Leukotrienes are inflammatory mediators generated from arachidonic acid (polyunsaturated n–6 fatty acid) by the enzyme 5-lipoxygenase. Since atherosclerosis involves arterial inflammation, we hypothesized that a polymorphism in the 5-lipoxygenase gene promoter could relate to atherosclerosis in humans and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates.

We determined 5-lipoxygenase genotypes, carotid-artery intima–media thickness, and markers of inflammation in a randomly sampled cohort of 470 healthy, middle-aged women and men from the Los Angeles Atherosclerosis Study. Dietary arachidonic acid and marine n–3 fatty acids (including a competing 5-lipoxygenase substrate that reduces the production of inflammatory leukotrienes) were measured with the use of six 24-hour recalls of food intake.

Variant 5-lipoxygenase genotypes (lacking the common allele) were found in 6.0 percent of the cohort. Mean (±SE) intima–media thickness adjusted for age, sex, height, and racial or ethnic group was increased by 80±19 μm (95 percent confidence interval, 43 to 116; P<0.001) among carriers of two variant alleles, as compared with carriers of the common (wild-type) allele. In multivariate analysis, the increase in intima–media thickness among carriers of two variant alleles (62 μm, P<0.001) was similar in this cohort to that associated with diabetes (64 μm, P=0.01), the strongest common cardiovascular risk factor. Increased dietary arachidonic acid significantly enhanced the apparent atherogenic effect of genotype, whereas increased dietary intake of n–3 fatty acids blunted the effect. Finally, the plasma level of C-reactive protein, a marker of inflammation, was increased by a factor of 2 among carriers of two variant alleles as compared with that among carriers of the common allele.

Variant 5-lipoxygenase genotypes identify a subpopulation with increased atherosclerosis. The observed diet–gene interactions further suggest that dietary n–6 polyunsaturated fatty acids promote, whereas marine n–3 fatty acids inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation.