Determinants of Erythrocyte Omega‐3 Fatty Acid Content in Response to Fish Oil Supplementation: A Dose–Response Randomized Controlled Trial

BACKGROUND: The erythrocyte membrane content of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which constitutes the omega‐3 index (O3I), predicts cardiovascular disease mortality. The amount of EPA+DHA needed to achieve a target O3I is poorly defined, as are the determinants of the O3I response to a change in EPA+DHA intake. The objective of this study was to develop a predictive model of the O3I response to EPA+DHA supplementation in healthy adults, specifically identifying factors that determine the response. METHODS AND RESULTS: A randomized, placebo‐controlled, double‐blind, parallel‐group study was conducted in 115 healthy men and women. One of 5 doses (0, 300, 600, 900, 1800 mg) of EPA+DHA was given daily as placebo or fish oil supplements for ≈5 months. The O3I was measured at baseline and at the end of the study. There were no significant differences in the clinical characteristics between the groups at baseline. The O3I increased in a dose‐dependent manner (P<0.0001), with the dose of EPA+DHA alone accounting for 68% (quadratic, P<0.0001) of the variability in the O3I response. Dose adjusted per unit body weight (g/kg) accounted for 70% (linear, P<0.0001). Additional factors that improved prediction of treatment response were baseline O3I, age, sex, and physical activity. Collectively, these explained 78% of the response variability (P<0.0001). CONCLUSIONS: Our findings validate the O3I as a biomarker of EPA+DHA consumption and identify additional factors, particularly body weight, that can be used to tailor EPA+DHA recommendations to achieve a target O3I.