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Biochemical and physiological responsiveness to low dose fish oil intakes: Impact of genotype, gender, age and geography

Project Code: N02028

20/11/2006

University of Reading
Minihane, A ;
University of Newcastle
Williams, D; Mathers, P

Introduction, objectives & aims

Although some inconsistencies in the literature exist, over the last 20 years a large body of epidemiological data and evidence from randomised controlled trials (RCTs) has demonstrated the cardioprotective action of the fish oil fatty acids eicosapentaenoic (EPA) and docosahexaenoic acids (DHA) (Hu et al., 2002; Burr et al., 1989; GISSI, 1999; Kris-Etherton et al., 2003; Hooper et al., 2006). At intakes of EPA+DHA of 0.5-1.0g per day, the cardioprotective benefits have largely been attributed to an anti-arrhythmic effect, with increased EPA/DHA content of heart muscle tissue resulting in decreased ventricular fibrillation and increased survival post-MI. Reductions in relative risk (RR) of 20-30% in total mortality, cardiovascular mortality and sudden death are frequently reported. The benefits of higher levels of intake of > 2g EPA+DHA have been attributed to: (a) a blood lipid modulatory effects, with fish oil fatty acids known to be potent hypotriglyceridaemic agents; (b) an anti-inflammatory action and (c) a positive impact on endothelial function (Minihane et al., 2000; Harris et al., 1997; Balk et al., 2006; Calder, 2004; Thies et al. 2003; Nestel, 2002). However the benefits of more modest EPA+DHA intakes on these components of the cardiovascular risk phenotype remain relatively unknown. Furthermore many of the intervention studies conducted to date have used middle aged males as the study population. Therefore a major aim of this dose response study was to investigate the impact of more modest (0.7 and 1.8g EPA+DHA per day), dietary achievable levels of intake, on a host of established and more novel risk factors for coronary heart disease (CHD) in men and women of all ages.

However, the primary objective of the study was to examine the impact of apoE genotype on the LDL cholesterol (LDLC) response to EPA+DHA intake. Numerous studies in the literature report increases ranging from 0-30% following high dose fish oil supplementation (Harris et al., 1997; Minihane et al., 2000; Balk et al., 2006; Mori and Woodman, 2006). Pilot data generated by the current consortium reporting that at intakes of 3g EPA+DHA per day, this deleterious response may be unique to apoE4 carriers (25% UK population)(Minihane et al., 2000). Therefore the primary aim of the trial was to use prospective recruitment according to apoE genotype (and age & gender) to examine the impact of modest dose fish oil intake on LDLC responsiveness.

These two main study aims are of major public health relevance. There is a relatively strong justification to increase the current EPA+DHA recommendation from the minimum of 0.45g/day. However, prior to this occurring a number of key questions regarding the safety and efficacy of dietary achievable levels of intakes in all populations subgroups, need to be addressed. The current trial makes a significant contribution to the knowledge deficit in this area.

Experimental procedures

The study was a 4 centre double blind placebo controlled trial, with 3 intervention arms of 8 week duration separated by 12 week wash-out periods. During the intervention periods participants consumed in random order either 0.7g EPA+DHA/day (low fish oil, LFO), 1.8g EPA+DHA per day (medium fish oil, MFO), or placebo (P), which consisted of a palm olein:soyabean oil mixture (80:20) with a fatty acid composition representative of a typical UK diet. Participants were prospectively recruited on the basis of apoE genotype (E2, E3, E4), gender, or age in order to ensure sufficient power to establish the impact of these and other variables on responsiveness to the intervention. At the beginning and end of each 8 week intervention arm volunteers attended the clinical unit and provided a fasting blood sample, spot urine sample and had their weight and blood pressure determined.

Furthermore vascular reactivity was measured at the Glasgow and Reading sites using the Laser Doppler Iontophoresis (LDI) technique. All volunteers completed a food
frequency questionnaire on 2 occasions, and had further anthropometric measurements taken which included waist and hip circumferences and skinfold thickness. The blood samples collected at each of the 6 pre- and post- intervention time points were analysed for 33 CHD risk outcomes, which included plasma lipid concentrations, LDL and HDL subclass profiles, inflammatory markers, markers of endothelial function, glucose and insulin concentration, red cell folate, homocysteine, thrombotic factors and plasma phospholipids fatty acids. Urinary F2-isoprostanes were also determined. The statistical significance of responsiveness to treatment according to genotype, age and gender was determined using a repeated measures multi-variate approach in (a) all individuals who commenced the study (intention to treat approach) or (b) in those who completed the intervention. Baseline associations between our design variable (age, genotype and gender) and CHD risk outcomes were analysed using ANOVA and linear regression modelling

Key findings

• Greater enrichment in the plasma phospholipid LC n-3 PUFA concentrations was evident in females than males in response to treatment, which is likely due to a greater dose consumed per unit weight rather than any gender mediated differences in EPA/DHA incorporation.

• Supplementation with 0.7g (LFO) and 1.8g EPA+DHA (MFO) per day resulted in a modest, but significant, 3% increase in circulating LDLC, with no impact of apoE genotype/age/gender on response to treatment.

• An 8% and 11% reduction in TG levels were observed in response to LFO and MFO respectively, with significantly greater reductions in males and apoE4 carriers.

• A significant impact of treatment on LDL and HDL particles size was evident, with fish oil mediated increases in particle size. Greater responsiveness was evident in male participants.

• No deleterious impact of treatment on oxidative status or insulin sensitivity was observed

• Although there was trends towards an improved inflammatory profile, the effects are modest and unlikely to be of major clinical significance

• No impact of treatment on blood pressure or vascular reactivity were observed

• In addition to its previously reported impact on LDL cholesterol metabolism the current study reports that apoE genotype emerges as a significant determinant of HDL particle size, VCAM-1, P-selectin, CRP and homocysteine, differences which are likely to in part explain the disease differential between the different apoE genotype groups.

• These outcomes are of major public health significance as they highlight the potential contribution of lipid modulation to the cardioprotective benefits of intakes < 2g/day EPA+DHA. Importantly these levels of intake had little effect on oxidative status and only resulted in modest 3% increases in LDLC, with no evidence of a greater response in apoE4 carriers.

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