Arachidonate 5-lipoxygenase promoter genotype, dietary arachidonic acid, and atherosclerosis

N Engl J Med. 2004 Jan 1;350(1):29-37. doi: 10.1056/NEJMoa025079.


Background: 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.

Methods: 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.

Results: 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 microm (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 microm, P<0.001) was similar in this cohort to that associated with diabetes (64 microm, 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.

Conclusions: 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Arachidonate 5-Lipoxygenase / genetics*
  • Arteriosclerosis / blood
  • Arteriosclerosis / genetics*
  • Arteriosclerosis / pathology
  • Carotid Arteries / anatomy & histology
  • Cholesterol, LDL / blood
  • Diet
  • Fatty Acids / blood
  • Fatty Acids / pharmacology
  • Female
  • Genotype
  • Humans
  • Inflammation / genetics
  • Logistic Models
  • Male
  • Middle Aged
  • Multivariate Analysis
  • Polymorphism, Genetic
  • Risk Factors
  • Tunica Intima / anatomy & histology
  • Tunica Media / anatomy & histology


  • Cholesterol, LDL
  • Fatty Acids
  • Arachidonate 5-Lipoxygenase