricted populations.” By contrast, DG-031 will be tested on patients with the at-risk genotype, in the hope of suppressing “key inflammatory markers that indicate arterial instability.” A trial will begin in the United States later this year.

Topol says he is not surprised by the cautionary comments of some of the expert referees. “More data are needed to convincingly prove the cause and effect relationship of the FLAP [association],” he says.

Such data can be found in a recent study in the New England Journal of Medicine. Researchers at the University of Southern California reported that variants in the gene for 5-lipoxygenase, another gene implicated in the pathogenesis of atherosclerosis, are associated with increased risk of heart disease (Dwyer, J. et al. NEJM 350, 29-37; 2004).

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Featured report: Heladottir, A. et al. “The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.” Nature Genetics 8 February 2004; doi: 10.1038/ng1311.

 


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