Background:
5-Lipoxygenase (5-LOX) is the rate-limiting enzyme in the biosynthesis of leukotrienes from arachidonic acid (Ara), an n-6 polyunsaturated fatty acid (PUFA). Previous studies suggest that polymorphisms in the number of tandem Sp1 binding sites in the promoter of the 5-LOX gene may have an atherogenic effect due to a heightened inflammatory state when dietary Ara is high and dietary long-chain n-3 PUFAs (eicosapentaenoic acid, EPA, plus docosahexaenoic acid, DHA) are low.
Methods:
We determined 5-LOX genotypes in 1,663 adults participating in one of five randomized controlled atherosclerosis trials using carotid artery intima-media thickness (CIMT) as the outcome. Baseline data on participant characteristics and clinic and laboratory measurements, including fasting lipids and CIMT, were obtained using the same methods in all trials. Diet was measured using 3-day records and intake of each PUFA was categorized as above or below the median. We used linear regression to examine the cross-sectional associations between 5-LOX genotype, dietary PUFAs, and CIMT.
Results:
Alleles were classified as wild-type (W, with 5 repeats), deletion (D, with 2– 4 repeats), or addition (A, with 6–9 repeats). The frequencies of the six genotypes were: 60.6% WW, 27.1% WD, 4.9% WA, 4.9% DD, 2.2% DA, and 0.4% AA. Among participants using lipid-lowering medication, mean CIMT was significantly elevated by 79.1 μm (95% CI = 5.3–152.9) in DD individuals compared to WW individuals after adjustment for sex, race, age, trial, and BMI >25 kg/m
2
. High dietary EPA+DHA blunted the gene-CIMT association (p for interaction = 0.007). In contrast, DD genotype was not associated with CIMT among non-users of lipid-lowering medication.
Conclusion:
The atherogenic effect of the shorter promoter alleles is modulated by dietary intake, especially in individuals using lipid-lowering medication, indicating a complex mechanism involving both inflammation and lipids.
Association of hemostatic variables with prevalent cardiovascular disease and asymptomatic carotid artery atherosclerosis. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.