The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

• Published in: Nature genetics Vol. 36; no. 3; pp. 233 - 239
• Main Authors: Stefansson, Kari, Helgadottir, Anna, Manolescu, Andrei, Thorleifsson, Gudmar, Gretarsdottir, Solveig, Jonsdottir, Helga, Thorsteinsdottir, Unnur, Samani, Nilesh J, Gudmundsson, Gudmundur, Grant, Struan F A, Thorgeirsson, Gudmundur, Sveinbjornsdottir, Sigurlaug, Valdimarsson, Einar M, Matthiasson, Stefan E, Johannsson, Halldor, Gudmundsdottir, Olof, Gurney, Mark E, Sainz, Jesus, Thorhallsdottir, Margret, Andresdottir, Margret, Frigge, Michael L, Topol, Eric J, Kong, Augustine, Gudnason, Vilmundur, Hakonarson, Hakon, Gulcher, Jeffrey R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01.03.2004
• Subjects: 5-Lipoxygenase-Activating Proteins; Atherosclerosis; Biological and medical sciences; Cardiology. Vascular system; Carrier Proteins - genetics; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 13; Classical genetics, quantitative genetics, hybrids; Coronary heart disease; Diagnosis; Fundamental and applied biological sciences. Psychology; Genes; Genetic aspects; Genetic Predisposition to Disease; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Haplotypes; Health risks; Heart; Heart attack; Heart attacks; Human; Humans; Leukotriene B4 - blood; Males; Medical sciences; Membrane Proteins - genetics; Microsatellite Repeats; Myocardial infarction; Myocardial Infarction - genetics; Neurology; Neutrophils; Oxidases; Pathogenesis; Physiological aspects; Polymorphism, Single Nucleotide; Proteins; Risk factors; Stroke; Stroke (Disease); Stroke - genetics; Vascular diseases and vascular malformations of the nervous system; Atlantic Ocean Islands; Iceland; United Kingdom; United Kingdom > UK; United States > US; Vascular disease; Human; Myocardial infarction; Nervous system diseases; Stroke; Enzyme; Risk factor; Central nervous system disease; Oxidoreductases; Lipoxygenase; Cerebral disorder
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/ng1311

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.