Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil

Atherosclerosis. 2010 Mar;209(1):104-10. doi: 10.1016/j.atherosclerosis.2009.08.024. Epub 2009 Aug 21.


Objectives: To investigate the impact of apolipoprotein E (apoE) genotype on the response of the plasma lipoprotein profile to eicosapentaenoic acid (EPA) versus docosahexaenoic acid (DHA) intervention in humans.

Methods and results: 38 healthy normolipidaemic males, prospectively recruited on the basis of apoE genotype (n=20 E3/E3 and n=18 E3/E4), completed a double-blind placebo-controlled cross-over trial, consisting of 3 x 4 week intervention arms of either control oil, EPA-rich oil (ERO, 3.3g EPA/day) or DHA-rich oil (DRO, 3.7g DHA/day) in random order, separated by 10 week wash-out periods. A significant genotype-independent 28% and 19% reduction in plasma triglycerides in response to ERO and DRO was observed. For total cholesterol (TC), no significant treatment effects were evident; however a significant genotype by treatment interaction emerged (P=0.045), with a differential response to ERO and DRO in E4 carriers. Although the genotype x treatment interaction for LDL-cholesterol (P=0.089) did not reach significance, within DRO treatment analysis indicated a 10% increase in LDL (P=0.029) in E4 carriers with a non-significant 4% reduction in E3/E3 individuals. A genotype-independent increase in LDL mass was observed following DRO intervention (P=0.018). Competitive uptake studies in HepG2 cells using plasma very low density lipoproteins (VLDL) from the human trial, indicated that following DRO treatment, VLDL(2) fractions obtained from E3/E4 individuals resulted in a significant 32% (P=0.002) reduction in LDL uptake relative to the control.

Conclusions: High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers, which appears to be due to an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Apolipoproteins E / genetics*
  • Cell Line
  • Cholesterol, LDL / blood*
  • Cholesterol, VLDL / blood*
  • Docosahexaenoic Acids / administration & dosage*
  • Eicosapentaenoic Acid / administration & dosage*
  • Fish Oils / administration & dosage*
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Young Adult


  • Apolipoproteins E
  • Cholesterol, LDL
  • Cholesterol, VLDL
  • Fish Oils
  • Docosahexaenoic Acids
  • Eicosapentaenoic Acid