Role of Polyunsaturated Fat in Modifying CVD Risk

Quick Takes

  • Using blood or tissue measurements of PUFA as surrogate markers of dietary intake, there is a significant interaction between low EPA/DHA, but not linoleic acid and alpha-linolenic acid, and a family history of CVD.
  • The findings suggest that persons with a family history of CVD might benefit more than the average person with the recommendation of higher intake of oily (cold water) fish and other foods rich in EPA/DHA. Oily fish provides about 1 g per EPA/DHA per serving.
  • In contrast, recent clinical trials have shown that 4 g of EPA/DPA had no benefit in high-risk persons with fasting triglycerides 150-500 mg/dL, while pure EPA resulted in a 30% reduction in major CV events including need for revascularization. Findings independent of the degree of lowering of triglyceride and suggesting DHA may be harmful for ASCVD.

Study Questions:

Does dietary intake of polyunsaturated fats (PUFAs) modify the cardiovascular disease (CVD) risk associated with a family history of CVD?


The authors of Fatty Acids and Outcomes Research Consortium (FORCE), a scientific collaboration effort whose aim is to investigate the relationship between fatty acids and several chronic diseases, pooled their 15 observational studies to assess interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium of subjects. Blood and tissue PUFA data from 40,885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linolenic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% confidence interval (CI) of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.


After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled, relative risk 1.09 [95% CI, 1.02-1.16]; p = 0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.


A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.


The findings are of interest but the conclusion that oily fish may reduce CVD in persons with a family history of CVD when they have low EPA/DHA intake also implies benefit from dietary supplements as capsules of ‘fish oil,’ which is not consistent with meta-analyses of n−3 supplementation trials and the more recent VITAL trial of about 1 g of EPA/DHA. In adults with CVD or at high risk for CVD, fish oil supplementation has no, or at most a weak, preventive effect on CV outcomes. Recent trials of high-dose EPA/DHA supplement (4 g/day) had no benefit in persons with triglycerides between 150-500 mg/dL and atherosclerotic CVD (ASCVD) or diabetes with two other CV risk factors. In contrast, pure EPA in the same dose was very effective in reducing CV events (about 30%), suggesting that DHA may have a negative effect on ASCVD.

Clinical Topics: Dyslipidemia, Lipid Metabolism, Nonstatins, Prevention

Keywords: Cardiometabolic Risk Factors, Fatty Acids, Omega-3

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