Nutrigenetic association of the 5-lipoxygenase gene with myocardial infarction.
BACKGROUND
5-Lipoxygenase (5-LO) catalyzes the rate-limiting step of the biosynthesis of proinflammatory leukotrienes from arachidonic acid (AA) and has been associated with atherosclerosis in animal models and humans. We previously reported that variants of a 5-LO promoter repeat polymorphism were associated with carotid atherosclerosis in humans, an effect that was exacerbated by high dietary AA but mitigated by high dietary n-3 fatty acids.


OBJECTIVE
We sought to confirm these initial observations with a more clinically relevant phenotype such as myocardial infarction (MI).


METHODS
The 5-LO polymorphism was genotyped in 1885 Costa Rican case-control pairs and tested for association with MI. Functional experiments were carried out to determine whether the associated alleles had differences in mRNA expression.


RESULTS
The frequency of variant genotype groups did not differ significantly between cases and controls. However, a significant gene x diet interaction was observed, in which, relative to the common 5 repeat allele, the 3 and 4 alleles were associated with a higher MI risk in the high (> or = 0.25 g/d) dietary AA group (odds ratio: 1.31; 95% CI: 1.07, 1.61) and with a lower risk in the low (<0. 25 g/d) AA group (0.77; 0.63, 0.94) (P for interaction = 0.015). Using allele-specific quantitation, the short alleles had expression approximately twice that of the 5 allele (P < 0.0001).


CONCLUSIONS
The 3 and 4 variants lead to higher 5-LO expression and provide additional evidence that these alleles are associated with greater risks of atherosclerosis and MI in the context of a high-AA diet.
Department of Preventive Medicine and the Institute for Genetic Medicine, the University of Southern California Keck School of Medicine, Los Angeles, CA 90089-9075, USA. hallayee@usc.edu
Hooman
H
Allayee
Ana
A
Baylin
Jaana
J
Hartiala
Hemani
H
Wijesuriya
Margarete
M
Mehrabian
Aldons J
AJ
Lusis
Hannia
H
Campos
D001094:Arachidonate 5-Lipoxygenase / Q000235:genetics*; D016718:Arachidonic Acid / Q000008:administration & dosage* / Q000378:metabolism; D050197:Atherosclerosis / Q000453:epidemiology / Q000235:genetics; D016022:Case-Control Studies; D016001:Confidence Intervals; D004032:Diet; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics*; D054647:Nutrigenomics; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D012307:Risk Factors
D012333:RNA, Messenger; D016718:Arachidonic Acid; D001094:Arachidonate 5-Lipoxygenase