A variant of the gene encoding leukotriene A4 hydrolase confers ethnicity-specific risk of myocardial infarction.
Variants of the gene ALOX5AP (also known as FLAP) encoding arachidonate 5-lipoxygenase activating protein are known to be associated with risk of myocardial infarction. Here we show that a haplotype (HapK) spanning the LTA4H gene encoding leukotriene A4 hydrolase, a protein in the same biochemical pathway as ALOX5AP, confers modest risk of myocardial infarction in an Icelandic cohort. Measurements of leukotriene B4 (LTB4) production suggest that this risk is mediated through upregulation of the leukotriene pathway. Three cohorts from the United States also show that HapK confers a modest relative risk (1.16) in European Americans, but it confers a threefold larger risk in African Americans. About 27% of the European American controls carried at least one copy of HapK, as compared with only 6% of African American controls. Our analyses indicate that HapK is very rare in Africa and that its occurrence in African Americans is due to European admixture. Interactions with other genetic or environmental risk factors that are more common in African Americans are likely to account for the greater relative risk conferred by HapK in this group.
Helgadottir
Anna
A
deCODE Genetics, Inc., Sturlugata 8, IS-101 Reykjavik, Iceland.
Manolescu
Andrei
A
Helgason
Agnar
A
Thorleifsson
Gudmar
G
Thorsteinsdottir
Unnur
U
Gudbjartsson
Daniel F
DF
Gretarsdottir
Solveig
S
Magnusson
Kristinn P
KP
Gudmundsson
Gudmundur
G
Hicks
Andrew
A
Jonsson
Thorlakur
T
Grant
Struan F A
SF
Sainz
Jesus
J
O'Brien
Stephen J
SJ
Sveinbjornsdottir
Sigurlaug
S
Valdimarsson
Einar M
EM
Matthiasson
Stefan E
SE
Levey
Allan I
AI
Abramson
Jerome L
JL
Reilly
Murdach P
MP
Vaccarino
Viola
V
Wolfe
Megan L
ML
Gudnason
Vilmundur
V
Quyyumi
Arshed A
AA
Topol
Eric J
EJ
Rader
Daniel J
DJ
Thorgeirsson
Gudmundur
G
Gulcher
Jeffrey R
JR
Hakonarson
Hakon
H
Kong
Augustine
A
Stefansson
Kari
K
D001741:Black or African American / Q000235:genetics*; D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D004851:Epoxide Hydrolases / Q000235:genetics* / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007055:Iceland; D015810:Linkage Disequilibrium; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000235:genetics*; D044465:White People / Q000235:genetics*
D004851:Epoxide Hydrolases; C043134:leukotriene A4 hydrolase