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Retrospective analysis of phytoSERM for management of menopause-associated vasomotor symptoms and cognitive decline: a pilot study on pharmacogenomic effects of mitochondrial haplogroup and APOE genotype on therapeutic efficacy.
Wang, Y, Hernandez, G, Mack, WJ, Schneider, LS, Yin, F, Brinton, RD
Menopause (New York, N.Y.). 2020;(1):57-65
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Abstract
OBJECTIVE PhytoSERM is a selective estrogen receptor beta (ERβ) modulator comprised of three phytoestrogens: genistein, daidzein, and S-equol. The PhytoSERM formulation promotes estrogenic action in the brain while largely inactive or inhibitory in reproductive tissue. A phase Ib/IIa clinical trial (ClinicalTrial.gov ID: NCT01723917) of PhytoSERM demonstrated safety and pharmacokinetics profile of PhytoSERM. While this study was not powered for efficacy analysis, we conducted a pilot, retrospective analysis to identify potential responders to PhytoSERM treatment, and to determine the optimal populations to pursue in a phase II clinical trial of efficacy of the PhytoSERM formulation. METHODS In this retrospective analysis involving 46 participants (n = 16, placebo; n = 18, 50 mg/d PhytoSERM; and n = 12, 100 mg/d PhytoSERM), the therapeutic effect of PhytoSERM was stratified by 2 genetic risk modulators for Alzheimer's disease: mitochondrial haplogroup and APOE genotype. RESULTS Our retrospective responder analysis indicated that participants on 50 mg of daily PhytoSERM (PS50) for 12 weeks significantly reduced hot flash frequency compared with their baseline (mean [95% CI])-1.61, [-2.79, -0.42], P = 0.007). Participants on 50 mg of PhytoSERM also had significantly greater reduction in hot flash frequency at 12 weeks compared with the placebo group (-1.38, -0.17 [median PS50, median placebo], P = 0.04). Fifty milligrams of daily PhytoSERM also preserved cognitive function in certain aspects of verbal learning and executive function. Our analysis further suggests that mitochondrial haplogroup and APOE genotype can modify PhytoSERM response. CONCLUSION Our data support a precision medicine approach for further development of PhytoSERM as a safe and effective alternative to hormone therapy for menopause-associated hot flash and cognitive decline. While definitive determination of PhytoSERM efficacy is limited by the small sample size, these data provide a reasonable rationale to extend analyses to a larger study set powered to address statistical significance.
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No evidence of association between variant rs2075650 in lipid metabolism-related locus APOE/TOMM40 and advanced age-related macular degeneration in Han Chinese population.
Kan, M, Weng, X, Wang, T, Liu, F, Ye, J, Zhang, H, Xu, M, Zhou, D, He, L, Liu, Y
Experimental biology and medicine (Maywood, N.J.). 2015;(2):230-4
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Abstract
Age-related macular degeneration (AMD) is a late-onset, neurodegenerative disease. Genes related to lipid metabolism are important in AMD pathogenesis. Recently, a variant rs2075650 located in lipid metabolism-related locus APOE/TOMM40 was identified to be associated with advanced AMD and early AMD, respectively, in two genome-wide association studies with European ancestry, while no association study between rs2075650 and overall advanced AMD in Chinese population has been conducted before. We evaluated the potential effect of this variant on advanced AMD in a Han Chinese cohort with 204 advanced AMD patients and 1536 healthy controls. The results suggested that rs2075650 was neither associated with advanced AMD in allele level (P = 0.348) nor in genotype level (P = 0.890 under additive model with age and sex adjusted). In conclusion, our study did not confirm the impact of rs2075650 on advanced AMD risk, indicating that rs2075650 is unlikely a superior marker for APOE/TOMM40 susceptible region with advanced AMD in Han Chinese population.
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Postprandial enrichment of triacylglycerol-rich lipoproteins with omega-3 fatty acids: lack of an interaction with apolipoprotein E genotype?
Conway, V, Allard, MJ, Minihane, AM, Jackson, KG, Lovegrove, JA, Plourde, M
Lipids in health and disease. 2014;:148
Abstract
BACKGROUND We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n - 3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n - 3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4-). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60 - 400 (VLDL1), and Sf 20 - 60 (VLDL2) according to APOE genotype. METHODS Postprandial TRL fractions were obtained in 11 E4+ (ϵ3/ϵ4) and 12 E4- (ϵ3/ϵ3) male from the SATgenϵ study following high saturated fat diet + 3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography. RESULTS At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P = 0.046) as well as a trend towards higher relative% of EPA (P = 0.063) in the Sf >400 fraction of E4+. Total n - 3 PUFA in the Sf 60 - 400 and Sf 20 - 60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time × genotype interaction (P = 0.081) for EPA in the Sf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R2 = 0.816). CONCLUSION Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n - 3 PUFA metabolism after receiving a high-dose of DHA. TRIAL REGISTRATION Registered at clinicaltrials.gov/show/NCT01544855.
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Obesity favors apolipoprotein E- and C-III-containing high density lipoprotein subfractions associated with risk of heart disease.
Talayero, B, Wang, L, Furtado, J, Carey, VJ, Bray, GA, Sacks, FM
Journal of lipid research. 2014;(10):2167-77
Abstract
Human HDLs have highly heterogeneous composition. Plasma concentrations of HDL with apoC-III and of apoE in HDL predict higher incidence of coronary heart disease (CHD). The concentrations of HDL-apoA-I containing apoE, apoC-III, or both and their distribution across HDL sizes are unknown. We studied 20 normal weight and 20 obese subjects matched by age, gender, and race. Plasma HDL was separated by sequential immunoaffinity chromatography (anti-apoA-I, anti-apoC-III, anti-apoE), followed by nondenaturing-gel electrophoresis. Mean HDL-cholesterol concentrations in normal weight and obese subjects were 65 and 50 mg/dl (P = 0.009), and total apoA-I concentrations were 119 and 118 mg/dl, respectively. HDL without apoE or apoC-III was the most prevalent HDL type representing 89% of apoA-I concentration in normal weight and 77% in obese (P = 0.01) individuals; HDL with apoE-only was 5% versus 8% (P = 0.1); HDL with apoC-III-only was 4% versus 10% (P = 0.009); and HDL with apoE and apoC-III was 1.5% versus 4.6% (P = 0.004). Concentrations of apoE and apoC-III in HDL were 1.5-2× higher in obese subjects (P ≤ 0.004). HDL with apoE or apoC-III occurred in all sizes among groups. Obese subjects had higher prevalence of HDL containing apoE or apoC-III, subfractions associated with CHD, whereas normal weight subjects had higher prevalence of HDL without apoE or apoC-III, subfractions with protective association against CHD.
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Effect of apolipoprotein E genotype on apolipoprotein B-100 metabolism in normolipidemic and hyperlipidemic subjects.
Ooi, EM, Janus, ED, Grant, SJ, Sinclair, LM, R Barrett, PH
Journal of lipid research. 2010;(8):2413-21
Abstract
The effect of apolipoprotein (apo) E genotype on apoB-100 metabolism was examined in three normolipidemic apoE2/E2, five type III hyperlipidemic apoE2/E2, and five hyperlipidemic apoE3/E2 subjects using simultaneous administration of (131)I-VLDL and (125)I-LDL, and multi-compartmental modeling. Compared with normolipidemic apoE2/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased plasma and VLDL cholesterol, plasma and VLDL triglycerides, and VLDL and intermediate density lipoprotein (IDL) apoB concentrations (P < 0.05). These abnormalities were chiefly a consequence of decreased VLDL and IDL apoB fractional catabolic rate (FCR). Compared with hyperlipidemic E3/E2 subjects, type III hyperlipidemic E2/E2 subjects had increased IDL apoB concentration and decreased conversion of IDL to LDL particles (P < 0.05). In a pooled analysis, VLDL cholesterol was positively associated with VLDL and IDL apoB concentrations and the proportion of VLDL apoB in the slowly turning over VLDL pool, and was negatively associated with VLDL apoB FCR after adjusting for subject group. VLDL triglyceride was positively associated with VLDL apoB concentration and VLDL and IDL apoB production rates after adjusting for subject group. A defective apoE contributes to altered lipoprotein metabolism but is not sufficient to cause overt hyperlipidemia. Additional genetic mutations and environmental factors, including insulin resistance and obesity, may contribute to the development of type III hyperlipidemia.
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APOE genotype affects black-white responses of high-density lipoprotein cholesterol subspecies to aerobic exercise training.
Obisesan, TO, Ferrell, RE, Goldberg, AP, Phares, DA, Ellis, TJ, Hagberg, JM
Metabolism: clinical and experimental. 2008;(12):1669-76
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The objective of the study was to determine whether ethnicity interacts with the APOE genotype to influence conventionally measured high-density lipoprotein cholesterol (HDL-C) subfraction levels and nuclear magnetic resonance-measured (HDL(NMR)-C) particle size at baseline and after training, and the changes with training. After a 6-week dietary stabilization period, men and postmenopausal women 50 to 75 years old underwent baseline testing (NMR lipid, maximum oxygen consumption, body composition, and genotyping assessments). Tests were repeated after completing 24 weeks of endurance exercise training. At baseline, APOE2/3 blacks had significantly larger particle size (P < .001) and higher total HDL(NMR)-C particle concentration (P = .006) than whites. After 6 months of endurance exercise training, APOE2/3 blacks maintained a significantly larger HDL(NMR)-C particle size (P < .001) and particle concentration of the large HDL(NMR)-C than APOE2/3 whites (P < .001). In multivariate analyses of variance adjusted for demographic and environmental confounding factors and for training-induced changes in lean body mass and intraabdominal fat, the model explained approximately 33% of the observed variability in training-induced improvements in HDL(NMR)-C particle size (P = .002), with APOE2/3 blacks having a greater increase in training-induced changes in HDL(NMR)-C particle size. In a separate but similarly adjusted model for conventionally measured HDL(2)-C, the model explained approximately 49% of the observed variability in training-induced changes in HDL(2)-C. Ethnicity interacted with the E2/3 genotype at the APOE gene locus to influence higher baseline and after-training levels, and greater exercise training-induced improvements in the advantageous HDL-C subfractions in blacks than in whites. APOE2/3 blacks may benefit more from aerobic fitness to reduce cardiovascular risk.
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apoE4 allele and the natural history of cardiovascular risk factors.
Scuteri, A, Najjar, SS, Muller, D, Andres, R, Morrell, CH, Zonderman, AB, Lakatta, EG
American journal of physiology. Endocrinology and metabolism. 2005;(2):E322-7
Abstract
The aims of the present study were to compare the longitudinal changes in traditional cardiovascular (CV) risk factors (blood pressure, BMI, total and HDL-cholesterol, triglycerides, and blood glucose) in men with and without the apolipoprotein (apo)E4 allele. Three hundred six men from the Baltimore Longitudinal Study of Aging, ranging in age from 20 to 92 yr, were studied. Repeated measurements of CV risk factors were performed over a median follow-up time of 7 yr (maximum 14.3 yr) for men. Longitudinal changes in these CV risk factors were analyzed by linear mixed-effects models. The prevalence of the apoE4 allele was 25.5%. apoE4 was independently associated with accelerated changes over time in fasting plasma glucose (+9.5% vs. no change in those without apoE4 in the 6th age-decade over 10 yr). No significant effect of apoE4 on longitudinal changes in total or HDL-cholesterol, triglycerides, or blood pressures was observed. In conclusion, apoE4 influences fasting plasma glucose and its changes over time. This could explain, in part, the increased CV risk associated with the apoE4 genotype observed in men.
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Microcrystalline chitosan is ineffective to decrease plasma lipids in both apolipoprotein E epsilon 4 carriers and non-carriers: a long-term placebo-controlled trial in hypercholesterolaemic volunteers.
Lehtimäki, T, Metso, S, Ylitalo, R, Rontu, R, Nikkilä, M, Wuolijoki, E, Ylitalo, P
Basic & clinical pharmacology & toxicology. 2005;(2):98-103
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Chitosan is a deacetylated product of chitin. Microcrystalline form of chitosan has a large adsorption area claimed to decrease gastrointestinal absorption of cholesterol. However, the long-term effect of chitosan on plasma lipids is variable, the averaged influence being negligible or lacking in mildly-to-moderately hypercholesterolaemic (4.8-6.8 mmol/l) subjects. We evaluated whether this variation and inefficacy depend on apolipoprotein E genotype. 130 middle-aged, otherwise healthy men (n=55) and women (n=75) were randomized into two treatment groups for a 7 month trial. During a 1 month run-in period all participants received placebo. Subsequently, one half first took placebo twice daily for 3 months and then 1.2 g chitosan twice daily for 3 months, and the other half vice versa in a cross-over way. Altogether 84 participants completed the study. Plasma lipids and glucose were determined at the end of each phase of the study, and all subjects undergone to the cross-over phases were apolipoprotein E genotyped. Chitosan altered plasma total, low- and high density cholesterol, triglycerides, and blood glucose in neither apolipoprotein E epsilon 4 allele carriers (n=29) nor non-carriers (n=55), compared to placebo. In conclusions, chitosan is ineffective to decrease plasma lipids in apolipoprotein E epsilon 4 carrier and non-carrier phenotypes with mildly-to-moderately increased plasma cholesterol.
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Greater enrichment of triacylglycerol-rich lipoproteins with apolipoproteins E and C-III after meals rich in saturated fatty acids than after meals rich in unsaturated fatty acids.
Jackson, KG, Wolstencroft, EJ, Bateman, PA, Yaqoob, P, Williams, CM
The American journal of clinical nutrition. 2005;(1):25-34
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BACKGROUND Although there is considerable interest in the postprandial events involved in the absorption of dietary fats and the subsequent metabolism of diet-derived triacylglycerol-rich lipoproteins, little is known about the effects of meal fatty acids on the composition of these particles. OBJECTIVE We examined the effect of meal fatty acids on the lipid and apolipoprotein contents of triacylglycerol-rich lipoproteins. DESIGN Ten normolipidemic men received in random order a mixed meal containing 50 g of a mixture of palm oil and cocoa butter [rich in saturated fatty acids (SFAs)], safflower oil [n-6 polyunsaturated fatty acids (PUFAs)], or olive oil [monounsaturated fatty acids (MUFAs)] on 3 occasions. Fasting and postprandial apolipoproteins B-48, B-100, E, C-II, and C-III and lipids (triacylglycerol and cholesterol) were measured in plasma fractions with Svedberg flotation rates (S(f)) >400, S(f) 60-400, and S(f) 20-60. RESULTS Calculation of the composition of the triacylglycerol-rich lipoproteins (expressed per mole of apolipoprotein B) showed notable differences in the lipid and apolipoprotein contents of the SFA-enriched particles in the S(f) > 400 and S(f) 60-400 fractions. After the SFA meal, triacylglycerol-rich lipoproteins in these fractions showed significantly greater amounts of triacylglycerol and of apolipoproteins C-II (S(f) 60-400 fraction only), C-III, and E than were found after the MUFA meal (P < 0.02) and more cholesterol, apolipoprotein C-III (S(f) > 400 fraction only), and apolipoprotein E than after the PUFA meal (P < 0.02). CONCLUSIONS Differences in the composition of S(f) > 400 and S(f) 60-400 triacylglycerol-rich lipoproteins formed after saturated compared with unsaturated fatty acid-rich meals may explain differences in the metabolic handling of dietary fats.
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The effect of dietary fat on LDL size is influenced by apolipoprotein E genotype in healthy subjects.
Moreno, JA, Pérez-Jiménez, F, Marín, C, Gómez, P, Pérez-Martínez, P, Moreno, R, Bellido, C, Fuentes, F, López-Miranda, J
The Journal of nutrition. 2004;(10):2517-22
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LDL particle size is dependent on both genetic factors and environmental factors such as dietary fat composition. The apolipoprotein E (apoE) genotype is a major genetic determinant of LDL size. Thus, the aim of this work was to study whether the apoE genotype interacts with the quantity and quality of dietary fat, modifying LDL size in young healthy subjects. Healthy subjects (n = 84; 66 apoE 3/3, 8 apoE 4/3, 10 apoE 3/2) were subjected to 3 dietary periods, each lasting 4 wk. The first was an SFA-enriched diet (38% fat, 20% SFA), which was followed by a carbohydrate (CHO)-rich diet (30% fat, < 10% SFA, 55% carbohydrate) or a monounsaturated fatty acid (MUFA) olive oil-rich diet (38% fat, 22% MUFA) following a randomized crossover design. At the end of each diet period, LDL particle size and plasma levels of total cholesterol, LDL cholesterol (LDL-C), HDL-C, apoB, apoA-I, and triacylglycerols were determined. LDL particle size was significantly higher (P < 0.04) in subjects with the apoE 4/3 genotype compared with those with apoE 3/3 and apoE 3/2 in the basal state. LDL size was smaller (P < 0.02) after the CHO diet than after the MUFA or SFA diets. After the CHO diet, a significant increase in LDL particle size (P < 0.035) was noted with respect to the MUFA diet in apoE 4/3 subjects, whereas a significant decrease was observed in the apoE 3/3 individuals (P < 0.043). In conclusion, a Mediterranean diet, high in MUFA-fat increases LDL particle size compared with a CHO diet, and this effect is dependent of apoE genotypes.