Background: Few studies have examined the associations of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with biomarkers of chronic disease risk in populations with high intakes.

Objective: We examined the associations of red blood cell (RBC) EPA and DHA, as percentages of total fatty acids, with biomarkers of chronic disease risk across a wide range of EPA and DHA intakes.

Design: In a cross-sectional study of 357 Yup'ik Eskimos, generalized additive models were used to plot covariate-adjusted associations of EPA and DHA with chronic disease biomarkers. Linear regression models were used to test for the statistical significance of these associations.

Results: Means (5th-95th percentiles) for RBC EPA and DHA were 2.8% (0.5-5.9%) and 6.8% (3.3-9.0%), respectively. Associations of EPA and DHA were inverse and linear for triglycerides (beta +/- SE = -0.10 +/- 0.01 and -0.05 +/- 0.01, respectively) and positive and linear for HDL cholesterol (beta +/- SE = 2.0 +/- 0.5 and 0.9 +/- 0.6, respectively) and apolipoprotein A-I (beta +/- SE = 2.6 +/- 0.8 and 1.7 +/- 0.8, respectively). Positive linear associations of DHA with LDL and total cholesterol (beta +/- SE = 7.5 +/- 1.4 and 6.80 +/- 1.57, respectively) were observed; for EPA, these associations were nonlinear and restricted to concentrations approximately <5% of total fatty acids. Associations of EPA and DHA with C-reactive protein were inverse and nonlinear: for EPA, the association appeared stronger at concentrations approximately >3% of total fatty acids; for DHA, it was observed only at concentrations approximately >7% of total fatty acids.

Conclusion: Increasing EPA and DHA intakes to amounts well above those consumed by the general US population may have strong beneficial effects on chronic disease risk.