ApoE Polymorphism and Fish Oil Supplementation in Subjects With an Atherogenic Lipoprotein Phenotype

Minihane, Anne M.; Khan, Syrah; Leigh-Firbank, Elizabeth C.; Talmud, Philippa; Wright, John W.; Murphy, Margaret C.; Griffin, Bruce A.; Williams, Christine M.

doi:10.1161/01.atv.20.8.1990

Cited by 215Fatty Acid Research and HealthLipoproteins and Cardiovascular HealthLipid metabolism and disorders

ApoE Polymorphism and Fish Oil Supplementation in Subjects With an Atherogenic Lipoprotein Phenotype

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Minihane, Anne M., Khan, Syrah, Leigh-Firbank, Elizabeth C., Talmud, Philippa, Wright, John W., Murphy, Margaret C., Griffin, Bruce A., Williams, Christine M.·2000·Arteriosclerosis, Thrombosis, and Vascular Biology

DOI 10.1161/01.atv.20.8.1990

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Abstract

Abstract —The study assessed the efficacy of fish oil supplementation in counteracting the classic dyslipidemia of the atherogenic lipoprotein phenotype (ALP). In addition, the impact of the common apolipoprotein E (apoE) polymorphism on the fasting and postprandial lipid profile and on responsiveness to the dietary intervention was established. Fifty-five ALP males (aged 34 to 69 years, body mass index 22 to 35 kg/m 2 , triglyceride [TG] levels 1.5 to 4.0 mmol/L, high density lipoprotein cholesterol [HDL-C] <1.1 mmol/l, and percent low density lipoprotein [LDL]-3 >40% total LDL) completed a randomized placebo-controlled crossover trial of fish oil (3.0 g eicosapentaenoic acid/docosahexaenoic acid per day) and placebo (olive oil) capsules with the 6-week treatment arms separated by a 12-week washout period. In addition to fasting blood samples, at the end of each intervention arm, a postprandial assessment of lipid metabolism was carried out. Fish oil supplementation resulted in a reduction in fasting TG level of 35% ( P <0.001), in postprandial TG response of 26% (TG area under the curve, P <0.001), and in percent LDL-3 of 26% ( P <0.05). However, no change in HDL-C levels was evident ( P =0.752). ANCOVA showed that baseline HDL-C levels were significantly lower in apoE4 carriers ( P =0.035). The apoE genotype also had a striking impact on lipid responses to fish oil intervention. Individuals with an apoE2 allele displayed a marked reduction in postprandial incremental TG response (TG incremental area under the curve, P =0.023) and a trend toward an increase in lipoprotein lipase activity relative to non-E2 carriers. In apoE4 individuals, a significant increase in total cholesterol and a trend toward a reduction in HDL-C relative to the common homozygous E3/E3 profile was evident. Our data demonstrate the efficacy of fish oil fatty acids in counteracting the proatherogenic lipid profile of the ALP but also that the apoE genotype influences responsiveness to this dietary treatment.

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Although most trials presented in Table 4 specified direct LDL-C measurement when triglycerides >400 mg/dL, only 3 trials reported LDL-C results obtained from direct LDL measurement throughout the triglyceride range.
“Although most trials presented in Table 4 specified direct LDL-C measurement in cases when triglycerides >400 mg/dL (as is standard for clinical practice), only 3 trials reported LDL-C results obtained from direct LDL measurement throughout the triglyceride range.28,30,45”
From Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association (2019) · cites this paper as [45]
The Biochemical Analysis section states that this trial computed LDL-C using the Friedewald formula, rather than measuring LDL-C directly throughout the triglyceride range. Thus, the paper contradicts its apparent identification as one of the three trials using direct LDL-C measurement. (LLM, conf=0.90)
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In monotherapy trials, the average triglyceride reduction was about 27%, with a range of 21% to 35%, except for a medical food study using 3.2 g/day EPA+DHA in people with very low n-3 fatty acid levels, which reported a 48% reduction.
“On average, the triglyceride reduction was ≈27% (range, 21%-35%), apart from the study of a medical food (3.2 g/d EPA+DHA), which specifically recruited people with very low blood levels of n-3 FA and reported a 48% reduction.”
From Omega-3 Fatty Acids for the Management of Hypertriglyceridemia: A Science Advisory From the American Heart Association (2019) · cites this paper as [45]
The Results and Discussion (page unavailable) report a 35.3% reduction in fasting triglycerides after fish-oil supplementation in this study, supporting the upper end of the stated range. They do not report a 27% average across monotherapy trials or the medical-food study's 48% reduction in people with very low n-3 fatty acid levels. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Total cholesterol levels increased in APOE4 carriers and LDL-C levels tended to increase more in APOE4 carriers than in APOE2 or APOE3 carriers following OM3FA treatment, although not statistically significant.
“Total cholesterol levels increased in APOE4 carriers and, although not statistically significant, LDL-C levels tended to increase more in APOE4 carriers than in APOE2 or APOE3 carriers following OM3FA treatment.”
From Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review (2017) · cites this paper as [59]
Small dense LDL levels decreased similarly in different APOE genotypes following OM3FA treatment.
“However, small dense LDL levels decreased similarly in the different APOE genotypes [59].”
From Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review (2017) · cites this paper as [59]
The effect of OM3FAs on LDL was dependent on APOE genotype.
“Minihane et al. were the first to show that the effect of OM3FAs on LDL was dependent on APOE genotype [59].”
From Omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid and their mechanisms of action on apolipoprotein B-containing lipoproteins in humans: a review (2017) · cites this paper as [59]

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ApoE polymorphism and fish oil supplementation in subjects with an antherogenic lipoprotein phenotype
Minihane, A., Khan, S., Leigh-Firbank, E., Talmud, P. J., Wright, J., Murphy, M., Griffin, B., & Williams, C. (2000) · UCL Discovery (University College London)
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Effect of sex and genotype on cardiovascular biomarker response to fish oils
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An adverse low density lipoprotein-cholesterol response to fish oil supplementation is observed in subjects with an apoE4 genotype.
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Contribution of apolipoprotein E genotype and docosahexaenoic acid to the LDL-cholesterol response to fish oil
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Self-citation

Authors: Minihane, A. M., Khan, S., Leigh-Firbank, E. C., Talmud, P., Wright, J. W., Murphy, M. C., Griffin, B. A., & Williams, C. M.
Affiliations: University of Surrey (GB)
ORCID: Minihane, Anne M.
Talmud, Philippa
Venue: Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2000-08
Volume: 20
Issue: 8
Pages: 1990-1997
ISSN: 1079-5642 (ISSN-L)
1524-4636
DOI: 10.1161/01.atv.20.8.1990
OpenAlex: W2133738729
Cited by: 215
References: 70
Citations by year: 2026: 2 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 5 · 2021: 8 · 2020: 4 · 2019: 8 · 2018: 6 · 2017: 13 · 2016: 7 · 2015: 5 · 2014: 12 · 2013: 12 · 2012: 12
FWCI: 7.99
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
PubMed (publishedVersion)
UEA Digital Repository (University of East Anglia) (submittedVersion)
Funders: Directorate for Biological Sciences
Biotechnology and Biological Sciences Research Council
Topics: Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords: APOE polymorphism, fish oil supplementation, eicosapentaenoic acid, docosahexaenoic acid, atherogenic lipoprotein phenotype, dyslipidemia, postprandial triglyceride response, HDL cholesterol, LDL cholesterol, lipoprotein lipase activity, APOE ε4 carriers, ApoE2 allele, olive oil placebo
MeSH terms: Adult, Aged, Apolipoproteins E, Arteriosclerosis, Double-Blind Method, Fasting, Fatty Acids, Nonesterified, Fish Oils, Food, Genotype, Humans, Lipoproteins, Cholesterol, HDL, Cholesterol, LDL, Male, Middle Aged, Phenotype, Placebos, Polymorphism, Genetic, Triglycerides, Cross-Over Studies

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ApoE Polymorphism and Fish Oil Supplementation in Subjects With an Atherogenic Lipoprotein Phenotype

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