Arachidonate 5-Lipoxygenase Promoter Genotype, Dietary Arachidonic Acid, and Atherosclerosis
James H. Dwyer, Ph.D., Hooman Allayee, Ph.D., Kathleen M. Dwyer, Ph.D., Jing Fan, M.S., Huiyun Wu, Ph.D., Rebecca Mar, B.S., Aldons J. Lusis, Ph.D., and Margarete Mehrabian, Ph.D.
Background Leukotrienes are inflammatory mediators generatedfrom arachidonic acid (polyunsaturated n–6 fatty acid)by the enzyme 5-lipoxygenase. Since atherosclerosis involvesarterial inflammation, we hypothesized that a polymorphism inthe 5-lipoxygenase gene promoter could relate to atherosclerosisin humans and that this effect could interact with the dietaryintake of competing 5-lipoxygenase substrates.
Methods We determined 5-lipoxygenase genotypes, carotid-arteryintima–media thickness, and markers of inflammation ina randomly sampled cohort of 470 healthy, middle-aged womenand men from the Los Angeles Atherosclerosis Study. Dietaryarachidonic acid and marine n–3 fatty acids (includinga competing 5-lipoxygenase substrate that reduces the productionof inflammatory leukotrienes) were measured with the use ofsix 24-hour recalls of food intake.
Results Variant 5-lipoxygenase genotypes (lacking the commonallele) 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) amongcarriers of two variant alleles, as compared with carriers ofthe common (wild-type) allele. In multivariate analysis, theincrease in intima–media thickness among carriers of twovariant alleles (62 µm, P<0.001) was similar in thiscohort to that associated with diabetes (64 µm, P=0.01),the strongest common cardiovascular risk factor. Increased dietaryarachidonic acid significantly enhanced the apparent atherogeniceffect of genotype, whereas increased dietary intake of n–3fatty acids blunted the effect. Finally, the plasma level ofC-reactive protein, a marker of inflammation, was increasedby a factor of 2 among carriers of two variant alleles as comparedwith that among carriers of the common allele.
Conclusions Variant 5-lipoxygenase genotypes identify a subpopulationwith increased atherosclerosis. The observed diet–geneinteractions further suggest that dietary n–6 polyunsaturatedfatty acids promote, whereas marine n–3 fatty acids inhibit,leukotriene-mediated inflammation that leads to atherosclerosisin this subpopulation.
Eicosanoids are lipid mediators of inflammation and hypersensitivityreactions,1 and arachidonate 5-lipoxygenase is the key enzymein the oxidative biosynthesis of a class of paracrine and autocrineeicosanoids known as leukotrienes.2 The dihydroxy leukotrieneB4 is a potent leukocyte chemoattractant, whereas the cysteinylleukotrienes increase vascular permeability and promote contractionof vascular smooth muscle.3 The cysteinyl leukotrienes havebeen linked to asthma,4 and 5-lipoxygenase promoter genotypeshave been identified that interacted strongly with the effectsof 5-lipoxygenase inhibition in patients with asthma.5,6 Thisdrug–gene interaction suggested a functional differencein the 5-lipoxygenase pathway between carriers of at least onecommon (wild-type) allele and carriers of two variant alleles.
Atherosclerosis is a chronic inflammatory process involvingthe recruitment and accumulation of monocytes, macrophages,and dendritic cells in artery walls, where they become loadedwith modified and aggregated low-density lipoproteins (LDLs).7,8Molecular determinants of the pathologic chronicity of thisprocess are unknown.
The 5-lipoxygenase pathway has been linked to atherosclerosisin mouse models9,10 and in a histologic study in humans.11 Thesefindings suggested the hypothesis that variation in the 5-lipoxygenasepromoter could alter eicosanoid-mediated inflammatory circuitsin the artery wall and promote atherogenesis. Since the intakeof arachidonic acid increases12,13 and the intake of marinen–3 fatty acids reduces14 the production of leukotrieneB4 in human monocytes, we further hypothesized that dietaryintake of competing 5-lipoxygenase substrates would interactwith an atherogenic effect of genotype. We investigated thesehypotheses by relating carotid-artery intima–media thicknessto 5-lipoxygenase promoter genotypes and dietary intake in theLos Angeles Atherosclerosis Study.15 Intima–media thicknessis an indicator of systemic atherosclerosis that strongly predictsatherothrombotic events.16
Methods
Cohort
The cohort of 573 women (age, 45 to 60 years) and men (age,40 to 60 years) was free of diagnosed cardiovascular diseasewhen randomly sampled from an employee population.17 Hispanicsubjects and smokers were oversampled, and the participationrate was 85 percent. Base-line examinations in 1995–1996were followed by two examinations at 1.5-year intervals, inwhich buffy coat was collected (from 500 subjects) for DNA extraction.
The study protocol was approved by the institutional reviewboard of the Keck School of Medicine in Los Angeles. All subjectsprovided written informed consent.
Carotid Intima–Media Thickness
The degree of atherosclerosis in the posterior wall of the commoncarotid arteries was estimated bilaterally in the base-lineexamination as intima–media thickness by high-resolutionB-mode ultrasonography, as described previously.18 The coefficientof variation was 2.8 percent for repeated scans by differentsonographers.18
Genotyping
DNA was isolated from 500 subjects, and the number of tandemSp1 binding motifs (5'GGGCGG3') in the 5-lipoxygenase (ALOX5)promoter was determined in 470 subjects according to previouslydescribed methods.5 This group included non-Hispanic whites(55.1 percent), Hispanic subjects (29.6 percent), Asian or PacificIslanders (7.7 percent), blacks (5.3 percent), and other groups(2.3 percent). The genotype of 30 specimens could not be determinedowing to polymerase-chain-reaction failure. The resulting sixalleles had relative frequencies of 2.9 percent, 13.1 percent,80.5 percent, 2.8 percent, 0.5 percent, and 0.2 percent forthree, four, five, six, seven, or eight tandem Sp1 motifs, respectively.Variant alleles involved deletions (one or two) or additions(one, two, or three) of Sp1 motifs to the five tandem motifsin the common allele. The distribution of the genotypes didnot significantly deviate from that expected by random combinationof variant and common alleles within any of the racial or ethnicgroups (P0.05 according to Hardy–Weinbergequilibrium 2).
Laboratory Measurements
Data on serum lipid levels were available for all 470 genotypedsubjects. Plasma levels of C-reactive protein, interleukin-6,interleukin-8, and tumor necrosis factor were measured at baseline in 27 of the 28 carriers of two variant alleles and in38 matched carriers of the common allele, with the use of commerciallyavailable, high-sensitivity kits. Fatty acids in frozen plasmawere also measured in this subgroup (at the Heber Laboratoryat UCLA) for validation of dietary measurements.
Dietary Intake
Six 24-hour recalls of food intake were obtained from the subjectsover a period of 1.5 years with the use of the Nutrition DataSystem.19 Fatty-acid intake (expressed as grams per 1000 kcal)was averaged over the six dietary recalls. Intakes of long-chainn–3 polyunsaturated fatty acids (eicosapentaenoic anddocosahexaenoic acids) were summed, owing to the high correlationbetween the intake of these two fatty acids (rank-order correlation,0.85). The intakes of arachidonic acid and its metabolic precursor(linoleic acid) were only weakly correlated (r=0.15) and wereestimated separately. Plasma and tissue levels of linoleic acidand long-chain n–3 polyunsaturated fatty acids correlatewith dietary intake of corresponding fatty acids,20 and theseassociations were estimated in a validation subsample of 66subjects. Spearman correlations between dietary intake (expressedas grams per 1000 kcal) and the corresponding fatty acid inplasma (expressed as a percentage of total fatty acids) were0.53 (P<0.001) for eicosapentaenoic plus docosahexaenoicacids and 0.32 (P=0.01) for linoleic acid.
Statistical Analysis
Adjusted means and P values for differences between genotypegroups were estimated at the mean value of covariates by least-squaresregression. The relative odds of an elevated intima–mediathickness were estimated by ordinal logistic regression withthe use of deciles of intima–media thickness as the ordinaloutcome. For figures depicting relations according to threeordinally ranked groups, reported P values are from models withcontinuous ordinal variables. The covariates in statisticalmodels relating intima–media thickness to genotype wereage, interaction of genotype with age (centered at 50 yearsof age), sex, height, and racial or ethnic group (model 1);all factors in model 1 plus cigarette-smoking status (currently,formerly, or never), level of physical activity, dietary intakeof saturated fat (expressed as a percentage of energy intake),and intake of alcohol (model 2, behavioral risk factors); andall factors in model 2 plus serum cholesterol level, serum high-densitylipoprotein (HDL) cholesterol level, systolic blood pressure,body-mass index (the weight in kilograms divided by the squareof the height in meters), presence or absence of diabetes (type1 or 2), use of antihypertensive medication, and use of lipid-loweringmedication (model 3, biologic risk factors and preventive treatments).
The primary analyses compared carriers of at least one commonallele with carriers of two variant alleles. This categorizationwas derived from a pharmacogenetic interaction involving thesetwo genotype groups.6 Some a posteriori comparisons for additional5-lipoxygenase genotype subgroups are also presented for thepurpose of hypothesis generation.
Results
Genotyping yielded 442 carriers of the 5-lipoxygenase commonallele (94.0 percent) and 28 carriers of two variant alleles(6.0 percent). Major cardiovascular risk factors are presentedfor the cohort in Table 1, according to promoter genotype. Nosignificant differences between carriers of the common alleleand carriers of two variant alleles were apparent. However,the prevalence of variant genotypes did differ across racialand ethnic groups (P<0.001 by the chi-square test), withhigher prevalences among Asians or Pacific Islanders (19.4 percent),blacks (24.0 percent), and other racial or ethnic groups (18.2percent) than among Hispanic subjects (3.6 percent) and non-Hispanicwhites (3.1 percent).
Table 1. Major Cardiovascular Risk Factors According to 5-Lipoxygenase Genotype.
5-Lipoxygenase Polymorphism and Atherosclerosis
Means and medians of carotid intima–media thickness accordingto 5-lipoxygenase genotype are presented in Table 2. The significancelevel of the unadjusted elevation of intima–media thicknessin the group with two variant alleles was confirmed by nonparametricbootstrap analysis. After adjustment for age, sex, height, andracial or ethnic group, the mean (±SE) intima–mediathickness was elevated by 80±19 µm among carriersof two variant alleles, as compared with carriers of the commonallele (95 percent confidence interval, 43 to 116; P<0.001)(Table 2). This elevation remained significant after adjustmentfor behavioral risk factors (78±19 µm, P<0.001)and biologic confounders or mediators and preventive treatments(62±17 µm, P<0.001) (Table 2). The magnitudeof the apparent genotype effect in this last model is similarto that associated with diabetes in this cohort (64±26µm, P=0.01) and larger than that associated with currentsmoking (45±11 µm, P<0.001).
Table 2. Carotid Intima–Media Thickness According to 5-Lipoxygenase Genotype.
This apparent atherogenic effect did not significantly interactwith sex or smoking status, but it did increase with age (Pfor interaction = 0.04). The intima–media thickness wasgreater in the group with two variant alleles within all fiveracial and ethnic categories. These differences between genotypeswere greatest among blacks and smallest among non-Hispanic whites,with the differences in other groups being intermediate (datanot shown). However, these differences were not statisticallysignificant (P=0.26).
The relative magnitude of this 5-lipoxygenase genotype associationwas estimated with the use of ordinal logistic regression. Afteradjustment for age, sex, height, and racial or ethnic group,the odds of increased wall thickness were elevated by a factorof 4 among carriers of two variant alleles as compared withcarriers of the common allele (odds ratio, 4.1; 95 percent confidenceinterval, 2.1 to 8.2; P<0.001). Adjustment for numerous potentialconfounders did not markedly attenuate this relation (odds ratio,3.7; P<0.001).
The association between genotype and intima–media thicknesswas further investigated in five 5-lipoxygenase genotype groupsderived from combinations of common (W), deletion (D), and addition(A) alleles: DD (18 subjects), DA (9), WD (105), WA (22), andWW (315); the AA genotype was observed in only 1 subject (intima–mediathickness, 661 µm). The differences among the five genotypegroups confirmed the presence of a recessive pattern of effects(Figure 1).
Figure 1. Mean (±SE) Carotid Intima–Media Thickness (IMT) in Five 5-Lipoxygenase Genotype Groups.
Means were adjusted for age, sex, height, racial or ethnic group, smoking status, level of physical activity, dietary intake of saturated fat, and intake of alcohol by analysis of covariance. D denotes deletion alleles, A addition alleles, and W common allele (five tandem Sp1 binding motifs). P values are for the differences between indicated genotype groups.
Diet–Gene Interactions
If the observed increase in the intima–media thicknessin the 5-lipoxygenase variants was due to increased productionof leukotrienes (e.g., leukotriene B4), then increased availabilityof the 5-lipoxygenase substrate arachidonic acid and its metabolicprecursor (linoleic acid) could amplify the atherogenic effectof the variant genotypes. Similarly, increased intake of eicosapentaenoicand docosahexaenoic acids could reduce the production of inflammatoryleukotrienes and inhibit this effect.14
Increased intima–media thickness was significantly associatedwith intake of both arachidonic acid (P for trend <0.001)and linoleic acid (P for trend = 0.03) among carriers of twovariant alleles (Figure 2A and Figure 2B) but not among carriersof the common allele (P values for interaction are listed inFigure 2). In contrast, the intake of marine n–3 fattyacids was significantly and inversely associated with intima–mediathickness only among carriers of two variant alleles (P fortrend = 0.007) (Figure 2C). Diet–gene interactions werespecific to these fatty acids and were not observed for dietaryintake of monounsaturated fat (Figure 2D), saturated fat (Figure 2E),or other measured fatty acids (data not shown).
Figure 2. Diet–Gene Interactions between Dietary Intake of Arachidonic Acid (Panel A), Linoleic Acid (Panel B), Eicosapentaenoic Acid (EPA) plus Docosahexaenoic Acid (DHA) (Panel C), Monounsaturated Fatty Acids (Panel D), or Saturated Fatty Acids (Panel E) and the Effect of 5-Lipoxygenase Promoter Genotype on Carotid Intima–Media Thickness (IMT).
All interactions were adjusted for age, sex, height, smoking status, and racial or ethnic group; the interactions shown in Panels A, B, and C were adjusted for one another. Arachidonic acid is 5,8,11,14-eicosatetraenoic acid (20:4n–6); linoleic acid is 9,12-octadecadienoic acid (18:2n–6); eicosapentaenoic acid is 5,8,11,14,17-eicosapentaenoic acid (20:5n–3); and docosahexaenoic acid is 4,7,10,13,16,19-docosahexaenoic acid (22:6n–3). Means (±SE) are shown. Because of rounding, categories appear to overlap.
LDL–Gene Interaction
LDL cholesterol levels in plasma did not differ significantlybetween 5-lipoxygenase carriers of two variant alleles and carriersof the common allele (P=0.33), nor were there significant differencesacross the five genotype groups (P=0.21 by analysis of variance)(Figure 3A). However, the LDL cholesterol level was a more potentatherogenic factor among carriers of two variant alleles thanamong carriers of the common allele (Figure 3B).
Figure 3. Mean (±SE) LDL Cholesterol Level According to the 5-Lipoxygenase Genotype Group (Panel A) and Mean (±SE) Carotid Intima–Media Thickness (IMT) According to the LDL Cholesterol Level among Carriers of the Common 5-Lipoxygenase Allele and Carriers of Two 5-Lipoxygenase Variant Alleles (Panel B).
Estimates in Panels A and B were adjusted for age, sex, height, smoking status, and racial or ethnic group. D denotes deletion alleles, A addition alleles, and W common allele (five tandem Sp1 binding motifs). To convert values for cholesterol to milligrams per deciliter, divide by 0.02586. Because of rounding, categories appear to overlap.
5-Lipoxygenase Polymorphism and Inflammation
The level of C-reactive protein was increased by a factor of2 among carriers of two variant alleles, as compared with carriersof the common allele (mean, 2.6 vs. 1.3 mg per liter; P=0.007),and levels of interleukin-6 and tumor necrosis factor weremarginally increased by 32 percent (P=0.07) and 17 percent (P=0.11),respectively. The level of interleukin-8 was decreased by 3percent among carriers of two variant alleles (P=0.77). Theseanalyses of logarithmically transformed values included thecovariates age, sex, height, smoking status, and racial or ethnicgroup.
Discussion
We found a large increase in carotid intima–media thicknessamong carriers of two variant 5-lipoxygenase promoter allelesas compared with carriers of the common allele. After multivariateadjustment, the apparent atherogenic effect remained as largeas that associated with diabetes. This association was alsorobust across racial and ethnic groups that differed in theprevalence of variant genotypes. This strong association contrastswith weak associations between polymorphic variation in otherinflammatory-pathway genes and cardiovascular disease outcomes.21,22,23,24
The diet–gene interactions we observed suggest an effectof genotype on atherosclerosis mediated by the 5-lipoxygenasepathway. Increased dietary intake of n–6 fatty acids (arachidonicacid and its metabolic precursor, linoleic acid) was associatedwith increased severity of atherosclerosis only among carriersof two variant alleles. Such an interaction would be expectedif, for example, the production of leukotrienes in the arterywall was increased and triggered atherogenesis in the variantgroup. Arachidonic acid is the primary substrate for 5-lipoxygenase,and increased intakes of linoleic acid and arachidonic acidenhance the production of leukotrienes.12,13 This increase couldinduce an atherogenic chronicity of inflammatory circuits inthe artery wall.11,25
We also found that increased dietary intake of marine n–3fatty acids blunted the apparent atherogenic effect of the variantgenotypes. This interaction was also suggestive of a leukotriene-mediatedeffect, since eicosapentaenoic acid is a competing substratefor 5-lipoxygenase. Feeding eicosapentaenoic acid and docosapentaenoicacid to humans reduces the production of leukotriene B4 by activatedmonocytes.14,26,27 The intake of marine n–3 fatty acidsshifts the production of leukotrienes from the more active B4form to the less active B5 form28,29 and may also induce theproduction of other antiinflammatory mediators.30 Involvementof the 5-lipoxygenase pathway in these diet–gene interactionswas further implicated by the lack of such interactions withother dietary fatty acids.
There is considerable evidence that fish-oil intake protectsagainst sudden death from cardiac causes31,32 — an antiarrhythmiceffect that could be mediated by cysteinyl leukotrienes.33 Takentogether, our findings suggest an antiatherosclerotic effectof fish oils among carriers of two 5-lipoxygenase variant allelesand are consistent with the occurrence of increased leukotrieneproduction in this group. The finding that LDL cholesterol wasmore atherogenic among carriers of two variant alleles is consistentwith enhanced LDL-mediated atherosclerosis in that group,34and among these subjects the C-reactive protein levels, whichincreased by a factor of two, were consistent with the presenceof markedly greater chronic arterial inflammation in this group.35
Although data on the 5-lipoxygenase pathway and atherosclerosisare limited, available evidence from two studies in animalsand a histologic study in humans is consistent with the hypothesisthat increased leukotriene production has an atherogenic effect.The extent of atherosclerosis in the aortic arch was greatlyreduced in susceptible mice carrying one null 5-lipoxygenaseallele, as compared with the extent among carriers of two functionalalleles,9 suggesting that this inflammatory pathway is importantin atherosclerosis. In a second study, foam-cell formation wasreduced in three strains of atherosclerosis-susceptible micetreated with a leukotriene-B4–receptor antagonist.10 Third,a recent histologic study in humans found an abundance of 5-lipoxygenase(but not 15-lipoxygenase) in macrophages and foam cells, dendriticcells, and artery-wall cells from atherosclerotic lesions.11
Combining these findings with those of recent studies of leukotrienereceptors expressed by endothelial cells and macrophages,25,36Habenicht's group has proposed a model of leukotriene-mediatedvascular inflammation in atherosclerosis.11,25 In this model,leukotrienes produced by macrophages and dendritic cells inthe artery wall have autocrine effects and paracrine effectson endothelial cells, lymphocytes, smooth-muscle cells, andother macrophages or dendritic cells. Up-regulation of this"inflammatory circuit" by environmental or genetic factors wouldpromote atherosclerosis by enhancing the known effects of leukotrieneson the recruitment of leukocytes, endothelial-cell dysfunction,intimal edema, the proliferation of smooth-muscle cells, andimmune reactivity.11 This model suggests a mechanism wherebyincreased expression of the 5-lipoxygenase gene or activityof the enzyme in carriers of variant genotypes leads to increasedcarotid intima–media thickness.
Although a previously reported drug–gene interaction suggestedthat variant 5-lipoxygenase genotypes have a strong effect onfunction,6 and the gene–diet interactions found in ourstudy are consistent with a hypothesis of increased leukotrieneproduction among promoter variants, findings in in vitro studiesof gene expression do not provide support for such a hypothesis.5,37Experiments with drosophila SL2 (Schneider) cells found increasedreporter construct activity for an addition allele (as comparedwith the common allele), but activity was reduced with transfectionof deletion alleles.37 Reporter constructs in HeLa cells showeda different pattern: gene expression was reduced for both additionand deletion alleles.5 However, these promoter–reporterconstruct studies in nonhuman cells (Schneider) and in tumorcells that do not express 5-lipoxygenase (HeLa) may not reflectthe in vivo process of vascular inflammation. Only certain typesof cells express the 5-lipoxygenase gene, apparently as a resultof different patterns of methylation,38 and expression of thegene is regulated by activating factors. Moreover, Serio andcolleagues found that the expression of the leukotriene C4 synthasegene (a leukotriene-pathway gene) in HeLa cells was not regulatedin the same manner as that observed in a monocyte-like cellline.39 Another investigation of the effect of this polymorphismon leukotriene production by human eosinophils found that variantpromoter genotypes only showed increased leukotriene productionwhen cells were stimulated by a calcium ionophore and cyclooxygenasepathways were inhibited.40 These findings suggest that the effectof variation in the 5-lipoxygenase promoter sequence of tandemSp1 motifs on leukotriene production in the artery wall mayonly be detectable in human macrophages and dendritic cellsunder conditions that mimic the intimal microenvironment.
If the 5-lipoxygenase pathway in cells involved in atherosclerosisis down-regulated among carriers of two variant alleles, assuggested by the reduction in reporter construct activity inHeLa cells, then our observation of increased atherosclerosisamong such subjects appears paradoxical. However, inflammatorypathways are redundant and interacting,41 and down-regulationof the 5-lipoxygenase pathway can result in up-regulation ofother eicosanoid pathways.42 Other candidate eicosanoid pathwaysfor the promotion of atherosclerosis include the 15-lipoxygenaseand cyclooxygenase 2 pathways,43,44 which are also differentiallyaffected by dietary intake of n–6 and marine n–3polyunsaturated fatty acids.29,45 However, evidence of the atherogeniceffects of these other eicosanoid pathways is mixed,11,46,47and n–3 polyunsaturated fatty acids have a much strongereffect on leukotriene production than on other eicosanoids.45
Another possible mechanism linking down-regulation of 5-lipoxygenaseto atherosclerosis in carriers of variant genotypes would involvereduced transcellular biosynthesis of antiinflammatory 5-lipoxygenaseproducts such as lipoxins.48 However, such a model is inconsistentwith the diet–gene interactions we observed and with thesubstantial reduction of atherosclerosis in 5-lipoxygenase–deficientmice.9
Weaknesses of our study stem from its observational design.The 5-lipoxygenase polymorphic variation could be confoundedby unmeasured environmental or genetic factors. The large magnitudeof the apparent effect of the genotype relative to other riskfactors for atherosclerosis makes confounding with known riskfactors unlikely. Although the possibility of linkage disequilibriumwith other polymorphisms clearly cannot be ruled out, the confoundingpolymorphism must have a profound effect on atherosclerosis.Furthermore, the observed diet–gene interactions providea clear link between the apparent atherogenic polymorphic effectand pathways affected by the intake of n–3 and n–6polyunsaturated fatty acids.
If replicated, our findings would constitute clear evidencethat genetic variation in an inflammatory pathway,7 and theleukotriene pathway in particular,49 can trigger atherogenesisin humans. These findings could lead to new dietary and targetedmolecular approaches to the prevention and treatment of cardiovasculardisease according to genotype, particularly in populations ofnon-European descent.
Supported by grants (HL-49910 for the Los Angeles AtherosclerosisStudy, to Drs. Dwyer and Dwyer, and HL-30568, to Drs. Lusisand Mehrabian) from the National Institutes of Health. Dr. Allayeewas supported by a Post-Doctoral Fellowship in Medical Geneticsthrough a National Institutes of Health Training Grant (5-T32-GM08243-15).
We are indebted to Dr. Alan Fogelman for his support and toLora Whitfield, R.N., Anne Shircore, and Jaana Hartiala forexcellent technical assistance.
Source Information
From the Department of Preventive Medicine, Keck School of Medicine, University of Southern California (J.H.D., K.M.D., J.F., H.W.); and the Departments of Human Genetics (H.A., R.M. A.J.L.) and Medicine (A.J.L., M.M.), David Geffen School of Medicine at UCLA — both in Los Angeles. Prof. James Dwyer and Dr. Allayee contributed equally to this article.
Address reprint requests to Prof. James Dwyer at the Keck School of Medicine, 1000 S. Fremont Ave., Unit 8, Alhambra, CA 91803-8000, or at jimdwye{at}usc.edu.
References
Funk CD. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 2001;294:1871-1875. [Free Full Text]
Samuelsson B. Leukotrienes: mediators of immediate hypersensitivity reactions and inflammation. Science 1983;220:568-575. [Free Full Text]
Samuelsson B, Dahlen SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 1987;237:1171-1176. [Free Full Text]
Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med 1999;340:197-206. [Erratum, N Engl J Med 1999;340:663, 341:1632.] [Free Full Text]
In KH, Asano K, Beier D, et al. Naturally occurring mutations in the human 5-lipoxygenase gene promoter that modify transcription factor binding and reporter gene transcription. J Clin Invest 1997;99:1130-1137. [Web of Science][Medline]
Drazen JM, Yandava CN, Dube L, et al. Pharmacogenetic association between ALOX5 promoter genotype and the response to anti-asthma treatment. Nat Genet 1999;22:168-170. [CrossRef][Web of Science][Medline]
Ross R. Atherosclerosis -- an inflammatory disease. N Engl J Med 1999;340:115-126. [Free Full Text]
Mehrabian M, Allayee H, Wong J, et al. Identification of 5-lipoxygenase as a major gene contributing to atherosclerosis susceptibility in mice. Circ Res 2002;91:120-126. [Erratum, Circ Res 2002;91(8):e27.] [Free Full Text]
Aiello RJ, Bourassa PA, Lindsey S, Weng W, Freeman A, Showell HJ. Leukotriene B4 receptor antagonism reduces monocytic foam cells in mice. Arterioscler Thromb Vasc Biol 2002;22:443-449. [Free Full Text]
Spanbroek R, Grabner R, Lotzer K, et al. Expanding expression of the 5-lipoxygenase pathway within the arterial wall during human atherogenesis. Proc Natl Acad Sci U S A 2003;100:1238-1243. [Free Full Text]
Ferretti A, Nelson GJ, Schmidt PC, Kelley DS, Bartolini G, Flanagan VP. Increased dietary arachidonic acid enhances the synthesis of vasoactive eicosanoids in humans. Lipids 1997;32:435-439. [Web of Science][Medline]
Kelley DS, Taylor PC, Nelson GJ, Mackey BE. Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men. Lipids 1998;33:125-130. [Web of Science][Medline]
Lee TH, Hoover RL, Williams JD, et al. Effect of dietary enrichment with eicosapentaenoic and docosahexaenoic acids on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. N Engl J Med 1985;312:1217-1224. [Abstract]
Dwyer JH, Navab M, Dwyer KM, et al. Oxygenated carotenoid lutein and progression of early atherosclerosis: the Los Angeles Atherosclerosis Study. Circulation 2001;103:2922-2927. [Free Full Text]
O'Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999;340:14-22. [Free Full Text]
Sun P, Dwyer KM, Merz CN, et al. Blood pressure, LDL cholesterol, and intima-media thickness: a test of the "response to injury" hypothesis of atherosclerosis. Arterioscler Thromb Vasc Biol 2000;20:2005-2010. [Free Full Text]
Dwyer JH, Sun P, Kwong-Fu H, Dwyer KM, Selzer RH. Automated intima-media thickness: the Los Angeles Atherosclerosis Study. Ultrasound Med Biol 1998;24:981-987. [CrossRef][Web of Science][Medline]
Feskanich D, Sielaff BH, Chong K, Buzzard IM. Computerized collection and analysis of dietary intake information. Comput Methods Programs Biomed 1989;30:47-57. [CrossRef][Web of Science][Medline]
Cantwell MM. Assessment of individual fatty acid intake. Proc Nutr Soc 2000;59:187-191. [Web of Science][Medline]
Andreotti F, Burzotta F, Mazza A, Manzoli A, Robinson K, Maseri A. Homocysteine and arterial occlusive disease: a concise review. Cardiologia 1999;44:341-345. [Medline]
Boekholdt SM, Bijsterveld NR, Moons AHM, Levi M, Buller HR, Peters RJG. Genetic variation in coagulation and fibrinolytic proteins and their relation with acute myocardial infarction: a systematic review. Circulation 2001;104:3063-3068. [Free Full Text]
Zee RYL, Ridker PM. Polymorphism in the human C-reactive protein (CRP) gene, plasma concentrations of CRP, and the risk of future arterial thrombosis. Atherosclerosis 2002;162:217-219. [CrossRef][Web of Science][Medline]
Kiechl S, Lorenz E, Reindl M, et al. Toll-like receptor 4 polymorphisms and atherogenesis. N Engl J Med 2002;347:185-192. [Free Full Text]
Lotzer K, Spanbroek R, Hildner M, et al. Differential leukotriene receptor expression and calcium responses in endothelial cells and macrophages indicate 5-lipoxygenase-dependent circuits of inflammation and atherogenesis. Arterioscler Thromb Vasc Biol 2003;23:E32-E36.
Sperling RI, Benincaso AI, Knoell CT, Larkin JK, Austen KF, Robinson DR. Dietary omega-3 polyunsaturated fatty acids inhibit phosphoinositide formation and chemotaxis in neutrophils. J Clin Invest 1993;91:651-660. [Web of Science][Medline]
Kelley DS, Taylor PC, Nelson GJ, et al. Docosahexaenoic acid ingestion inhibits natural killer cell activity and production of inflammatory mediators in young healthy men. Lipids 1999;34:317-324. [Web of Science][Medline]
Lee TH, Sethi T, Crea AE, et al. Characterization of leukotriene B3: comparison of its biological activities with leukotriene B4 and leukotriene B5 in complement receptor enhancement, lysozyme release and chemotaxis of human neutrophils. Clin Sci (Lond) 1988;74:467-475. [Medline]
Koller M, Senkal M, Kemen M, Konig W, Zumtobel V, Muhr G. Impact of omega-3 fatty acid enriched TPN on leukotriene synthesis by leukocytes after major surgery. Clin Nutr 2003;22:59-64. [CrossRef][Web of Science][Medline]
Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells: autacoids in anti-inflammation. J Biol Chem 2003;278:14677-14687. [Free Full Text]
Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897-1903. [Free Full Text]
Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain n-3 fatty acids and the risk of sudden death. N Engl J Med 2002;346:1113-1118. [Free Full Text]
Allen S, Dashwood M, Morrison K, Yacoub M. Differential leukotriene constrictor responses in human atherosclerotic coronary arteries. Circulation 1998;97:2406-2413. [Free Full Text]
Prescott SM, McIntyre TM, Zimmerman GA, Stafforini DM. Sol Sherry lecture in thrombosis: molecular events in acute inflammation. Arterioscler Thromb Vasc Biol 2002;22:727-733. [Free Full Text]
Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002;105:1135-1143. [Free Full Text]
Sjostrom M, Johansson AS, Schroder O, Qiu H, Palmblad J, Haeggstrom JZ. Dominant expression of the CysLT2 receptor accounts for calcium signaling by cysteinyl leukotrienes in human umbilical vein endothelial cells. Arterioscler Thromb Vasc Biol 2003;23:E37-E41.
Silverman ES, Du J, De Sanctis GT, et al. Egr-1 and Sp1 interact functionally with the 5-lipoxygenase promoter and its naturally occurring mutants. Am J Respir Cell Mol Biol 1998;19:316-323. [Free Full Text]
Uhl J, Klan N, Rose M, Entian KD, Werz O, Steinhilber D. The 5-lipoxygenase promoter is regulated by DNA methylation. J Biol Chem 2002;277:4374-4379. [Free Full Text]
Serio KJ, Hodulik CR, Bigby TD. Sp1 and Sp3 function as key regulators of leukotriene C(4) synthase gene expression in the monocyte-like cell line, THP-1. Am J Respir Cell Mol Biol 2000;23:234-240. [Free Full Text]
Sampson AP, Siddiqui S, Buchanan D, et al. Variant LTC(4) synthase allele modifies cysteinyl leukotriene synthesis in eosinophils and predicts clinical response to zafirlukast. Thorax 2000;55:Suppl 2:S28-S31. [Web of Science][Medline]
Serhan CN. Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): a jungle of cell-cell interactions or a therapeutic opportunity? Prostaglandins 1997;53:107-137. [CrossRef][Web of Science][Medline]
Goulet JL, Snouwaert JN, Latour AM, Coffman TM, Koller BH. Altered inflammatory responses in leukotriene-deficient mice. Proc Natl Acad Sci U S A 1994;91:12852-12856. [Free Full Text]
Cyrus T, Pratico D, Zhao L, et al. Absence of 12/15-lipoxygenase expression decreases lipid peroxidation and atherogenesis in apolipoprotein e-deficient mice. Circulation 2001;103:2277-2282. [Free Full Text]
Burleigh ME, Babaev VR, Oates JA, et al. Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation 2002;105:1816-1823. [Free Full Text]
Li B, Birdwell C, Whelan J. Antithetic relationship of dietary arachidonic acid and eicosapentaenoic acid on eicosanoid production in vivo. J Lipid Res 1994;35:1869-1877. [Abstract]
Shen J, Herderick E, Cornhill JF, et al. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J Clin Invest 1996;98:2201-2208. [Web of Science][Medline]
Cayatte AJ, Du Y, Oliver-Krasinski J, Lavielle G, Verbeuren TJ, Cohen RA. The thromboxane receptor antagonist S18886 but not aspirin inhibits atherogenesis in apo E-deficient mice: evidence that eicosanoids other than thromboxane contribute to atherosclerosis. Arterioscler Thromb Vasc Biol 2000;20:1724-1728. [Free Full Text]
Serhan CN, Takano T, Chiang N, Gronert K, Clish CB. Formation of endogenous "antiinflammatory" lipid mediators by transcellular biosynthesis: lipoxins and aspirin-triggered lipoxins inhibit neutrophil recruitment and vascular permeability. Am J Respir Crit Care Med 2000;161:S95-S101. [Free Full Text]
Radmark O. 5-Lipoxygenase-derived leukotrienes: mediators also of atherosclerotic inflammation. Arterioscler Thromb Vasc Biol 2003;23:1140-1142. [Free Full Text]
Vikman, S., Brena, R. M., Armstrong, P., Hartiala, J., Stephensen, C. B., Allayee, H.
(2009). Functional analysis of 5-lipoxygenase promoter repeat variants. Hum Mol Genet
18: 4521-4529
[Abstract][Full Text]
Klingenberg, R., Hansson, G. K.
(2009). Treating inflammation in atherosclerotic cardiovascular disease: emerging therapies. Eur Heart J
0: ehp477v1-ehp477
[Abstract][Full Text]
An, W. S., Kim, H. J., Cho, K.-H., Vaziri, N. D.
(2009). Omega-3 fatty acid supplementation attenuates oxidative stress, inflammation, and tubulointerstitial fibrosis in the remnant kidney. Am. J. Physiol. Renal Physiol.
297: F895-F903
[Abstract][Full Text]
Mizota, T., Fujita-Kambara, C., Matsuya, N., Hamasaki, S., Fukudome, T., Goto, H., Nakane, S., Kondo, T., Matsuo, H.
(2009). Effect of Dietary Fatty Acid Composition on Th1/Th2 Polarization in Lymphocytes. JPEN J Parenter Enteral Nutr
33: 390-396
[Abstract][Full Text]
Duffield-Lillico, A. J., Boyle, J. O., Zhou, X. K., Ghosh, A., Butala, G. S., Subbaramaiah, K., Newman, R. A., Morrow, J. D., Milne, G. L., Dannenberg, A. J.
(2009). Levels of Prostaglandin E Metabolite and Leukotriene E4 Are Increased in the Urine of Smokers: Evidence that Celecoxib Shunts Arachidonic Acid into the 5-Lipoxygenase Pathway. Cancer Prevention Research
2: 322-329
[Abstract][Full Text]
Marnett, L. J.
(2009). Mechanisms of Cyclooxygenase-2 Inhibition and Cardiovascular Side Effects--The Plot Thickens. Cancer Prevention Research
2: 288-290
[Full Text]
Radmark, O., Samuelsson, B.
(2009). 5-Lipoxygenase: mechanisms of regulation. J. Lipid Res.
50: S40-S45
[Abstract][Full Text]
Bevan, S., Lorenz, M. W, Sitzer, M., Markus, H. S.
(2009). Genetic Variation in the Leukotriene Pathway and Carotid Intima-Media Thickness: A 2-Stage Replication Study. Stroke
40: 696-701
[Abstract][Full Text]
Serhan, C. N., Yang, R., Martinod, K., Kasuga, K., Pillai, P. S., Porter, T. F., Oh, S. F., Spite, M.
(2009). Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actions. JEM
206: 15-23
[Abstract][Full Text]
Su, Z., Cox, A., Shen, Y., Stylianou, I. M., Paigen, B.
(2009). Farp2 and Stk25 Are Candidate Genes for the HDL Cholesterol Locus on Mouse Chromosome 1. Arterioscler. Thromb. Vasc. Bio.
29: 107-113
[Abstract][Full Text]
Shin, S. M., Kim, S. G.
(2009). Inhibition of Arachidonic Acid and Iron-Induced Mitochondrial Dysfunction and Apoptosis by Oltipraz and Novel 1,2-Dithiole-3-thione Congeners. Mol. Pharmacol.
75: 242-253
[Abstract][Full Text]
Sanchez-Galan, E., Gomez-Hernandez, A., Vidal, C., Martin-Ventura, J. L., Blanco-Colio, L. M., Munoz-Garcia, B., Ortega, L., Egido, J., Tunon, J.
(2009). Leukotriene B4 enhances the activity of nuclear factor-{kappa}B pathway through BLT1 and BLT2 receptors in atherosclerosis. Cardiovasc Res
81: 216-225
[Abstract][Full Text]
Lopez-Parra, M., Titos, E., Horrillo, R., Ferre, N., Gonzalez-Periz, A., Martinez-Clemente, M., Planaguma, A., Masferrer, J., Arroyo, V., Claria, J.
(2008). Regulatory effects of arachidonate 5-lipoxygenase on hepatic microsomal TG transfer protein activity and VLDL-triglyceride and apoB secretion in obese mice. J. Lipid Res.
49: 2513-2523
[Abstract][Full Text]
Riccioni, G., Capra, V., D'Orazio, N., Bucciarelli, T., Bazzano, L. A.
(2008). Leukotriene modifiers in the treatment of cardiovascular diseases. J. Leukoc. Biol.
84: 1374-1378
[Abstract][Full Text]
Moos, M. P. W., Mewburn, J. D., Kan, F. W. K., Ishii, S., Abe, M., Sakimura, K., Noguchi, K., Shimizu, T., Funk, C. D.
(2008). Cysteinyl leukotriene 2 receptor-mediated vascular permeability via transendothelial vesicle transport. FASEB J.
22: 4352-4362
[Abstract][Full Text]
Allayee, H., Baylin, A., Hartiala, J., Wijesuriya, H., Mehrabian, M., Lusis, A. J, Campos, H.
(2008). Nutrigenetic association of the 5-lipoxygenase gene with myocardial infarction. Am. J. Clin. Nutr.
88: 934-940
[Abstract][Full Text]
Wingrove, J. A., Daniels, S. E., Sehnert, A. J., Tingley, W., Elashoff, M. R., Rosenberg, S., Buellesfeld, L., Grube, E., Newby, L. K., Ginsburg, G. S., Kraus, W. E.
(2008). Correlation of Peripheral-Blood Gene Expression With the Extent of Coronary Artery Stenosis. Circ Cardiovasc Genet
1: 31-38
[Abstract][Full Text]
Wang, J., John, E. M., Ingles, S. A.
(2008). 5-Lipoxygenase and 5-Lipoxygenase-Activating Protein Gene Polymorphisms, Dietary Linoleic Acid, and Risk for Breast Cancer. Cancer Epidemiol. Biomarkers Prev.
17: 2748-2754
[Abstract][Full Text]
Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N., Chan, L.
(2008). Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J.
22: 3595-3606
[Abstract][Full Text]
Ye, Y., Lin, Y., Perez-Polo, J. R., Uretsky, B. F., Ye, Z., Tieu, B. C., Birnbaum, Y.
(2008). Phosphorylation of 5-Lipoxygenase at Ser523 by Protein Kinase A Determines Whether Pioglitazone and Atorvastatin Induce Proinflammatory Leukotriene B4 or Anti-Inflammatory 15-Epi-Lipoxin A4 Production. J. Immunol.
181: 3515-3523
[Abstract][Full Text]
Lefebvre, B., Pepin, J-L., Baguet, J-P., Tamisier, R., Roustit, M., Riedweg, K., Bessard, G., Levy, P., Stanke-Labesque, F.
(2008). Leukotriene B4: early mediator of atherosclerosis in obstructive sleep apnoea?. Eur Respir J
32: 113-120
[Abstract][Full Text]
Simopoulos, A. P.
(2008). The Importance of the Omega-6/Omega-3 Fatty Acid Ratio in Cardiovascular Disease and Other Chronic Diseases. Exp. Biol. Med.
233: 674-688
[Abstract][Full Text]
Vaccarino, V., Rutledge, T., Bittner, V., Bairey Merz, C. N.
(2008). Reply. J Am Coll Cardiol
51: 1991-1991
[Full Text]
Freiberg, J. J., Tybjaerg-Hansen, A., Sillesen, H., Jensen, G. B., Nordestgaard, B. G.
(2008). Promotor Polymorphisms in Leukotriene C4 Synthase and Risk of Ischemic Cerebrovascular Disease. Arterioscler. Thromb. Vasc. Bio.
28: 990-996
[Abstract][Full Text]
Wung, S.-F., Aouizerat, B. E.
(2008). Candidate Genes of the 5-Lipoxygenase Pathway in Acute Coronary Syndrome: A Pilot Study. Biol Res Nurs
9: 280-292
[Abstract]
Herb, F., Thye, T., Niemann, S., Browne, E. N.L., Chinbuah, M. A., Gyapong, J., Osei, I., Owusu-Dabo, E., Werz, O., Rusch-Gerdes, S., Horstmann, R. D., Meyer, C. G.
(2008). ALOX5 variants associated with susceptibility to human pulmonary tuberculosis. Hum Mol Genet
17: 1052-1060
[Abstract][Full Text]
Fortunato, G., Di Taranto, M. D., Bracale, U. M., Del Guercio, L., Carbone, F., Mazzaccara, C., Morgante, A., D'Armiento, F. P., D'Armiento, M., Porcellini, M., Sacchetti, L., Bracale, G., Salvatore, F.
(2008). Decreased Paraoxonase-2 Expression in Human Carotids During the Progression of Atherosclerosis. Arterioscler. Thromb. Vasc. Bio.
28: 594-600
[Abstract][Full Text]
Peters-Golden, M., Henderson, W. R. Jr.
(2007). Leukotrienes. NEJM
357: 1841-1854
[Full Text]
Manev, H., Manev, R.
(2007). 5-Lipoxygenase as a Possible Biological Link Between Depressive Symptoms and Atherosclerosis. Arch Gen Psychiatry
64: 1333-1333
[Full Text]
Kaetsu, Y., Yamamoto, Y., Sugihara, S., Matsuura, T., Igawa, G., Matsubara, K., Igawa, O., Shigemasa, C., Hisatome, I.
(2007). Role of cysteinyl leukotrienes in the proliferation and the migration of murine vascular smooth muscle cells in vivo and in vitro. Cardiovasc Res
76: 160-166
[Abstract][Full Text]
Ahluwalia, N., Lin, A. Y., Tager, A. M., Pruitt, I. E., Anderson, T. J. T., Kristo, F., Shen, D., Cruz, A. R., Aikawa, M., Luster, A. D., Gerszten, R. E.
(2007). Inhibited Aortic Aneurysm Formation in BLT1-Deficient Mice. J. Immunol.
179: 691-697
[Abstract][Full Text]
Schirmer, M. A., Phinney, S. D.
(2007). {gamma}-Linolenate Reduces Weight Regain in Formerly Obese Humans. J. Nutr.
137: 1430-1435
[Abstract][Full Text]
Worrall, B. B., Brott, T. G., Brown, R. D. Jr, Brown, W. M., Rich, S. S., Arepalli, S., Wavrant-De Vrieze, F., Duckworth, J., Singleton, A. B., Hardy, J., Meschia, J. F., for the SWISS, ISGS, and MSGD Investigators,
(2007). IL1RN VNTR Polymorphism in Ischemic Stroke: Analysis in 3 Populations. Stroke
38: 1189-1196
[Abstract][Full Text]
Arita, M., Ohira, T., Sun, Y.-P., Elangovan, S., Chiang, N., Serhan, C. N.
(2007). Resolvin E1 Selectively Interacts with Leukotriene B4 Receptor BLT1 and ChemR23 to Regulate Inflammation. J. Immunol.
178: 3912-3917
[Abstract][Full Text]
Iovannisci, D. M., Lammer, E. J., Steiner, L., Cheng, S., Mahoney, L. T., Davis, P. H., Lauer, R. M., Burns, T. L.
(2007). Association Between A Leukotriene C4 Synthase Gene Promoter Polymorphism and Coronary Artery Calcium in Young Women: The Muscatine Study. Arterioscler. Thromb. Vasc. Bio.
27: 394-399
[Abstract][Full Text]
Shaikh, S. R., Edidin, M.
(2006). Polyunsaturated fatty acids, membrane organization, T cells, and antigen presentation. Am. J. Clin. Nutr.
84: 1277-1289
[Abstract][Full Text]
Schadt, E. E., Lum, P. Y.
(2006). Thematic review series: Systems Biology Approaches to Metabolic and Cardiovascular Disorders. Reverse engineering gene networks to identify key drivers of complex disease phenotypes. J. Lipid Res.
47: 2601-2613
[Abstract][Full Text]
Topol, E. J., Smith, J., Plow, E. F., Wang, Q. K.
(2006). Genetic susceptibility to myocardial infarction and coronary artery disease. Hum Mol Genet
15: R117-R123
[Abstract][Full Text]
Hansson, G. K.
(2006). Epidemiology Complements Immunology in the Heart. Arterioscler. Thromb. Vasc. Bio.
26: 2178-2180
[Full Text]
Ghazalpour, A., Wang, X., Lusis, A. J., Mehrabian, M.
(2006). Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice. Genetics
173: 943-951
[Abstract][Full Text]
Qiu, H., Gabrielsen, A., Agardh, H. E., Wan, M., Wetterholm, A., Wong, C.-H., Hedin, U., Swedenborg, J., Hansson, G. K., Samuelsson, B., Paulsson-Berne, G., Haeggstrom, J. Z.
(2006). Expression of 5-lipoxygenase and leukotriene A4 hydrolase in human atherosclerotic lesions correlates with symptoms of plaque instability. Proc. Natl. Acad. Sci. USA
103: 8161-8166
[Abstract][Full Text]
Qiu, H., Johansson, A.-S., Sjostrom, M., Wan, M., Schroder, O., Palmblad, J., Haeggstrom, J. Z.
(2006). Differential induction of BLT receptor expression on human endothelial cells by lipopolysacharide, cytokines, and leukotriene B4. Proc. Natl. Acad. Sci. USA
103: 6913-6918
[Abstract][Full Text]
Lai, C.-Q., Corella, D., Demissie, S., Cupples, L. A., Adiconis, X., Zhu, Y., Parnell, L. D., Tucker, K. L., Ordovas, J. M.
(2006). Dietary Intake of n-6 Fatty Acids Modulates Effect of Apolipoprotein A5 Gene on Plasma Fasting Triglycerides, Remnant Lipoprotein Concentrations, and Lipoprotein Particle Size: The Framingham Heart Study. Circulation
113: 2062-2070
[Abstract][Full Text]
Tedgui, A., Mallat, Z.
(2006). Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways. Physiol. Rev.
86: 515-581
[Abstract][Full Text]
Sasada, S., Ogata, Y., Kobayashi, M., Hirashima, T., Kawahara, K., Matsui, K., Kawase, I.
(2006). Angled Forceps Used for Transbronchial Biopsy in Which Standard Forceps Are Difficult To Manipulate: A Comparative Study. Chest
129: 725-733
[Abstract][Full Text]
Friedman, A., Moe, S.
(2006). Review of the Effects of Omega-3 Supplementation in Dialysis Patients. CJASN
1: 182-192
[Abstract][Full Text]
Lima, J. J., Zhang, S., Grant, A., Shao, L., Tantisira, K. G., Allayee, H., Wang, J., Sylvester, J., Holbrook, J., Wise, R., Weiss, S. T., Barnes, K.
(2006). Influence of Leukotriene Pathway Polymorphisms on Response to Montelukast in Asthma. Am. J. Respir. Crit. Care Med.
173: 379-385
[Abstract][Full Text]
De Caterina, R., Zampolli, A., Del Turco, S., Madonna, R., Massaro, M.
(2006). Nutritional mechanisms that influence cardiovascular disease. Am. J. Clin. Nutr.
83: 421S-426S
[Abstract][Full Text]
Ordovas, J. M
(2006). Genetic interactions with diet influence the risk of cardiovascular disease. Am. J. Clin. Nutr.
83: 443S-446S
[Abstract][Full Text]
Kornman, K. S
(2006). Interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging. Am. J. Clin. Nutr.
83: 475S-483S
[Abstract][Full Text]
Duff, G. W, Libby, P., Ordovas, J. M, Reilly, P. R
(2006). The future of living well to 100. Am. J. Clin. Nutr.
83: 488S-490S
[Full Text]
Luo, M., Jones, S. M., Flamand, N., Aronoff, D. M., Peters-Golden, M., Brock, T. G.
(2005). Phosphorylation by Protein Kinase A Inhibits Nuclear Import of 5-Lipoxygenase. J. Biol. Chem.
280: 40609-40616
[Abstract][Full Text]
Klein-Platat, C., Drai, J., Oujaa, M., Schlienger, J.-L., Simon, C.
(2005). Plasma fatty acid composition is associated with the metabolic syndrome and low-grade inflammation in overweight adolescents. Am. J. Clin. Nutr.
82: 1178-1184
[Abstract][Full Text]
Back, M., Bu, D.-x., Branstrom, R., Sheikine, Y., Yan, Z.-Q., Hansson, G. K.
(2005). Leukotriene B4 signaling through NF-{kappa}B-dependent BLT1 receptors on vascular smooth muscle cells in atherosclerosis and intimal hyperplasia. Proc. Natl. Acad. Sci. USA
102: 17501-17506
[Abstract][Full Text]
Knoflach, M., Kiechl, S., Mayr, A., Willeit, J., Poewe, W., Wick, G.
(2005). Allergic Rhinitis, Asthma, and Atherosclerosis in the Bruneck and ARMY Studies. Arch Intern Med
165: 2521-2526
[Abstract][Full Text]
Ginsburg, G. S., Donahue, M. P., Newby, L. K.
(2005). Prospects for Personalized Cardiovascular Medicine: The Impact of Genomics. J Am Coll Cardiol
46: 1615-1627
[Abstract][Full Text]
Topol, E. J.
(2005). The Genomic Basis of Myocardial Infarction. J Am Coll Cardiol
46: 1456-1465
[Full Text]
Antman, E. M., DeMets, D., Loscalzo, J.
(2005). Cyclooxygenase Inhibition and Cardiovascular Risk. Circulation
112: 759-770
[Full Text]
Cipollone, F., Mezzetti, A., Fazia, M. L., Cuccurullo, C., Iezzi, A., Ucchino, S., Spigonardo, F., Bucci, M., Cuccurullo, F., Prescott, S. M., Stafforini, D. M.
(2005). Association Between 5-Lipoxygenase Expression and Plaque Instability in Humans. Arterioscler. Thromb. Vasc. Bio.
25: 1665-1670
[Abstract][Full Text]
Heller, E. A., Liu, E., Tager, A. M., Sinha, S., Roberts, J. D., Koehn, S. L., Libby, P., Aikawa, E. R., Chen, J. Q., Huang, P., Freeman, M. W., Moore, K. J., Luster, A. D., Gerszten, R. E.
(2005). Inhibition of Atherogenesis in BLT1-Deficient Mice Reveals a Role for LTB4 and BLT1 in Smooth Muscle Cell Recruitment. Circulation
112: 578-586
[Abstract][Full Text]
Leopold, J. A., Loscalzo, J.
(2005). Oxidative Enzymopathies and Vascular Disease. Arterioscler. Thromb. Vasc. Bio.
25: 1332-1340
[Abstract][Full Text]
Sabirsh, A., Wetterholm, A., Bristulf, J., Leffler, H., Haeggstrom, J. Z., Owman, C.
(2005). Fluorescent leukotriene B4: potential applications. J. Lipid Res.
46: 1339-1346
[Abstract][Full Text]
Hakonarson, H., Thorvaldsson, S., Helgadottir, A., Gudbjartsson, D., Zink, F., Andresdottir, M., Manolescu, A., Arnar, D. O., Andersen, K., Sigurdsson, A., Thorgeirsson, G., Jonsson, A., Agnarsson, U., Bjornsdottir, H., Gottskalksson, G., Einarsson, A., Gudmundsdottir, H., Adalsteinsdottir, A. E., Gudmundsson, K., Kristjansson, K., Hardarson, T., Kristinsson, A., Topol, E. J., Gulcher, J., Kong, A., Gurney, M., Thorgeirsson, G., Stefansson, K.
(2005). Effects of a 5-Lipoxygenase-Activating Protein Inhibitor on Biomarkers Associated With Risk of Myocardial Infarction: A Randomized Trial. JAMA
293: 2245-2256
[Abstract][Full Text]
Serio, K. J., Reddy, K. V., Bigby, T. D.
(2005). Lipopolysaccharide induces 5-lipoxygenase-activating protein gene expression in THP-1 cells via a NF-{kappa}B and C/EBP-mediated mechanism. Am. J. Physiol. Cell Physiol.
288: C1125-C1133
[Abstract][Full Text]
Moreno, P. R., Fuster, V.
(2004). The year in atherothrombosis. J Am Coll Cardiol
44: 2099-2110
[Full Text]
Bloomgarden, Z. T.
(2004). Dyslipidemia and the Metabolic Syndrome. Diabetes Care
27: 3009-3016
[Full Text]
Goodman, J. E., Bowman, E. D., Chanock, S. J., Alberg, A. J., Harris, C. C.
(2004). Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk. Carcinogenesis
25: 2467-2472
[Abstract][Full Text]
Fan, Y.-Y., Ly, L. H., Barhoumi, R., McMurray, D. N., Chapkin, R. S.
(2004). Dietary Docosahexaenoic Acid Suppresses T Cell Protein Kinase C{theta} Lipid Raft Recruitment and IL-2 Production. J. Immunol.
173: 6151-6160
[Abstract][Full Text]
Baylin, A., Campos, H.
(2004). Arachidonic Acid in Adipose Tissue Is Associated with Nonfatal Acute Myocardial Infarction in the Central Valley of Costa Rica. J. Nutr.
134: 3095-3099
[Abstract][Full Text]
Barter, P. J., Nicholls, S., Rye, K.-A., Anantharamaiah, G.M., Navab, M., Fogelman, A. M.
(2004). Antiinflammatory Properties of HDL. Circ. Res.
95: 764-772
[Abstract][Full Text]
Mao, J. T., Tsu, I-H., Dubinett, S. M., Adams, B., Sarafian, T., Baratelli, F., Roth, M. D., Serio, K. J.
(2004). Modulation of Pulmonary Leukotriene B4 Production by Cyclooxygenase-2 Inhibitors and Lipopolysaccharide. Clin. Cancer Res.
10: 6872-6878
[Abstract][Full Text]
Lusis, A. J., Fogelman, A. M., Fonarow, G. C.
(2004). Genetic Basis of Atherosclerosis: Part II: Clinical Implications. Circulation
110: 2066-2071
[Full Text]
Stocker, R., Keaney, J. F. Jr.
(2004). Role of Oxidative Modifications in Atherosclerosis. Physiol. Rev.
84: 1381-1478
[Abstract][Full Text]
Mehrabian, M., Allayee, H.
(2004). Vascular Cross-Talk: A Conversation. Arterioscler. Thromb. Vasc. Bio.
24: 1748-1749
[Full Text]
Luo, M., Jones, S. M., Phare, S. M., Coffey, M. J., Peters-Golden, M., Brock, T. G.
(2004). Protein Kinase A Inhibits Leukotriene Synthesis by Phosphorylation of 5-Lipoxygenase on Serine 523. J. Biol. Chem.
279: 41512-41520
[Abstract][Full Text]
Huang, L., Zhao, A., Wong, F., Ayala, J. M., Struthers, M., Ujjainwalla, F., Wright, S. D., Springer, M. S., Evans, J., Cui, J.
(2004). Leukotriene B4 Strongly Increases Monocyte Chemoattractant Protein-1 in Human Monocytes. Arterioscler. Thromb. Vasc. Bio.
24: 1783-1788
[Abstract][Full Text]
Lusis, A. J., Fogelman, A. M., Fonarow, G. C.
(2004). Genetic Basis of Atherosclerosis: Part I: New Genes and Pathways. Circulation
110: 1868-1873
[Full Text]
Manolio, T. A., Boerwinkle, E., O'Donnell, C. J., Wilson, A. F.
(2004). Genetics of Ultrasonographic Carotid Atherosclerosis. Arterioscler. Thromb. Vasc. Bio.
24: 1567-1577
[Abstract][Full Text]
Back, M., Qiu, H., Haeggstrom, J. Z., Sakata, K.
(2004). Leukotriene B4 is an indirectly acting vasoconstrictor in guinea pig aorta via an inducible type of BLT receptor. Am. J. Physiol. Heart Circ. Physiol.
287: H419-H424
[Abstract][Full Text]
Zureik, M., Kony, S., Neukirch, C., Courbon, D., Leynaert, B., Vervloet, D., Ducimetiere, P., Neukirch, F.
(2004). Bronchial Hyperresponsiveness to Methacholine Is Associated With Increased Common Carotid Intima-Media Thickness in Men. Arterioscler. Thromb. Vasc. Bio.
24: 1098-1103
[Abstract][Full Text]
0.05 according to Hardy–Weinberg equilibrium 
2). 
were measured at base line in 27 of the 28 carriers of two variant alleles and in 38 matched carriers of the common allele, with the use of commercially available, high-sensitivity kits. Fatty acids in frozen plasma were also measured in this subgroup (at the Heber Laboratory at UCLA) for validation of dietary measurements. 
Previous
