Hyperlipidemias: Mensink RP

Hovenkamp E, Demonty I, Plat J, Lütjohann D, Mensink RP, Trautwein EA. · Unilever Food and Health Research Institute, 3130 AC Vlaardingen, The Netherlands. · Prog Lipid Res. · Pubmed #18022398 No free full text.

Abstract: The cholesterol-lowering effect of phytosterols has been extensively studied, and consumption of phytosterols is among the recommendations to lower LDL-cholesterol concentrations. Due to their structural similarity with cholesterol, phytosterols may undergo oxidative processes comparable to those involved in cholesterol oxidation. Consumption of phytosterols could therefore lead to increased systemic concentrations of oxidized phytosterols (oxyphytosterols) via increased dietary intake or in vivo formation from non-oxidized phytosterols. While the biological effects of oxidized cholesterol (oxycholesterol) have been well studied, the amount of biological research on oxyphytosterols is scarce. Most reports on oxyphytosterols cover their quantitative analysis. Whether oxyphytosterols may play similar biological roles as compared to oxycholesterol has not been fully elucidated. The usual perception about oxyphytosterols is that these components present a concern in terms of food quality and health. This perception originates from the parallel that is made with oxycholesterol. Yet, in line with results for oxycholesterol, recent data suggest that oxyphytosterols--depending on the type of oxidation product--may also have beneficial biological properties. Therefore, the objective of this review is to summarise the current understanding of the biological effects, next to identifying future research needs that will help to clarify the possible impact of oxyphytosterols on human health.

Dullens SP, Plat J, Mensink RP. · Department of Human Biology, Maastricht University, Universiteitssingel 50, Maastricht, The Netherlands. · Nutr Metab Cardiovasc Dis. · Pubmed #17703927 No free full text.

Abstract: Dyslipidemia leading to coronary heart diseases (CHD) enables venues to prevent or treat CHD by other strategies than only lowering serum LDL cholesterol (LDL-C) concentrations, which is currently the most frequently targeted change. Unlike LDL-C, elevated high-density lipoprotein cholesterol (HDL-C) concentrations may protect against the development of CHD as demonstrated in numerous large-scale epidemiological studies. In this review we describe that besides elevating serum HDL-C concentrations by increasing alpha-HDL particles, approaches to elevate HDL-C concentrations by increasing pre-beta HDL particle concentrations seems more attractive. Besides infusion of apoA-I(Milano), using apoA-I mimetics, or delipidation of alpha-HDL particles, elevating de novo apoA-I production may be a suitable target to functionally increase pre-beta HDL particle concentrations. Therefore, a detailed description of the molecular pathways underlying apoA-I synthesis and secretion, completed with an overview of known effects of pharmacological and nutritional compounds on apoA-I synthesis will be presented. This knowledge may ultimately be applied in developing dietary intervention strategies to elevate apoA-I production and serum HDL-C concentrations and consequently lower CHD risk.

Plat J, Mensink RP. · Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Am J Cardiol. · Pubmed #15992511 No free full text.

Abstract: Incorporation of plant stanol esters into margarine is among the first examples of a functional food with proven low-density lipoprotein (LDL) cholesterol-lowering effectiveness. Recently, there have been many studies on the effects of plant stanols/sterols on cholesterol metabolism. It has been found that the serum LDL cholesterol-lowering effect of plant stanols/sterols originates from reduced intestinal cholesterol absorption, a process in which changes in micellar composition are thought to play a major role. However, recent findings suggest that there is an additional process in which plant stanols/sterols actively influence cellular cholesterol metabolism within intestinal enterocytes. Furthermore, in response to the reduced supply of exogenous cholesterol, receptor-mediated lipoprotein cholesterol uptake is probably enhanced, as shown by increased LDL receptor expression. At recommended intakes of about 2 to 2.5 g/day, products enriched with plant stanol/sterol esters lower plasma LDL cholesterol levels by 10% to 14% without any reported side effects. Thus, plant stanols/sterols can be considered to be effective and safe cholesterol-lowering functional food ingredients.

Kerckhoffs DA, Hornstra G, Mensink RP. · Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Am J Clin Nutr. · Pubmed #12885701 links to  free full text

Abstract: BACKGROUND: Findings about the effects of beta-glucan on serum lipoproteins are conflicting. OBJECTIVE: The study investigated the effects of beta-glucan from oat bran in bread and cookies (study 1) and in orange juice (study 2) on serum lipoproteins in mildly hypercholesterolemic subjects. DESIGN: In study 1, 48 subjects (21 men, 27 women) received for 3 wk control bread and cookies rich in wheat fiber. For the next 4 wk, by random assignment, 23 subjects continued to consume the control products, and 25 received bread and cookies rich in beta-glucan. Mean daily intake of beta-glucan was 5.9 g. Total dietary fiber intake did not differ significantly between the groups. In study 2, the same sources of control fiber and beta-glucan (5 g/d) as in study 1 were provided. For 2 wk, 25 of the original 48 subjects (10 men, 15 women) were randomly assigned to consume orange juice containing either wheat fiber (n = 13) or beta-glucan from oat bran (n = 12). After a washout period of 1 wk, dietary regimens were crossed over. RESULTS: In study 1, the change in LDL cholesterol did not differ significantly (-0.12 mmol/L; P = 0.173) between the 2 groups. In study 2, the drink rich in beta-glucan decreased LDL cholesterol by 0.26 +/- 0.07 mmol/L (6.7 +/- 1.8%; P = 0.001) and the ratio of total to HDL cholesterol by 0.26 +/- 0.11 (5.4 +/- 2.1%; P = 0.029) compared with the other drink. HDL-cholesterol and triacylglycerol concentrations did not change significantly. CONCLUSIONS: The food matrix or the food processing, or both, could have adverse effects on the hypocholesterolemic properties of oat beta-glucan.

Lagrost L, Mensink RP, Guyard-Dangremont V, Temme EH, Desrumaux C, Athias A, Hornstra G, Gambert P. · Laboratoire de Biochimie des Lipoprotéines, INSERM U498, Faculté de Médecine, Hôpital du Bocage, Dijon, France. · Atherosclerosis. · Pubmed #10030391 No free full text.

Abstract: Cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP) activities were measured in sera from 32 normolipidemic women and men consuming diets enriched in lauric, palmitic, or oleic acids. Serum CETP activity, measured as the rate of radiolabeled cholesteryl esters transferred from HDL toward serum apo B-containing lipoproteins, was higher with the palmitic acid diet (25.1+/-2.5%) than with the lauric acid (23.7+/-2.4%) and the oleic acid (24.0+/-2.7%) diets (P = 0.0028 and 0.0283, respectively). CETP mass concentrations, as measured with an enzyme-linked immunosorbent assay were increased after the lauric acid diet (2.57+/-0.63 mg/l) and the palmitic acid diet (2.49+/-0.64 mg/l) as compared with the oleic acid diet (2.34+/-0.45 mg/l) (P = 0.0035 and 0.0249, respectively). In contrast with CETP, serum PLTP activity, as measured as the rate of radiolabeled phosphatidylcholine transferred from liposomes toward serum HDL, was significantly higher with the lauric acid diet (23.5+/2.6%) than with the palmitic acid diet (22.5+/-2.5%) (P = 0.0013), while no significant differences were noted when comparing the saturated diets versus the oleic acid diet (23.0+/-2.3%). No significant alterations in the mean apparent diameter of LDL, and in the relative proportions of individual HDL subpopulations were observed from one dietary period to another. Nevertheless, lipid transfer activities correlated significantly with the relative abundance of HDL2b, HDL2a, HDL3b, and HDL3c, with opposite tendencies being observed for cholesteryl ester transfer and phospholipid transfer activities. In general, serum CETP activity correlated negatively with HDL cholesterol, but positively with triglyceride concentrations after the dietary interventions, and the relations with serum lipids were just the opposite for PLTP activity. In addition, CETP and PLTP activities correlated negatively when subjects consumed the standardized diets (P < 0.05 in all cases), but not when subjects consumed their habitual diet. It is concluded that serum lipid transfer activities in normolipidemic subjects can be significantly affected by the fatty acid content of the diet, with differential effects on CETP and PLTP activities.

Mensink RP, van Houwelingen AC, Kromhout D, Hornstra G. · Department of Human Biology, Maastricht University, Netherlands. · Am J Clin Nutr. · Pubmed #9989682 links to  free full text

Abstract: BACKGROUND: Tocotrienols, lipid-soluble antioxidants with vitamin E activity, have been reported to lower LDL-cholesterol concentrations and platelet aggregation in men, but results are contradictory. OBJECTIVE: To examine in detail the effects of a vitamin E concentrate rich in tocotrienols on serum lipoproteins and on platelet function in men at risk for cardiovascular disease. DESIGN: In this randomized, double-blind, placebo-controlled parallel trial, 20 men received daily for 6 wk 4 capsules, each containing 35 mg tocotrienols and 20 mg alpha-tocopherol; 20 other men received 4 capsules daily, each providing 20 mg alpha-tocopherol. All men had concentrations of serum total cholesterol between 6.5 and 8.0 mmol/L or lipoprotein(a) concentrations > 150 mg/L. RESULTS: Compliance was confirmed by changes in serum tocopherol and tocotrienol concentrations. Serum LDL cholesterol in the tocotrienol group was 4.80 mmol/L before and 4.79 mmol/L after intervention, and increased from 4.70 to 4.86 mmol/L in the placebo group (95% CI for the difference: -0.54, 0.19 mmol/L; P = 0.333). Also, changes in HDL cholesterol, triacylglycerol, lipoprotein(a), and lipid peroxide concentrations did not differ between the groups. After adjustment for differences in initial values, no effects were found on collagen-induced platelet aggregation velocity, maximum aggregation, or thromboxane B2 formation in citrated whole blood. ATP release, however, was lower in the tocotrienol group. Urinary thromboxane B2 and 11-keto-thromboxane B2 concentrations and coagulation and fibrinolytic measures did not change. CONCLUSION: The tocotrienol supplements used had no marked favorable effects on the serum lipoprotein profile or on platelet function in men with slightly elevated lipid concentrations.

Schiepers OJ, de Groot RH, van Boxtel MP, Jolles J, de Jong A, Lütjohann D, Plat J, Mensink RP. · School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Maastricht University, 6200 MD Maastricht, The Netherlands. · J Nutr. · Pubmed #19458031 No free full text.

Abstract: Recent animal and human studies have shown that plant sterols and stanols, which are used as functional food ingredients to lower increased LDL cholesterol concentrations, pass the blood-brain barrier. Whether this affects neurocognitive functioning and mental well-being in humans has, to our knowledge, never been investigated. The aim of the present study was therefore to examine the effects of long-term plant sterol or stanol consumption on neurocognitive functioning and mood in a randomized, double-blind, placebo-controlled dietary intervention trial. To this end, hypercholesterolemic individuals, aged 43-69 y, receiving stable statin treatment were randomly assigned to an 85-wk supplementation with margarines enriched with plant sterol esters (2.5 g/d), plant stanol esters (2.5 g/d), or placebo. At baseline and at the end of the intervention period, all participants underwent a cognitive assessment. In addition, subjective cognitive functioning and mood were assessed by means of questionnaires (Cognitive Failure Questionnaire and depression subscale of the Symptom Checklist 90, respectively). Long-term supplementation with plant sterol or stanol esters did not affect cognitive performance (memory, simple information processing speed, complex information processing speed, Letter-Digit Substitution test performance), subjective cognitive functioning, or mood. In conclusion, the present results indicate that long-term use of plant sterols or stanols at recommended intakes of 2.5 g/d does not affect neurocognitive functioning or mood in hypercholesterolemic individuals receiving statin treatment.

Theuwissen E, Plat J, Mensink RP. · Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Mol Nutr Food Res. · Pubmed #18979504 No free full text.

Abstract: We have earlier demonstrated that muesli enriched with oat beta-glucan effectively lowered serum LDL cholesterol. Addition of plant stanols further lowered LDL cholesterol. Besides these hypocholesterolemic effects, beta-glucan and plant stanol esters (PSE) may also affect inflammatory processes. Forty-two mildly hypercholesterolemic subjects randomly consumed for 4 wk (crossover design) control muesli (4.8 g control fiber), beta-glucan muesli (4.8 g oat beta-glucan), or combination muesli (4.8 g oat beta-glucan plus 1.4 g stanol as PSE). Changes in cytokine production (IL-6, IL-8, and TNF-alpha) of LPS-stimulated peripheral blood mononuclear cells (PBMC) and whole blood were evaluated, as well as changes in plasma high-sensitivity (hs)-CRP. Additionally, changes in expression profiles of 84 genes involved in atherosclerosis metabolism were assessed in isolated PBMC. IL-6, IL-8, and TNF-alpha production by PBMC and whole blood after LPS stimulation did not differ between the treatments. Also high-sensitivity C-reactive protein (hs-CRP) levels were similar. beta-Glucan consumption did not change gene expression, while only 3 genes (ADFP, CDH5, CSF2) out of the 84 genes from the atherosclerotic risk panel were differentially expressed (p < 0.05) after consumption of PSE. Consumption of beta-glucan with or without PSE did not influence inflammatory parameters in mildly hypercholesterolemic subjects.

de Jong A, Plat J, Lütjohann D, Mensink RP. · Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Br J Nutr. · Pubmed #18846701 No free full text.

Abstract: Consumption of plant sterol- or stanol-enriched margarines by statin users results in an additional LDL-cholesterol reduction of approximately 10 %, which may be larger than the average decrease of 3-7 % achieved by doubling the statin dose. However, whether this effect persists in the long term is not known. Therefore, we examined in patients already on stable statin treatment the effects of 85 weeks of plant sterol and stanol ester consumption on the serum lipoprotein profile, cholesterol metabolism, and bile acid synthesis. For this, a double-blind randomised trial was designed in which fifty-four patients consumed a control margarine with no added plant sterols or stanols for 5 weeks (run-in period). For the next 85 weeks, seventeen subjects continued with the control margarine and the other two groups with either a plant sterol (n 18) or plant stanol (n 19) (2.5 g/d each) ester-enriched margarine. Blood was sampled at the end of the run-in period and every 20 weeks during the intervention period. Compared with the control group, plant sterol and stanol ester consumption reduced LDL-cholesterol by 0.28 mmol/l (or 8.7 %; P = 0.08) and 0.42 mmol/l (13.1 %; P = 0.006) respectively after 85 weeks. No effects were found on plasma concentrations of oxysterols or 7 alpha-hydroxy-4-cholesten-3-one, a bile acid synthesis marker. We conclude that long-term consumption of both plant sterol and stanol esters effectively lowered LDL-cholesterol concentrations in statin users.

Theuwissen E, Mensink RP. · Maastricht University, Department of Human Biology, 6200 MD Maastricht, The Netherlands. · J Nutr. · Pubmed #17311944 links to  free full text

Abstract: Intake of food products rich in water-soluble fiber beta-glucan and products enriched with plant stanol esters lower serum cholesterol. Combining 2 functional food ingredients into one food product may achieve additional reductions of serum cholesterol. Our objective was to investigate the effects of a simultaneous intake of beta-glucan plus plant stanol esters on lipid metabolism in mildly hypercholesterolemic volunteers. In a randomized, controlled, 3-period crossover study, 40 mildly hypercholesterolemic men and women received muesli in random order twice a day for 4 wk, which provided, in total, 5 g control fiber from wheat (control muesli), 5 g oat beta-glucan (beta-glucan muesli), or 5 g oat beta-glucan plus 1.5 g plant stanols (combination muesli). beta-Glucan muesli decreased serum LDL cholesterol by 5.0% compared with control muesli (P = 0.013). Combination muesli reduced LDL cholesterol by 9.6% compared with control muesli (P < 0.001), and by 4.4% compared with beta-glucan muesli (P = 0.036). Serum HDL cholesterol and triacylglycerol concentrations did not differ after the 3 treatments. Compared with control muesli, beta-glucan muesli increased bile acid synthesis (P = 0.043) and decreased cholesterol absorption (P = 0.011). Addition of plant stanols did not influence bile acid synthesis but decreased cholesterol absorption (P < 0.001) and raised cholesterol synthesis (P = 0.016) compared with control muesli, and the plant stanols decreased cholesterol absorption compared with beta-glucan muesli (P = 0.004). The combination muesli decreased serum concentrations of sitostanol compared with control muesli (P = 0.010). Plasma concentrations of lipid-soluble antioxidants did not differ after the 3 treatments. beta-Glucan muesli effectively lowered serum LDL cholesterol concentrations. The addition of plant stanol esters to beta-glucan-enriched muesli further lowered serum LDL cholesterol, although effects were slightly less than predicted.

Goyens PL, Mensink RP. · Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Eur J Clin Nutr. · Pubmed #16482073 No free full text.

Abstract: OBJECTIVE: To compare the effects of alpha-linolenic acid (ALA, C18:3n-3) to those of eicosapentaenoic acid (EPA, C20:5n-3) plus docosahexaenoic acid (DHA, C22:6n-3) on cardiovascular risk markers in healthy elderly subjects. DESIGN: A randomized double-blind nutritional intervention study. SETTING: Department of Human Biology, Maastricht University, the Netherlands. SUBJECTS: Thirty-seven mildly hypercholesterolemic subjects, 14 men and 23 women aged between 60 and 78 years. INTERVENTIONS: During a run-in period of 3 weeks, subjects consumed an oleic acid-rich diet. The following 6 weeks, 10 subjects remained on the control diet, 13 subjects consumed an ALA-rich diet (6.8 g/day) and 14 subjects an EPA/DHA-rich diet (1.05 g EPA/day + 0.55 g DHA/day). RESULTS: Both n-3 fatty acid diets did not change concentrations of total-cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerol and apoA-1 when compared with the oleic acid-rich diet. However, after the EPA/DHA-rich diet, LDL-cholesterol increased by 0.39 mmol/l (P = 0.0323, 95% CI (0.030, 0.780 mmol/l)) when compared with the ALA-rich diet. Intake of EPA/DHA also increased apoB concentrations by 14 mg/dl (P = 0.0031, 95% CI (4, 23 mg/dl)) and 12 mg/dl (P = 0.005, 95% CI (3, 21 mg/dl)) versus the oleic acid and ALA-rich diet, respectively. Except for an EPA/DHA-induced increase in tissue factor pathway inhibitor (TFPI) of 14.6% (P = 0.0184 versus ALA diet, 95% CI (1.5, 18.3%)), changes in markers of hemostasis and endothelial integrity did not reach statistical significance following consumption of the two n-3 fatty acid diets. CONCLUSIONS: In healthy elderly subjects, ALA might affect concentrations of LDL-cholesterol and apoB more favorably than EPA/DHA, whereas EPA/DHA seems to affect TFPI more beneficially.

de Jong A, Plat J, Mensink RP. · Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Eur J Clin Nutr. · Pubmed #16482072 No free full text.

Abstract: OBJECTIVE: To assess the effects of plant sterol or stanol ester consumption on their incorporation into erythrocytes and their effects on osmotic fragility of red blood cells. DESIGN: Double-blind, randomized, placebo-controlled intervention trial. SUBJECTS AND INTERVENTION: Forty-one subjects on stable statin treatment - who already have increased serum plant sterol and stanol concentrations - first received for 4 weeks a control margarine. For the next 16 weeks, subjects were randomly assigned to one of three possible interventions. Eleven subjects continued with control margarine, 15 subjects with plant sterol ester enriched and 15 subjects with plant stanol ester-enriched margarine. Daily plant sterol or stanol intake was 2.5 g. Erythrocyte haemolysis was measured spectrophotometrically at five different saline concentrations. RESULTS: Despite significant (P = 0.004) increases of, respectively, 42 and 59% in cholesterol-standardized serum sitosterol and campesterol concentrations in the plant sterol group as compared to the control group, campesterol levels in the red blood cells did not change (P = 0.196). Osmotic fragility did not change significantly (P = 0.757) in the plant sterol and plant stanol groups as compared to the control group. CONCLUSION: We conclude that plant sterol and stanol ester consumption for 16 weeks does not change osmotic fragility of erythrocytes in statin-treated patients. SPONSORSHIP: Netherlands Organisation for Health Research and Development (Program Nutrition: Health, Safety and Sustainability, Grant 014-12-010).

Biörklund M, van Rees A, Mensink RP, Onning G. · Biomedical Nutrition, Center for Chemistry and Chemical Engineering, Lund University, Lund, Sweden. · Eur J Clin Nutr. · Pubmed #16015250 No free full text.

Abstract: OBJECTIVES: To investigate side by side the effects on serum lipoproteins and postprandial glucose and insulin concentrations of beverages enriched with 5 or 10 g of beta-glucans from oats or barley. DESIGN AND SETTING: An 8-week single blind, controlled study with five parallel groups carried out at two centres under identical conditions. SUBJECTS: A total of 100 free-living hypercholesterolaemic subjects were recruited locally and 89 completed the study. INTERVENTIONS: During a 3-week run-in period all subjects consumed a control beverage. For the following 5-week period four groups received a beverage with 5 or 10 g beta-glucans from oats or barley and one group continued with the control beverage. Blood samples in weeks 0, 2, 3, 7 and 8 were analysed for serum lipids, lipoproteins, glucose and insulin. Postprandial concentrations of glucose and insulin were compared between control and the beverage with 5 g of beta-glucans from oats or barley. RESULTS: Compared to control, 5 g of beta-glucans from oats significantly lowered total-cholesterol by 7.4% (P<0.01), and postprandial concentrations of glucose (30 min, P=0.005) and insulin (30 min, P=0.025). The beverage with 10 g of beta-glucans from oats did not affect serum lipids significantly in comparison with control. No statistically significant effects compared to control of the beverages with barley beta-glucans were found. CONCLUSIONS: A daily consumption of 5 g of oat beta-glucans in a beverage improved the lipid and glucose metabolism, while barley beta-glucans did not.

Muurling M, van den Hoek AM, Mensink RP, Pijl H, Romijn JA, Havekes LM, Voshol PJ. · Netherlands Organization for Applied Scientific Research-Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands. · J Lipid Res. · Pubmed #14523051 links to  free full text

Abstract: Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin sensitivity in a less-extreme model, we generated obob mice with mild overexpression of APOC1 (obob/APOC1(+/-)) and performed hyperinsulinemic clamp analysis. Compared with obob littermates, obob/APOC1(+/-) mice showed reduced body weight (-25%) and increased plasma levels of TG (+632%), total cholesterol (+134%), FFA (+65%), glucose (+73%), and insulin (+49%). Hyperinsulinemic clamp analysis revealed severe whole-body and hepatic insulin resistance in obob/APOC1(+/-) mice and, in addition, increased hepatic uptake of FFA and hepatic TG content. Treatment of obob/APOC1(+/-) mice with rosiglitazone strongly improved whole-body insulin sensitivity as well as hepatic insulin sensitivity, despite a further increase of hepatic fatty acid (FA) uptake and a panlobular increase of hepatic TG accumulation. We conclude that overexpression of APOC1 prevents rosiglitazone-induced peripheral FA uptake leading to severe hepatic steatosis. Interestingly, despite rosiglitazone-induced hepatic steatosis, hepatic insulin sensitivity improves dramatically. We hypothesize that the different hepatic fat accumulation and/or decrease in FA intermediates has a major effect on the insulin sensitivity of the liver.

Rump P, Mensink RP, Hornstra G. · Nutrition and Toxicology Research Institute Maastricht (NUTRIM), Department of Human Biology, Maastricht University, Maastricht, The Netherlands. · Nutr Metab Cardiovasc Dis. · Pubmed #12669678 No free full text.

Abstract: BACKGROUND AND AIM: Common variations in genes, such as apolipoprotein E (apo E) and cholesteryl ester transfer protein (CETP), are major determinants of plasma lipid and lipoprotein levels. As both apo E and CETP contribute to the reverse transport of cholesterol to the liver, the effects of variations at the CETP locus may very well interact with the apo E genotype. METHODS AND RESULTS: As part of an ongoing study, the combined effects of the apo E genotype and heterogeneity at the CETP gene locus on plasma lipids and lipoproteins were studied in a birth cohort sample of 257 Dutch prepubescent boys and girls (aged 6.7-8.1 years). The children with an apo E2E3 genotype (carrying the epsilon 2 allele; arg158-->cys) had lower concentrations of low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apo B) than those with an apo E4E3 (carrying the epsilon 4 allele; cys112-->arg) or apo E3E3 genotype (homozygous for the parent epsilon 3 allele). These associations were statistically significant in children who were homozygous (p = 0.004 for LDL; p = 0.002 for apo B) or heterozygous (p < 0.0001 for LDL and apo B) for the absence of the Taq-IB polymorphism at the CETP gene locus (B2 allele), but not in those homozygous for the presence of this variant (B1B1). The highest plasma high-density lipoprotein cholesterol (HDL-C) concentrations were observed in children with the CETP B2B2 genotype. The difference in HDL-C levels between the CETP genotype groups was statistically significant only in E2E3 carriers (p = 0.01). The LDL/HDL ratio was significantly lower in E2E3 carriers, but not when combined with a CETP B1B1 genotype. CONCLUSION: These findings indicate that the apo E genotype and heterogeneity at the CETP gene locus have an additive and interactive influence on plasma lipid and lipoprotein levels in children.