ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation

Charles B Stephensen,Patrice Armstrong,John W Newman,Theresa L Pedersen,Jillian Legault,Gertrud U Schuster,Darshan Kelley,Susanna Vikman,Jaana Hartiala,Rami Nassir,Michael F Seldin,Hooman Allayee

doi:10.1194/jlr.p012864

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.

Highlights

The objective of this study was to determine whether 5-lipoxygenase (ALOX5) gene variants associated with cardiovascular disease affect eicosanoid production by monocytes
The ALOX5 gene encodes the 5-lipoxygenase (5-LO) enzyme, which acts with 5-lipoxygenase activating protein (FLAP) to catalyze the first two steps in LT synthesis, the production of 5-hydroperoxyeicosatetraenoate (5-HpETE), followed by its conversion to LTA4 or its glutathione peroxidase-dependent conversion to 5-hydroxyeicosatetraenoate (5-HETE) [3]. 5-HETE is a bioactive semistable metabolite that reversibly forms a lactone (5-hydroxy-6dlactone) [4, 5] and is converted by 5-hydroxyeicosanoid dehydrogenase (5-HEDH) to the active metabolite 5-oxo-ETE [6]
Our a priori hypothesis predicted that ALOX5 protein levels and production of LTB4 and other ALOX5-derived metabolites by monocytes would be higher in subjects with the dd promoter genotype than in subjects with the 55 genotype

Summary

Introduction

The objective of this study was to determine whether 5-lipoxygenase (ALOX5) gene variants associated with cardiovascular disease affect eicosanoid production by monocytes. 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.— Stephensen, C. Contains supplementary data in the form of materials and methods (Study Design, Laboratory Methods, and Results), seven tables, and one figure

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