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Title:   Author  item
                                            Stephensen, Charlesitem
                                            ARMSTRONG, PATRICE - University Of Californiaitem
                                            Newman, Johnitem
                                            Pedersen, Theresaitem
                                            LEGAULT, JILLIAN - University Of Californiaitem
                                            SCHUSTER, GERTRUD - University Of Californiaitem
                                            Kelley, Darshanitem
                                            VIKMAN, SUSANNA - University Of Californiaitem
                                            HARTIALA, JAANA - University Of Californiaitem
                                            HOOMAN, ALLAYEE - University Of California
  Submitted to: Journal of Lipid Research
                                    Publication Type: Peer Reviewed Journal
                                    Publication Acceptance Date: 1/28/2011
                                    Publication  Date: 5/1/2011
                                    Citation: Stephensen, C.B., Armstrong, P., Newman, J.W., Pedersen, T.L., Legault, J., Schuster, G., Kelley, D.S., Vikman, S., Hartiala, J., Hooman, A. 2011. ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation. Journal of Lipid Research. 52(5):991-1003.Interpretive Summary: Omega-3 fatty acid intake from food or supplements decreases pathogenic inflammation by modulating production of fatty acid-based mediators of inflammation, such as leukotrienes.  The 5-lipoxygenase gene (ALOX5) encodes an enzyme that catalyzes the production of these leukotrienes from fatty acids.  Previous work has shown that variants in this gene may interact with dietary omega-3 intake to affect risk of cardiovascular disease (CVD).  The present study was designed to determine if subjects with putative high and low risk variants of the gene had different levels of expression of the ALOX5 protein and different levels of leukotriene production before and after supplementation.  The study randomized volunteers of African ancestry with the putative high and low risk variants of the ALOX5 gene to receive fish oil or placebo oil.  Subjects of African ancestry were recruited because they have a higher prevalence of the high risk variant of the ALOX5 gene.  The study found that ALOX5 protein levels in monocytes (a cell type that can mediate CVD development by affecting coronary artery inflammation) isolated from peripheral blood of volunteers did not vary by genotype. Production of leukotriene metabolites did differ by genotype.  The production of leukotrienes produced from omega-3 fatty acids increased more in the subjects with the low risk genotype, suggesting that differences in leukotriene metabolism among these ALOX5 genotypes may mediate the different risk of CVD previously identified for subjects with these genotypes.
                                Technical Abstract: The objective of this study was to determine whether 5-lipoxygenase (ALOX5) gene variants associated with cardiovascular disease affect eicosanoid production by monocytes. The study was a randomized, double-masked, parallel intervention trial with fish oil (5.0 g of fish oil daily, containing 2.0 g of eicosapentaenoic acid [EPA] and 1.0 g of docosahexaenoic acid [DHA]) or placebo oil (5.0 g of corn/soy mixture). A total of 116 subjects (68% female, 20-59 years old) of African American ancestry enrolled, and 98 subjects completed the study. Neither ALOX5 protein nor arachidonic acid-derived LTB4, LTD4, and LTE4 varied by genotype, but 5-hydroxyeicosatetraenoate (5-HETE), 6-trans-LTB4, 5-oxo-ETE, 15-HETE, and 5,15-diHETE levels were higher in subjects homozygous for the ALOX5 promoter allele containing five Sp1 element tandem repeats ("55" genotype) than in subjects with one deletion (d) (three or four repeats) and one common ("d5" genotype) allele or with two deletion ("dd") alleles. The EPA-derived metabolites 5-HEPE and 15-HEPE and the DHA-derived metabolite 17-HDoHE had similar associations with genotype and increased with supplementation; 5-HEPE and 15-HEPE increased, and 5-oxo-ETE decreased to a greater degree in the 55 than in the other genotypes. This differential eicosanoid response is consistent with the previously observed interaction of these variants with dietary intake of omega-3 fatty acids in predicting cardiovascular disease risk.


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