February 6, 2004

Gene encoding FLAP also confers risk for stroke; discovery pinpoints common biological mechanism underlying two of the world’s biggest public health challenges

In a paper published in the online edition of Nature Genetics, a deCODE-led team of scientists describes the identification of the first gene found to confer significant risk of the common form of heart attack. The paper, entitled “The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke,” presents the results of a major population study of heart attack linking a version of the gene encoding FLAP with a nearly twofold increased risk of heart attack. The same haplotype also confers a similarly elevated risk for stroke, making it, after the PDE4D gene published by deCODE late last year, the second major genetic factor identified in the common form of stroke. The study is lead-authored by deCODE project leader Anna Helgadottir, and is available online at www.nature.com/ng in advance of its publication in the March print edition of the journal.

The deCODE team, working with clinicians and researchers at Iceland’s National University Hospital and the Icelandic Heart Association, identified the at-risk haplotype through the analysis of detailed genotypic data from several thousand patients and unaffected relatives in Iceland participating in the company’s cardiovascular disease programs. Analysis of a linkage peak on chromosome 13 with a dense set of SNPs (single nucleotide polymorphisms) revealed a four-SNP haplotype spanning the gene encoding FLAP (ALOX5AP) that confers an approximately twofold increased risk of myocardial infarction, or heart attack. By genotyping and comparing the same SNPs in a large group of Icelandic stroke patients versus control subjects, the same haplotype was also found to correlate with a significantly higher risk of stroke. Working in collaboration with doctors in the United Kingdom, the deCODE team analyzed genotypic data from a total of 1500 British heart attack patients and controls and found a similar risk associated with variations in the gene encoding FLAP, but with a different four-SNP haplotype.

Functional work by the deCODE team, combined with previous studies of FLAP and the 5-lipoxygenase pathway, suggest that upregulation of the gene encoding FLAP may contribute to the inflammation and rupture of atherosclerotic plaque. Plaque rupture is a common event directly preceding both heart attack and stroke. deCODE’s findings suggest that inhibiting the activity of FLAP may thus be an effective means of reducing inflammation and thereby preventing the development of heart attack and stroke. deCODE has in-licensed a compound, DG031, designed to inhibit FLAP, and the company has designed clinical trials to test its effectiveness in reducing key measures of inflammation and in preventing heart attack.