The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke.
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.
Helgadottir
Anna
A
deCODE genetics, Sturlugata 8, Reykjavik, Iceland.
Manolescu
Andrei
A
Thorleifsson
Gudmar
G
Gretarsdottir
Solveig
S
Jonsdottir
Helga
H
Thorsteinsdottir
Unnur
U
Samani
Nilesh J
NJ
Gudmundsson
Gudmundur
G
Grant
Struan F A
SF
Thorgeirsson
Gudmundur
G
Sveinbjornsdottir
Sigurlaug
S
Valdimarsson
Einar M
EM
Matthiasson
Stefan E
SE
Johannsson
Halldor
H
Gudmundsdottir
Olof
O
Gurney
Mark E
ME
Sainz
Jesus
J
Thorhallsdottir
Margret
M
Andresdottir
Margret
M
Frigge
Michael L
ML
Topol
Eric J
EJ
Kong
Augustine
A
Gudnason
Vilmundur
V
Hakonarson
Hakon
H
Gulcher
Jeffrey R
JR
Stefansson
Kari
K
D058927:5-Lipoxygenase-Activating Proteins; D002352:Carrier Proteins / Q000235:genetics*; D002874:Chromosome Mapping; D002882:Chromosomes, Human, Pair 13; D020022:Genetic Predisposition to Disease; D006801:Humans; D007975:Leukotriene B4 / Q000097:blood; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020521:Stroke / Q000235:genetics*
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D007975:Leukotriene B4