Nature Genetics36, 233 - 239 (2004)
Published online: 8 February 2004; | doi:10.1038/ng1311
The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke
Anna Helgadottir1, Andrei Manolescu1, Gudmar Thorleifsson1, Solveig Gretarsdottir1, Helga Jonsdottir1, Unnur Thorsteinsdottir1, Nilesh J Samani2, Gudmundur Gudmundsson1, Struan F A Grant1, Gudmundur Thorgeirsson3, Sigurlaug Sveinbjornsdottir3, Einar M Valdimarsson3, Stefan E Matthiasson3, Halldor Johannsson3, Olof Gudmundsdottir1, Mark E Gurney1, Jesus Sainz1, Margret Thorhallsdottir1, Margret Andresdottir1, Michael L Frigge1, Eric J Topol4, Augustine Kong1, Vilmundur Gudnason5, Hakon Hakonarson1, Jeffrey R Gulcher1
& Kari Stefansson1
Correspondence should be addressed to Kari Stefansson kstefans@decode.is
We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12−13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
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