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Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis.
Scholz, M, Horn, K, Pott, J, Gross, A, Kleber, ME, Delgado, GE, Mishra, PP, Kirsten, H, Gieger, C, Müller-Nurasyid, M, et al
Nature communications. 2022;(1):143
Abstract
Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.
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Effects of phytosterols supplementation on blood pressure: A systematic review and meta-analysis.
Ghaedi, E, Foshati, S, Ziaei, R, Beigrezaei, S, Kord-Varkaneh, H, Ghavami, A, Miraghajani, M
Clinical nutrition (Edinburgh, Scotland). 2020;(9):2702-2710
Abstract
Several reports have indicated a positive effect of phytosterols on blood pressure (BP), nevertheless these findings have been controversial. Therefore, a systematic review and meta-analysis of randomized controlled trials (RCTs) was aimed to investigate the effects of phytosterol supplementation on BP. An online search was carried out in PubMed, Scopus, ISI Web of Science, Cochrane library and Google Scholar up to May 2019. Weighted Mean difference (WMD) with 95% confidence intervals (CIs) were calculated using a fixed-effects model. The present meta-analysis of 19 RCTs showed that supplementation with phytosterols can decrease both systolic BP (WMD: -1.55 mmHg, 95% CI: -2.67 to -0.42, p = 0.007) and diastolic BP (WMD: -0.84 mmHg, 95% CI: -1.60 to -0.08, p = 0.03). Dose-response analysis revealed that phytosterol intake change SBP significantly based on treatment dose in nonlinear fashion. Subgroup analysis based on duration showed a significant effect of phytosterol on SBP and DBP in subsets of <12 weeks. In addition, a significant effect of phytosterol was observed in dosage of ≥2000 mg for SBP and <2000 mg for DBP. Based on current findings supplementation with phytosterol may be a beneficial adjuvant therapy in hypertensive patients as well as a complementary preventive option in prehypertensive and normotensive individuals. However, this issue is still open and requires further investigation in future studies.
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Diet and Cardiovascular Disease Risk Among Individuals with Familial Hypercholesterolemia: Systematic Review and Meta-Analysis.
Barkas, F, Nomikos, T, Liberopoulos, E, Panagiotakos, D
Nutrients. 2020;(8)
Abstract
BACKGROUND Although a cholesterol-lowering diet and the addition of plant sterols and stanols are suggested for the lipid management of children and adults with familial hypercholesterolemia, there is limited evidence evaluating such interventions in this population. OBJECTIVES To investigate the impact of cholesterol-lowering diet and other dietary interventions on the incidence or mortality of cardiovascular disease and lipid profile of patients with familial hypercholesterolemia. SEARCH METHODS Relevant trials were identified by searching US National Library of Medicine National Institutes of Health Metabolism Trials Register and clinicaltrials.gov.gr using the following terms: diet, dietary, plant sterols, stanols, omega-3 fatty acids, fiber and familial hypercholesterolemia. SELECTION CRITERIA Randomized controlled trials evaluating the effect of cholesterol-lowering diet or other dietary interventions in children and adults with familial hypercholesterolemia were included. DATA COLLECTION AND ANALYSIS Two authors independently assessed the eligibility of the included trials and their bias risk and extracted the data which was independently verified by other colleagues. RESULTS A total of 17 trials were finally included, with a total of 376 participants across 8 comparison groups. The included trials had either a low or unclear bias risk for most of the assessed risk parameters. Cardiovascular incidence or mortality were not evaluated in any of the included trials. Among the planned comparisons regarding patients' lipidemic profile, a significant difference was noticed for the following comparisons and outcomes: omega-3 fatty acids reduced triglycerides (mean difference (MD): -0.27 mmol/L, 95% confidence interval (CI): -0.47 to -0.07, p < 0.01) when compared with placebo. A non-significant trend towards a reduction in subjects' total cholesterol (MD: -0.34, 95% CI: -0.68 to 0, mmol/L, p = 0.05) and low-density lipoprotein cholesterol (MD: -0.31, 95% CI: -0.61 to 0, mmol/L, p = 0.05) was noticed. In comparison with cholesterol-lowering diet, the additional consumption of plant stanols decreased total cholesterol (MD: -0.62 mmol/L, 95% CI: -1.13 to -0.11, p = 0.02) and low-density lipoprotein cholesterol (MD: -0.58 mmol/L, 95% CI: -1.08 to -0.09, p = 0.02). The same was by plant sterols (MD: -0.46 mmol/L, 95% CI: -0.76 to -0.17, p < 0.01 for cholesterol and MD: -0.45 mmol/L, 95% CI: -0.74 to -0.16, p < 0.01 for low-density lipoprotein cholesterol). No heterogeneity was noticed among the studies included in these analyses. CONCLUSIONS Available trials confirm that the addition of plant sterols or stanols has a cholesterol-lowering effect on such individuals. On the other hand, supplementation with omega-3 fatty acids effectively reduces triglycerides and might have a role in lowering the cholesterol of patients with familial hypercholesterolemia. Additional studies are needed to investigate the efficacy of cholesterol-lowering diet or the addition of soya protein and dietary fibers to a cholesterol-lowering diet in patients with familial hypercholesterolemia.
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Factors influencing the cardiometabolic response to (poly)phenols and phytosterols: a review of the COST Action POSITIVe activities.
Gibney, ER, Milenkovic, D, Combet, E, Ruskovska, T, Greyling, A, González-Sarrías, A, de Roos, B, Tomás-Barberán, F, Morand, C, Rodriguez-Mateos, A
European journal of nutrition. 2019;(Suppl 2):37-47
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Abstract
PURPOSE Evidence exists regarding the beneficial effects of diets rich in plant-based foods regarding the prevention of cardiometabolic diseases. These plant-based foods are an exclusive and abundant source of a variety of biologically active phytochemicals, including polyphenols, carotenoids, glucosinolates and phytosterols, with known health-promoting effects through a wide range of biological activities, such as improvements in endothelial function, platelet function, blood pressure, blood lipid profile and insulin sensitivity. We know that an individual's physical/genetic makeup may influence their response to a dietary intervention, and thereby may influence the benefit/risk associated with consumption of a particular dietary constituent. This inter-individual variation in responsiveness has also been described for dietary plant bioactives but has not been explored in depth. To address this issue, the European scientific experts involved in the COST Action POSITIVe systematically analyzed data from published studies to assess the inter-individual variation in selected clinical biomarkers associated with cardiometabolic risk, in response to the consumption of plant-based bioactives (poly)phenols and phytosterols. The present review summarizes the main findings resulting from the meta-analyses already completed. RESULTS Meta-analyses of randomized controlled trials conducted within POSITIVe suggest that age, sex, ethnicity, pathophysiological status and medication may be responsible for the heterogeneity in the biological responsiveness to (poly)phenol and phytosterol consumption and could lead to inconclusive results in some clinical trials aiming to demonstrate the health effects of specific dietary bioactive compounds. However, the contribution of these factors is not yet demonstrated consistently across all polyphenolic groups and cardiometabolic outcomes, partly due to the heterogeneity in trial designs, low granularity of data reporting, variety of food vectors and target populations, suggesting the need to implement more stringent reporting practices in the future studies. Studies investigating the effects of genetic background or gut microbiome on variability were limited and should be considered in future studies. CONCLUSION Understanding why some bioactive plant compounds work effectively in some individuals but not, or less, in others is crucial for a full consideration of these compounds in future strategies of personalized nutrition for a better prevention of cardiometabolic disease. However, there is also still a need for the development of a substantial evidence-base to develop health strategies, food products or lifestyle solutions that embrace this variability.
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Possible anti-obesity effects of phytosterols and phytostanols supplementation in humans: A systematic review and dose-response meta-analysis of randomized controlled trials.
Ghaedi, E, Varkaneh, HK, Rahmani, J, Mousavi, SM, Mohammadi, H, Fatahi, S, Pantovic, A, Darooghegi Mofrad, M, Zhang, Y
Phytotherapy research : PTR. 2019;(5):1246-1257
Abstract
Present meta-analysis investigates the effects of phytosterols and phytostanol (PS) supplementation on anthropometric indices, using data from randomized controlled trials. We performed a systematic search in the databases: PubMed, Scopus, Cochran, and Web of Science. Weighted mean difference (WMD) with 95% confidence intervals (CIs) were presented. Overall, 79 randomized controlled trials investigated the effects of PS on anthropometric indices. Meta-analysis results did not reveal any significant effect of PS supplementation on weight (66 trials-WMD: -0.083 kg; CI [-0.233, 0.066]; I2 = 42.5%), percentage fat mass (6 trials-WMD: -0.090%; CI [-0.789, 0.610]; I2 = 0.0%), and waist circumference (WC; 5 trials-WMD: -0.039 cm; CI [-0.452, 0.374]; I2 = 0.0%). However, body mass index (BMI) significantly decreased after PS supplementation (39 trials-WMD: -0.063 kg/m2, p = 0.024, I2 = 25.1%). Subgroup analyses showed that PS supplementation in subjects with baseline BMI ≥25 and hyperlipidemic significantly decreased body weight and BMI. The overall results showed that although PS supplementation did not affect anthropometric indices (except BMI), baseline status regarding BMI and hyperlipidemia and also dose and duration could be contributing factors for favorable effects.
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The effects of cinnamon supplementation on blood lipid concentrations: A systematic review and meta-analysis.
Maierean, SM, Serban, MC, Sahebkar, A, Ursoniu, S, Serban, A, Penson, P, Banach, M, ,
Journal of clinical lipidology. 2017;(6):1393-1406
Abstract
BACKGROUND Cinnamon is a rich botanical source of polyphenols, whose positive effects on blood lipid concentrations have been hypothesized, but have not been conclusively studied. OBJECTIVE The objective of the study was to systematically review and evaluate the effect of administration of cinnamon on blood lipid concentrations. METHODS We assessed 13 randomized controlled trials with 750 participants investigating the effect of cinnamon supplementation on blood lipid concentrations. A meta-analysis was performed using random effect models, with weighted mean differences (WMDs; with 95% confidence interval [CI]) for endpoints calculated using a random effects model. RESULTS No statistically significant effect of cinnamon was observed on blood low-density lipoprotein cholesterol (LDL-C; WMD: -0.16 mmol/L [-6.19 mg/dL], 95% CI: -0.35, 0.03 [-13.53, 1.16], P = .10) and high-density lipoprotein cholesterol (HDL-C; WMD: 0.05 mmol/L [1.92 mg/dL], 95% CI: -0.03, 0.12 [-0.03, 4.64], P = .21) concentrations. However, a statistically significant reduction in blood triglycerides (WMD: -0.27 mmol/L [-23.91 mg/dL], 95% CI: -0.39, -0.14 [-34.54, -12.40], P < .01) and total cholesterol concentrations (WMD: -0.36 mmol/L [-13.92 mg/dL], 95% CI: -0.63, -0.09 [-24.36, -3.48], P < .01) was observed. HDL-C was significantly elevated after the omission of 1 study (WMD: 0.04 mmol/L [1.54 mg/dL], 95% CI: 0.03, 0.06 [1.16, 2.32], P < .01) during our sensitivity analysis. A meta-regression analysis was conducted, and no significant association was found between changes in lipid parameters and cinnamon dose. In contrast, changes in blood levels of total cholesterol (slope: 0.09; 95% CI: 0.02, 0.16; P < .01), LDL-C (slope: 0.05; 95% CI: 0.001, 0.10; P = .05) and triglycerides (slope: 0.06; 95% CI: 0.04, 0.09; P < .01) were significantly and positively associated with the duration of supplementation. No statistically significant association was found between blood HDL-C changes and duration of supplementation. CONCLUSION Cinnamon supplementation significantly reduced blood triglycerides and total cholesterol concentrations without any significant effect on LDL-C and HDL-C.
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Plasma fat-soluble vitamin and carotenoid concentrations after plant sterol and plant stanol consumption: a meta-analysis of randomized controlled trials.
Baumgartner, S, Ras, RT, Trautwein, EA, Mensink, RP, Plat, J
European journal of nutrition. 2017;(3):909-923
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Abstract
PURPOSE Plant sterols and stanols interfere with intestinal cholesterol absorption, and it has been questioned whether absorption and plasma concentrations of fat-soluble vitamins and carotenoids are also affected. We conducted a meta-analysis to assess the effects of plant sterol and stanol consumption on plasma fat-soluble vitamin and carotenoid concentrations. METHODS Forty-one randomized controlled trials involving 3306 subjects were included. Weighted absolute and relative changes of non-standardized and total cholesterol (TC)-standardized values (expressed as summary estimates and 95 % CIs) were calculated for three fat-soluble vitamins (α- and γ-tocopherol, retinol and vitamin D) and six carotenoids (β-carotene, α-carotene, lycopene, lutein, zeaxanthin and β-cryptoxanthin) using a random effects model. Heterogeneity was assessed using predefined subject and treatment characteristics. RESULTS Average plant sterol or stanol intake was 2.5 g/d. Relative non-standardized and TC-standardized concentrations of β-carotene decreased by, respectively, -16.3 % (95 % CI -18.3; -14.3) and -10.1 % (-12.3; -8.0), α-carotene by -14.4 % (-17.5; 11.3) and -7.8 % (-11.3; -4.3), and lycopene by -12.3 % (-14.6; -10.1) and -6.3 % (-8.6; -4.0). Lutein concentrations decreased by -7.4 % (-10.1; -4.8), while TC-standardized concentrations were not changed. For zeaxanthin, these values were -12.9 % (-18.9; -6.8) and -7.7 % (-13.8; -1.7) and for β-cryptoxanthin -10.6 % (-14.3; -6.9) and -4.8 % (-8.7; -0.9). Non-standardized α-tocopherol concentrations decreased by -7.1 % (-8.0; -6.2) and γ-tocopherol by -6.9 % (-9.8; -3.9), while TC-standardized tocopherol concentrations were not changed. Non-standardized retinol and vitamin D concentrations were not affected. Results were not affected by baseline concentrations, dose, duration and type of plant sterols/stanols, except for significant effects of duration (≤4 vs. >4 weeks) on TC-standardized lutein concentrations (1.0 vs. -5.6 %) and type of plant sterol/stanol on TC-standardized β-carotene concentrations (-8.9 vs. -14.2 %). CONCLUSIONS Plant sterol and stanol intake lowers TC-standardized hydrocarbon carotenoid concentrations, differently affects TC-standardized oxygenated carotenoid concentrations, but does not affect TC-standardized tocopherol concentrations or absolute retinol and vitamin D concentrations. Observed concentrations remained within normal ranges.
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Effects of phytosterols on markers of inflammation: A systematic review and meta-analysis.
Rocha, VZ, Ras, RT, Gagliardi, AC, Mangili, LC, Trautwein, EA, Santos, RD
Atherosclerosis. 2016;:76-83
Abstract
BACKGROUND AND AIMS Regular intake of phytosterols (PS) is proven to dose-dependently lower LDL-cholesterol (LDL-C). Whether PS consumption can also impact low-grade inflammation is unclear. Considering the low feasibility of outcomes studies involving PS consumption, investigation of surrogate markers of atherosclerosis represents a valuable approach. This study assessed the anti-inflammatory effect of PS consumption, according to inflammatory biomarkers, mainly C-reactive protein (CRP). METHODS AND RESULTS A systematic search of Medline, Cab Abstracts, and Food Science & Technology Abstracts was conducted through January 2015. Our study selection included randomized controlled trials (RCT), involving intake of PS-enriched foods as active treatment, and measurement of plasma inflammatory biomarkers. Random-effects meta-analyses were performed using average baseline and end-of-intervention concentrations and control-adjusted absolute changes in CRP and blood lipids. There were 20 eligible RCTs including a total of 1308 subjects. The absolute change of plasma CRP levels with PS consumption was -0.10 mg/L (95%CI -0.26; 0.05), a non-significant change, and heterogeneity had borderline significance (I(2) = 29.1; p-value = 0.073). The absolute reduction of LDL-C was -14.3 mg/dL (95%CI -17.3; -11.3). Meta-regression analyses showed that both the dose and duration of PS intake significantly influenced the absolute changes in plasma CRP (β = -0.35, p = 0.0255 and β = -0.03, p = 0.0209, respectively). CONCLUSIONS In this meta-analysis, regular intake of PS-enriched foods did not significantly change CRP, whilst LDL-C concentrations were significantly reduced. Further studies with higher PS doses may provide more definite conclusions on a potential anti-inflammatory effect of PS intake.
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Combined effect of plant sterols and dietary fiber for the treatment of hypercholesterolemia.
Castellanos-Jankiewicz, A, Del Bosque-Plata, L, Tejero, ME
Plant foods for human nutrition (Dordrecht, Netherlands). 2014;(2):93-100
Abstract
Hypercholesterolemia is a major contributor for disease burden in both the developed and developing world and an important risk factor for cardiovascular diseases (CVD). Phytosterols (PhS) and dietary fiber (DF) act as low density lipoprotein cholesterol (LDL-C) lowering agents, offering an effective treatment against high blood cholesterol and CVD. The aim of this review was to consider clinical evidence that analyzed the combination of PhS and DF in a cereal carrier for lowering LDL-C. Electronic database searches were carried out to identify peer-reviewed journal articles, from which five intervention studies that combined both components in a cereal carrier were identified and included in the present review. LDL-C lowering effects varied widely among studies, due to large heterogeneity in study design, subject baseline characteristics, length of the interventions, PhS and DF dosage and type of DF used. In relation to a time of intake, three studies suggested a frequency or distribution of the product's consumption during the day, while two studies did not consider this factor. Overall, the selected studies found significant differences on LDL-C concentrations, although not all of them reached the expected outcomes. Future research should be conducted to explore the effect that different types of DF exert on LDL-C when combined with PhS, and to analyze the effect of the product's time of intake in order to suggest an optimal moment of the day for its consumption.
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Plant sterols and cardiovascular disease: a systematic review and meta-analysis.
Genser, B, Silbernagel, G, De Backer, G, Bruckert, E, Carmena, R, Chapman, MJ, Deanfield, J, Descamps, OS, Rietzschel, ER, Dias, KC, et al
European heart journal. 2012;(4):444-51
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Abstract
The impact of increased serum concentrations of plant sterols on cardiovascular risk is unclear. We conducted a systematic review and meta-analysis aimed to investigate whether there is an association between serum concentrations of two common plant sterols (sitosterol, campesterol) and cardiovascular disease (CVD). We systematically searched the databases MEDLINE, EMBASE, and COCHRANE for studies published between January 1950 and April 2010 that reported either risk ratios (RR) of CVD in relation to serum sterol concentrations (either absolute or expressed as ratios relative to total cholesterol) or serum sterol concentrations in CVD cases and controls separately. We conducted two meta-analyses, one based on RR of CVD contrasting the upper vs. the lower third of the sterol distribution, and another based on standardized mean differences between CVD cases and controls. Summary estimates were derived by fixed and random effects meta-analysis techniques. We identified 17 studies using different designs (four case-control, five nested case-control, three cohort, five cross-sectional) involving 11 182 participants. Eight studies reported RR of CVD and 15 studies reported serum concentrations in CVD cases and controls. Funnel plots showed evidence for publication bias indicating small unpublished studies with non-significant findings. Neither of our meta-analyses suggested any relationship between serum concentrations of sitosterol and campesterol (both absolute concentrations and ratios to cholesterol) and risk of CVD. Our systematic review and meta-analysis did not reveal any evidence of an association between serum concentrations of plant sterols and risk of CVD.