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Nutrigenetic association of the 5-lipoxygenase gene with myocardial infarction^1,2,3

¹ From the Department of Preventive Medicine and the Institute for Genetic Medicine, the University of Southern California Keck School of Medicine, Los Angeles, CA (HA, JH, and HW); the Department of Community Health, Brown University, Providence, RI (AB); the Departments of Medicine (MM and AJL) and Human Genetics (AJL), David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, CA; and the Department of Nutrition, Harvard University School of Public Health, Boston, MA (HC)

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).

Design: 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 (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.