Abstract 3458: Dietary Arachidonic Acid, 5-Lipoxygenase and Myocardial Infarction
Five-lipoxygenase (5-LO), the rate-limiting enzyme in the biosynthesis of leukotrienes from arachidonic acid, has been associated with the development of atherosclerosis in mouse models, and a 5-LO promoter repeat polymorphism has been implicated in atherosclerosis in humans. To test the effect of the 5-LO polymorphism on risk of MI and whether dietary arachidonic acid modified the observed results, we studied 1,885 cases of myocardial infarction (MI) and 1,885 controls matched for age, sex, and area of residence, all living in Costa Rica. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (95%CI). Dietary intake was assessed by a validated food frequency questionnaire. No case-control differences in the frequency of deletion (DD/WD) or addition (AA/WA) alleles were identified: DD/WD=28.7% and 29.7%; AA/WA=2.35% and 3.1%, respectively. However, a significant gene-diet interaction was found between the 5-LO polymorphism, arachidonic acid intake, and MI (P=0.014). Compared to the wildtype (WW), the D allele was associated with increased MI in the high (>0.25 g/d) dietary arachidonic acid group (OR=1.23, 95%CI 0.99 –1.53) and with decreased MI in the low (≤ 0.25) arachidonic acid group (OR=0.79 95%CI 0.63– 0.98). The A allele was inversely associated with MI in both diet groups, although this association was not statistically significant perhaps due to its low frequency. To examine if functional differences between alleles explain the observed results, we measured relative amounts of RNA from the D allele compared to the W allele in 66 heterozygous individuals from the same population using allele specific quantitation with Pyrosequencing technology. As a control, DNA from the same heterozygote individuals for each respective allele was used. Consistent with the results above, the D allele had a ~50% increased expression relative to the W allele. Thus, carriers of the 5-LO D allele are more susceptible to the effects of arachidonic acid on risk of MI. The finding of increased expression of 5-LO from the D allele is consistent with the observation that this allele is associated with increased atherosclerosis and risk of MI, at least in the context of a diet high in arachidonic acid.