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Grant Abstract

Grant Number: 1R21AT003411-01A1
PI Name: STEPHENSEN, CHARLES B.
Project Title: Variation in the ALOX5 gene and response to omega-3 fatty acid supplements

Abstract: DESCRIPTION (provided by applicant): Genetic differences among individuals may affect nutrient requirements and the potential health benefits from dietary interventions. Some nutritional supplements, such as omega-3 fatty acids, are widely used in the US as a complementary or alternative medical strategy. In particular, omega-3 supplements from a variety of sources are recommended for prevention of or symptomatic relief for many chronic inflammatory diseases, including cardiovascular disease, hypertension, arthritis and asthma. Many of these diseases affect black Americans at a higher rate or with greater severity than they do white Americans. Such health disparities have multiple causes, both social and biological, and may be partially due to different dietary practices or differences in genetic risk. While the benefit of omega-3 supplements for cardiovascular disease are widely recognized, recent observational data indicates that subjects with a variant allele for the arachidonate 5-lipoxygenase gene (ALOX5) may be at greater risk for cardiovascular disease and, at the same time, may derive a greater benefit from omega-3 fatty acid supplements than do subjects homozygous for the common allele. The variant alleles of interest have 3 or 4 repeats of the Sp1/Egr-1 transcription factor binding site in the ALOX5 promoter, while the common allele has 5 repeats. The variant alleles are less common in the white population (18%) than in the black population (52%). The epidemiologic data suggest that subjects with two variant alleles will have greater ALOX5 gene expression, greater production of arachidonic acid-derived leukotrienes and a more "proinflammatory" phenotype than subjects with two common alleles. These data also suggest that subjects with the variant alleles will derive greater health benefits from omega-3 supplementation. In the pilot study proposed here we will recruit black subjects who have (a) 2 variant alleles; (b) 2 common alleles or (3) one of each to determine if ALOX5 mRNA, ALOX5 protein, leukotriene production and inflammatory cytokine production differ among the genotypes. Subjects will then receive placebo or omega-3 fatty acid supplements for 6 wk to determine if the expected decreases in leukotriene and cytokine production are greater in subjects homozygous or heterozygous for the variant alleles. Indicators of cardiovascular risk will also be assessed before and after intervention, including blood lipid profile, blood pressure, heart rate, and plasma CRP, glucose and insulin concentrations.

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