The enzyme 5-lipoxygenase catalyzes the conversion of arachidonic acid to leukotrienes, which are involved in the inflammatory process. Chronic inflammation is believed to play an important role in the development of atherosclerosis. In the present study, 5-lipoxygenase genotypes, carotid-artery intima-media thickness (a measure of the severity of atherosclerosis), and markers of inflammation were determined in 470 healthy men and women (aged 40-60 years) participating in the Los Angeles Atherosclerosis Study. Variant 5-lipoxygenase genotypes (lacking the common allele) were found in 6% of the participants, whereas 94% had at least one copy of the common allele. The mean carotid-artery intima-media thickness was 12% greater (p < 0.001) among carriers of two variant alleles than among carriers of the common allele. The increase in intima-media thickness associated with the genetic variant was similar in this cohort to that associated with diabetes. Increased dietary intake of arachidonic acid significantly increased the atherogenic effect of the variant genotype, whereas increased intake of marine omega-3 fatty acids blunted the effect. In contrast, neither of these dietary factors was associated with intima-media thickness in subjects carrying the common allele. The plasma level of C-reactive protein (a marker of inflammation) was two-fold higher (2.6 vs. 1.3 mg/L; p = 0.007) among carriers of two variant alleles than among carriers of the common allele.

Comment: Atherosclerosis is considered a polygenic disease, in that numerous different genetic influences are involved in its development. Some genetic variations interact with specific environmental factors. For example, people who carry a gene for iron overload might be able to reduce their risk of atherosclerosis by avoiding excessive intake of iron. Those with the common genetic variant of the methylenetetrahydrofolate reductase enzyme have a higher-than-normal requirement for folic acid, and may be able to reduce their risk of atherosclerosis by increasing their intake of folic acid. Some people who develop premature atherosclerosis have elevated homocysteine levels due to a defect in the vitamin B6-dependent enzyme cystathionine synthase; in those people homocysteine levels can be reduced by supplementing with vitamin B6.

The results of the present study indicate that about 1 in 16 people have a genetic variant of an enzyme that influences fatty acid metabolism. People with this variant are more susceptible to the potential adverse effects of eating meat (which is high in arachidonic acid), and more likely to be protected by eating fish, than are people with the more common variant. Genetic factors may explain why some people can abuse their bodies and not develop chronic illness, while others seem to suffer the consequences of even minimal dietary and lifestyle indiscretions.

Dwyer JH, et al. Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis. N Engl J Med 2004;350:29-37.