A. L. Carvalho-Wells

APOE genotype influences triglyceride and C-reactive protein responses to altered dietary fat intake in UK adults

BACKGROUND The response of plasma lipids to dietary fat manipulation is highly heterogeneous, with some indications that APOE genotype may be important. OBJECTIVE The objective was to use a prospective recruitment approach to determine the effect of dietary fat quantity and composition on both lipid and nonlipid cardiovascular disease biomarkers according to APOE genotype. DESIGN Participants had a mean (±SD) age of 51 ± 9 y and a BMI (in kg/m²) of 26.0 ± 3.8 (n = 44 E3/E3, n = 44 E3/E4) and followed a sequential dietary intervention (the SATgenε study) in which they were assigned to a low-fat diet, a high-fat high-SFA (HSF) diet, and the HSF diet with 3.45 g DHA/d (HSF-DHA), each for 8 wk. Fasting blood samples were collected at the end of each intervention arm. RESULTS An overall diet effect was evident for all cholesterol fractions (P < 0.01), with no significant genotype × diet interactions observed. A genotype × diet interaction (P = 0.033) was evident for plasma triglycerides, with 17% and 30% decreases in APOE3/E3 and APOE3/E4 individuals after the HSF-DHA diet relative to the low-fat diet. A significant genotype × diet interaction (P = 0.009) was also observed for C-reactive protein (CRP), with only significant increases in concentrations after the HSF and HSF-DHA diets relative to the low-fat diet in the APOE3/E4 group (P < 0.015). CONCLUSIONS Relative to the wild-type APOE3/E3 group, our results indicate a greater sensitivity of fasting triglycerides and CRP to dietary fat manipulation in those with an APOE3/E4 genotype (25% population), with no effect of this allelic profile on cholesterol concentrations.

Interactions between age and apoE genotype on fasting and postprandial triglycerides levels.

OBJECTIVE The influences of genetic determinants on the magnitude of postprandial lipaemia are presently unclear. Here the impact of the common apolipoprotein (apo)E epsilon mutation on the postprandial triglyceride (TG) response is determined, along with an assessment of genotype penetrance according to age, body mass index and gender. METHODS AND RESULTS Healthy adults (n=251) underwent a postprandial investigation, in which blood samples were taken at regular intervals after a test breakfast (0 min, 49 g fat) and lunch (330 min, 29 g fat) until 480 min after the test breakfast. There was a significant impact of apoE genotype on fasting total cholesterol (TC), (P=0.027), LDL-cholesterol (LDL-C), (P=0.008), and %LDL(3) (P=0.001), with higher and lower levels in the E4 and E2 carriers respectively relative to the E3/E3 genotype. Reflective of a higher fasting TG (P=0.001), a significantly higher area under the curve for the postprandial TG response (TG AUC) was evident in the E4 carriers relative to the E3/E3 group (P=0.038). In the group as a whole, a significant age×genotype interaction was observed for fasting TC (P=0.021). In the participants>50 years there was a significant impact of genotype on TC (P=0.005), LDL-C (P=0.001) and TAG AUC (P=0.028). CONCLUSIONS It is possible that an exaggerated postprandial lipaemia contributes to the increased coronary heart disease risk associated with carriers of the E4 allele; an effect which is more evident in older adults.

SATgenε dietary model to implement diets of differing fat composition in prospectively genotyped groups (apoE) using commercially available foods.

Response to dietary fat manipulation is highly heterogeneous, yet generic population-based recommendations aimed at reducing the burden of CVD are given. The APOE epsilon genotype has been proposed to be an important determinant of this response. The present study reports on the dietary strategy employed in the SATgenε (SATurated fat and gene APOE) study, to assess the impact of altered fat content and composition on the blood lipid profile according to the APOE genotype. A flexible dietary exchange model was developed to implement three isoenergetic diets: a low-fat (LF) diet (target composition: 24 % of energy (%E) as fat, 8 %E SFA and 59 %E carbohydrate), a high-saturated fat (HSF) diet (38 %E fat, 18 %E SFA and 45 %E carbohydrate) and a HSF-DHA diet (HSF diet with 3 g DHA/d). Free-living participants (n 88; n 44 E3/E3 and n 44 E3/E4) followed the diets in a sequential design for 8 weeks, each using commercially available spreads, oils and snacks with specific fatty acid profiles. Dietary compositional targets were broadly met with significantly higher total fat (42·8 %E and 41·0 %E v. 25·1 %E, P ≤ 0·0011) and SFA (19·3 %E and 18·6 %E v. 8·33 %E, P ≤ 0·0011) intakes during the HSF and HSF-DHA diets compared with the LF diet, in addition to significantly higher DHA intake during the HSF-DHA diet (P ≤ 0·0011). Plasma phospholipid fatty acid analysis revealed a 2-fold increase in the proportion of DHA after consumption of the HSF-DHA diet for 8 weeks, which was independent of the APOE genotype. In summary, the dietary strategy was successfully implemented in a free-living population resulting in well-tolerated diets which broadly met the dietary targets set.

Dietary fat manipulation has a greater impact on postprandial lipid metabolism than the apolipoprotein E (epsilon) genotype-insights from the SATgenε study.

SCOPE Our aim was to determine the effects of chronic dietary fat manipulation on postprandial lipaemia according to apolipoprotein (APO)E genotype. METHODS AND RESULTS Men (mean age 53 (SD 9) years), prospectively recruited for the APOE genotype (n = 12 E3/E3, n = 11 E3/E4), were assigned to a low fat (LF), high fat, high-saturated fat (HSF), and HSF diet with 3.45 g/day docosahexaenoic acid (HSF-DHA), each for an 8-week period in the same order. At the end of each dietary period, a postprandial assessment was performed using a test meal with a macronutrient profile representative of that dietary intervention. A variable postprandial plasma triacylglycerol (TAG) response according to APOE genotype was evident, with a greater sensitivity to the TAG-lowering effects of DHA in APOE4 carriers (p ≤ 0.005). There was a lack of an independent genotype effect on any of the lipid measures. In the groups combined, dietary fat manipulation had a significant impact on lipids in plasma and Svedberg flotation rate (S(f) ) 60-400 TAG-rich lipoprotein fraction, with lower responses following the HSF-DHA than HSF intervention (p < 0.05). CONCLUSION Although a modest impact of APOE genotype was observed on the plasma TAG profile, dietary fat manipulation emerged as a greater modulator of the postprandial lipid response in normolipidaemic men.

APOE genotype influences insulin resistance, apolipoprotein CII and CIII according to plasma fatty acid profile in the Metabolic Syndrome

Metabolic markers associated with the Metabolic Syndrome (MetS) may be affected by interactions between the APOE genotype and plasma fatty acids (FA). In this study, we explored FA-gene interactions between the missense APOE polymorphisms and FA status on metabolic markers in MetS. Plasma FA, blood pressure, insulin sensitivity and lipid concentrations were determined at baseline and following a 12-week randomized, controlled, parallel, dietary FA intervention in 442 adults with MetS (LIPGENE study). FA-APOE gene interactions at baseline and following change in plasma FA were assessed using adjusted general linear models. At baseline E4 carriers had higher plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) compared with E2 carriers; and higher TC, LDL-C and apo B compared with E3/E3. Whilst elevated plasma n-3 polyunsaturated FA (PUFA) was associated with a beneficially lower concentration of apo CIII in E2 carriers, a high proportion of plasma C16:0 was associated with insulin resistance in E4 carriers. Following FA intervention, a reduction in plasma long-chain n-3 PUFA was associated with a reduction in apo CII concentration in E2 carriers. Our novel data suggest that individuals with MetS may benefit from personalized dietary interventions based on APOE genotype.

Greater impact of dietary fat manipulation than apolipoprotein E genotype on ex vivo cytokine production – Insights from the SATgenε study

Highlights • The effect of diet and genotype on inflammatory response was explored in humans.• Cytokine production was not affected by apolipoprotein E (APOE) genotype.• TNF-α concentration significantly increased after a high saturated fat diet.• IL-10 concentration was significantly higher after a low fat diet.• The amount and type of dietary fat modulated cytokine production.

Interactions between APOE genotype and plasma fatty acids on cardiometabolic risk markers in individuals with the Metabolic Syndrome

Interactions between APOE genotype and plasma fatty acids on cardiometabolic risk markers in individuals with the Metabolic Syndrome

SATgenε dietary strategy to investigate the impact of the apo E genotype on LDL-cholesterol response to dietary fat manipulation

There is emerging evidence that polymorphisms in the gene encoding for apoE impact on the LDL-cholesterol (LDL-C) response to dietary fat intake. It has been reported that carriers of the apoE4 allele have higher plasma LDL-C concentrations after ingestion of saturated fat (SFA) and docosahexanaeoic acid (DHA) (>2g/d) compared with the apoE3 wild-type. The aim of the SATgene study was to investigate the impact of a combination of SFA and DHA intake on plasma lipids according to apoE genotype.

Postprandial effects of supplementing a moderate-fat meal with long-chain n -3 PUFA on measures of arterial stiffness

It is well established that the consumption of long-chain (LC) n-3 PUFA, EPA and DHA, found in fish oils are cardio-protective. Arterial stiffening is a manifestation of vascular dysfunction and is recognised as a biomarker for CVD. There are limited and inconsistent data on the influence of LC n-3 PUFA on arterial stiffness in the postprandial state. The aim of the present study was to investigate the effects of a moderate-fat meal enriched with LC n-3 PUFA on arterial stiffness determined by two different techniques, digital volume pulse analysis (DVP) and pulse wave analysis (PWA), both of which have been described previously. The DVP was obtained by photoplethysmography using the PulseTrace system (Micro Medical, Chatham Maritime, Kent, UK) to calculate stiffness index (SI). PWA was performed by applanation tonometry at the radial artery using the SphygmoCor (ScanMed Medical, Moreton-in-Marsh, Glos., UK) to calculate augmentation index (AIx). Twenty-five healthy subjects (twelve males, thirteen females; age 47 (SD 4) years, BMI 23.4 (SD 0.7) kg/m received either a control (CT) meal (30 g mixed fat; fatty acid profile representative of the UK diet) or an LC n-3 PUFA-rich meal (23 g mixed fat, 6.7 g fish oil, which provided 2.0 g EPA and 2.7 g DHA) on two occasions in a random order. DVP and PWA measurements were taken at baseline and 30, 60, 90, 120, 180 and 240 min after meal consumption to derive SI and AIx respectively. Blood samples were taken at baseline and 120 and 240 min after meal consumption and were analysed for glucose, TAG, insulin and NEFA.