Nutritional aspects of metabolic inflammation in relation to health-insights from transcriptomic biomarkers in PBMC of fatty acids and polyphenols
Afman, L.A. ; Milenkovic, D. ; Roche, H. - \ 2014
Molecular Nutrition & Food Research 58 (2014)8. - ISSN 1613-4125 - p. 1708 - 1720.
blood mononuclear-cells - gene-expression profiles - fish-oil supplementation - improves insulin sensitivity - randomized controlled-trial - coronary-artery-disease - adipose-tissue - postmenopausal women - nlrp3 inflammasome - in-vivo
Recent research has highlighted potential important interaction between metabolism and inflammation, within the context of metabolic health and nutrition, with a view to preventing diet-related disease. In addition to this, there is a paucity of evidence in relation to accurate biomarkers that are capable of reflecting this important biological interplay or relationship between metabolism and inflammation, particularly in relation to diet and health. Therefore the objective of this review is to highlight the potential role of transcriptomic approaches as a tool to capture the mechanistic basis of metabolic inflammation. Within this context, this review has focused on the potential of peripheral blood mononuclear cells transcriptomic biomarkers, because they are an accessible tissue that may reflect metabolism and subacute chronic inflammation. Also these pathways are often dysregulated in the common diet-related diseases obesity, type 2 diabetes, and cardiovascular disease, thus may be used as markers of systemic health. The review focuses on fatty acids and polyphenols, two classes of nutrients/nonnutrient food components that modulate metabolism/inflammation, which we have used as an example of a proof-of-concept with a view to understanding the extent to which transcriptomic biomarkers are related to nutritional status and/or sensitive to dietary interventions. We show that both nutritional components modulate inflammatory markers at the transcriptomic level with the capability of profiling pro- and anti-inflammatory mechanisms in a bidirectional fashion; to this end transcriptomic biomarkers may have potential within the context of metabolic inflammation. This transcriptomic biomarker approach may be a sensitive indicator of nutritional status and metabolic health.
Distinct associations of complement C3a and its precursor C3 with atherosclerosis and cardiovascular disease
Hertle, E. ; Greevenbroek, M.M.J. van; Arts, I.C.W. ; Kallen, C.J.H. van der; Geijselaers, S.L.C. ; Feskens, E.J.M. ; Jansen, E.H. ; Schalkwijk, C.G. ; Stehouwer, C.D.A. - \ 2014
Thrombosis and Haemostasis 111 (2014)6. - ISSN 0340-6245 - p. 1102 - 1111.
coronary-artery-disease - acylation-stimulating protein - intima-media thickness - low-grade inflammation - metabolic syndrome - anaphylatoxins c3a - insulin-resistance - diabetes-mellitus - endothelial-cells - cigarette-smoke
Complement C3 is a novel risk factor for cardiovascular disease (CVD), but the underlying mechanism is currently unknown. We determined the associations of the anaphylatoxin C3a, the activation product of C3, and of C3 itself with estimates of atherosclerosis and CVD. We studied associations of C3a and C3 with carotid intima-media thickness (cIMT), ankle-arm blood pressure index (AAIx) and CVD in cross-sectional analyses among 545 participants of the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study (61% men, 59.4 ± 6.9 years) and examined effect modification by smoking. We conducted linear and logistic regression analyses with adjustments for age, sex, glucose metabolism status, lipids, adiposity, renal function, blood pressure, pack-years smoked, physical activity, use of medication and investigated mediation by inflammation. C3a was independently associated with cIMT (ß=0.032 mm, [95% confidence interval: 0.004; 0.060]) and AAIx (ß=-0.022, [-0.043; –0.001]), but C3 was not. Effect modification by smoking was only observed for CVD (Psmoking*C3a=0.008, Psmoking*C3=0.018), therefore these associations were stratified for smoking behaviour. Both C3a (odds ratio [OR] =2.96, [1.15; 7.62]) and C3 (OR =1.98, [1.21; 3.22]) were independently associated with CVD in heavy smokers. The association of C3 with CVD was independent of C3a. Low-grade inflammation did partially explain the association of C3a with AAIx, but not the other observed associations. This suggests that C3a and C3 have distinct roles in pathways leading to CVD. C3a may promote atherosclerosis and additionally advance CVD in heavy smokers. Conversely, C3 may be associated with CVD in heavy smokers via pathways other than atherosclerosis.
Interactions of blacktea polyphenols with human gut microbiota: implications for gut and cardiovascular health
Duynhoven, J.P.M. van; Vaughan, E.E. ; Dorsten, F. van; Gomez-Roldan, V. ; Vos, R. de; Vervoort, J.J.M. ; Hooft, J.J.J. van der; Roger, L. ; Draijer, R. ; Jacobs, D.M. - \ 2013
American Journal of Clinical Nutrition 98 (2013)6. - ISSN 0002-9165 - p. 1631S - 1641S.
red wine/grape juice - density-lipoprotein oxidation - coronary-artery-disease - vein endothelial-cells - human fecal microbiota - in-vitro - phenolic-acids - green tea - ellagitannin metabolites - dietary polyphenols
Epidemiologic studies have convincingly associated consumption of black tea with reduced cardiovascular risk. Research on the bioactive molecules has traditionally been focused on polyphenols, such as catechins. Black tea polyphenols (BTPs), however, mainly consist of high-molecular-weight species that predominantly persist in the colon. There, they can undergo a wide range of bioconversions by the resident colonic microbiota but can in turn also modulate gut microbial diversity. The impact of BTPs on colon microbial composition can now be assessed by microbiomics technologies. Novel metabolomics platforms coupled to de novo identification are currently available to cover the large diversity of BTP bioconversions by the gut microbiota. Nutrikinetic modeling has been proven to be critical for defining nutritional phenotypes related to gut microbial bioconversion capacity. The bioactivity of circulating metabolites has been studied only to a certain extent. Bioassays dedicated to specific aspects of gut and cardiovascular health have been used, although often at physiologically irrelevant concentrations and with limited coverage of relevant metabolite classes and their conjugated forms. Evidence for cardiovascular benefits of BTPs points toward antiinflammatory and blood pressure–lowering properties and improvement in platelet and endothelial function for specific microbial bioconversion products. Clearly, more work is needed to fill in existing knowledge gaps and to assess the in vitro and in vivo bioactivity of known and newly identified BTP metabolites. It is also of interest to assess how phenotypic variation in gut microbial BTP bioconversion capacity relates to gut and cardiovascular health predisposition.
Gene–environment and gene–gene interactions of specific MTHFR, MTR and CBS gene variants in relation to homocysteine in black South Africans
Nienaber-Rousseau, C. ; Ellis, S.M. ; Moss, S. ; Boonstra, A. ; Towers, G.W. - \ 2013
Gene 530 (2013)1. - ISSN 0378-1119 - p. 113 - 118.
beta-synthase gene - coronary-artery-disease - plasma homocysteine - methylenetetrahydrofolate reductase - methionine synthase - risk-factors - cardiovascular-disease - heart-disease - vascular-disease - high prevalence
The methylenetetrahydrofolate reductase (MTHFR), cystathione-beta-synthase (CBS) and methionine synthase (MTR) genes interact with each other and the environment. These interactions could influence homocysteine (Hcy) and diseases contingent thereon. We determined single nucleotide polymorphisms (SNPs) within these genes, their relationships and interactions with total Hcy concentrations within black South Africans to address the increased prevalence of diseases associated with Hcy. The MTHFR 677 TT and MTR 2756 AA genotypes were associated with higher Hcy concentrations (16.6 and 10.1 mu mol/L; p <0.05) compared to subjects harboring the MTHFR 677 CT/CC and the MTR 2756 AG genotypes (10.5, 9.7 and 9.5 mu mol/L, respectively). The investigated CBS genotypes did not influence Hcy. We demonstrated interactions between the area of residence and the CBS T833C/844ins68 genotypes (p = 0.005) so that when harboring the wildtype allele, rural subjects had significantly higher Hcy than their urban counterparts, but when hosting the variant allele the environment made no difference to Hcy. Between the CBS T833C/844ins68 or G9276A and MTHFR C677T genotypes, there were two-way interactions (p = 0.003 and = 0.004, respectively), with regard to Hcy. Subjects harboring the MTHFR 677 TT genotype in combination with the CBS 833 TT/homozygous 844 non-insert or the MTHFR 677 IF genotype in combination with the CBS 9276 GA/GG displayed higher Hcy concentrations. Therefore, some of the investigated genotypes affected Hcy; residential area changed the way in which the CBS T833C/844ins68 SNPs influenced Hcy concentrations highlighting the importance of environmental factors; and gene-gene interactions allude to epistalic effects. (C) 2013 Elsevier B.V. All rights reserved.
A consideration of biomarkers to be used for evaluation of inflammation in human nutritional studies
Calder, P.C. ; Ahluwalia, N. ; Albers, R. ; Bosco, N. ; Bourdet-Sicard, R. ; Haller, D. ; Holgate, S.T. ; Jönsson, L.S. ; Latulippe, M.E. ; Marcos, A. ; Moreines, J. ; M'Rini, C. ; Müller, M.R. ; Pawelec, G. ; Neerven, R.J.J. van; Watzl, B. ; Zhao, J. - \ 2013
The British journal of nutrition 109 (2013)S1. - ISSN 0007-1145 - p. S1 - S34.
c-reactive protein - necrosis-factor-alpha - low-grade inflammation - coronary-artery-disease - blood mononuclear-cells - ischemic-heart-disease - plasma il-6 levels - obstructive pulmonary-disease - endoplasmic-reticulum stress - systemic-lupus-erythematosus
To monitor inflammation in a meaningful way, the markers used must be valid: they must reflect the inflammatory process under study and they must be predictive of future health status. In 2009, the Nutrition and Immunity Task Force of the International Life Sciences Institute, European Branch, organized an expert group to attempt to identify robust and predictive markers, or patterns or clusters of markers, which can be used to assess inflammation in human nutrition studies in the general population. Inflammation is a normal process and there are a number of cells and mediators involved. These markers are involved in, or are produced as a result of, the inflammatory process irrespective of its trigger and its location and are common to all inflammatory situations. Currently, there is no consensus as to which markers of inflammation best represent low-grade inflammation or differentiate between acute and chronic inflammation or between the various phases of inflammatory responses. There are a number of modifying factors that affect the concentration of an inflammatory marker at a given time, including age, diet and body fatness, among others. Measuring the concentration of inflammatory markers in the bloodstream under basal conditions is probably less informative compared with data related to the concentration change in response to a challenge. A number of inflammatory challenges have been described. However, many of these challenges are poorly standardised. Patterns and clusters may be important as robust biomarkers of inflammation. Therefore, it is likely that a combination of multiple inflammatory markers and integrated readouts based upon kinetic analysis following defined challenges will be the most informative biomarker of inflammation.
EURRECA—Estimating Zinc Requirements for Deriving Dietary Reference Values
Lowe, N.M.M. ; Dykes, F.C. ; Skinner, A.L. ; Patel, S. ; Warthon-Medina, M. ; Decsi, T. ; Fekete, K. ; Souverein, O.W. ; Dullemeijer, C. ; Cavelaars, A.J.E.M. ; Serra-Majem, L. ; Nissensohn, M. ; Bel, S. ; Moreno, L.A. ; Hermoso, M. ; Vollhardt, C. ; Berti, C. ; Cetin, I. ; Gurinovic, M. ; Novakovic, R.N. ; Harvey, L.J. ; Collings, R. ; Hall-Moran, V. - \ 2013
Critical Reviews in Food Science and Nutrition 53 (2013)10. - ISSN 1040-8398 - p. 1110 - 1123.
current micronutrient recommendations - coronary-artery-disease - lung-cancer - serum zinc - genetic-polymorphism - stable-isotope - old patients - absorption - phytate - copper
Zinc was selected as a priority micronutrient for EURRECA, because there is significant heterogeneity in the Dietary Reference Values (DRVs) across Europe. In addition, the prevalence of inadequate zinc intakes was thought to be high among all population groups worldwide, and the public health concern is considerable. In accordance with the EURRECA consortium principles and protocols, a series of literature reviews were undertaken in order to develop best practice guidelines for assessing dietary zinc intake and zinc status. These were incorporated into subsequent literature search strategies and protocols for studies investigating the relationships between zinc intake, status and health, as well as studies relating to the factorial approach (including bioavailability) for setting dietary recommendations. EMBASE (Ovid), Cochrane Library CENTRAL, and MEDLINE (Ovid) databases were searched for studies published up to February 2010 and collated into a series of Endnote databases that are available for the use of future DRV panels. Meta-analyses of data extracted from these publications were performed where possible in order to address specific questions relating to factors affecting dietary recommendations. This review has highlighted the need for more high quality studies to address gaps in current knowledge, in particular the continued search for a reliable biomarker of zinc status and the influence of genetic polymorphisms on individual dietary requirements. In addition, there is a need to further develop models of the effect of dietary inhibitors of zinc absorption and their impact on population dietary zinc requirements.
Multiple inflammatory biomarker detection in a prospective cohort study: a cross-validation between well-established single-biomarker techniques and electrochemiluminescense-based multi-array platform
Bussel, B.C.T. van; Ferreira, I. ; Waarenburg, M.P.H. ; Greevenbroek, M.M.J. van; Kallen, C.J.H. van der; Henry, R.M.A. ; Feskens, E.J.M. ; Stehouwer, C.D.A. ; Schalkwijk, C.G. - \ 2013
PLoS ONE 8 (2013)3. - ISSN 1932-6203 - 11 p.
coronary-artery-disease - public-health practice - low-grade inflammation - cardiovascular-disease - deming regression - atherosclerosis - risk - cytokines - markers - association
Background - In terms of time, effort and quality, multiplex technology is an attractive alternative for well-established single-biomarker measurements in clinical studies. However, limited data comparing these methods are available. Methods - We measured, in a large ongoing cohort study (n = 574), by means of both a 4-plex multi-array biomarker assay developed by MesoScaleDiscovery (MSD) and single-biomarker techniques (ELISA or immunoturbidimetric assay), the following biomarkers of low-grade inflammation: C-reactive protein (CRP), serum amyloid A (SAA), soluble intercellular adhesion molecule 1 (sICAM-1) and soluble vascular cell adhesion molecule 1 (sVCAM-1). These measures were realigned by weighted Deming regression and compared across a wide spectrum of subjects’ cardiovascular risk factors by ANOVA. Results - Despite that both methods ranked individuals’ levels of biomarkers very similarly (Pearson’s r all=0.755) absolute concentrations of all biomarkers differed significantly between methods. Equations retrieved by the Deming regression enabled proper realignment of the data to overcome these differences, such that intra-class correlation coefficients were then 0.996 (CRP), 0.711 (SAA), 0.895 (sICAM-1) and 0.858 (sVCAM-1). Additionally, individual biomarkers differed across categories of glucose metabolism, weight, metabolic syndrome and smoking status to a similar extent by either method. Conclusions - Multiple low-grade inflammatory biomarker data obtained by the 4-plex multi-array platform of MSD or by well-established single-biomarker methods are comparable after proper realignment of differences in absolute concentrations, and are equally associated with cardiovascular risk factors, regardless of such differences. Given its greater efficiency, the MSD platform is a potential tool for the quantification of multiple biomarkers of low-grade inflammation in large ongoing and future clinical studies.
Flow-mediated dilation and cardiovascular risk prediction: a systematic review with meta-analysis
Ras, R.T. ; Streppel, M.T. ; Draijer, R. ; Zock, P.L. - \ 2013
International Journal of Cardiology 168 (2013)1. - ISSN 0167-5273 - p. 344 - 351.
coronary-artery-disease - chronic heart-failure - endothelial dysfunction - brachial-artery - prognostic role - chest-pain - postmenopausal women - mortality risk - events - vasodilation
Background Flow-mediated dilation (FMD) is an accepted technique to quantify endothelial function and has shown to have prognostic value for future cardiovascular disease (CVD). The predictive strength of FMD in CVD patients compared to populations not diagnosed for CVD warrants further investigation. We systematically reviewed prospective studies that investigated the association between brachial FMD and future cardiovascular events, with particular focus on the role of underlying health status. Methods To obtain eligible studies, several literature databases were systematically searched through March 2011. Pooled overall risk estimates were calculated separately for continuous risk estimates for CVD (per 1% higher FMD) and for categorical risk estimates for CVD (having high vs. low FMD), based on random-effects models. Results A total of 23 studies including 14,753 subjects were eligible for inclusion in the meta-analysis. For studies reporting continuous risk estimates, the pooled overall CVD risk was 0.92 (95%CI: 0.88; 0.95) per 1% higher FMD. The observed association seemed stronger (P-value <0.01) in diseased populations than in asymptomatic populations (0.87 (95%CI: 0.83; 0.92) and 0.96 (95%CI: 0.92; 1.00) per 1% higher FMD, respectively). For studies reporting categorical risk estimates, the pooled overall CVD risk for high vs. low FMD was similar in both types of populations, on average 0.49 (95%CI: 0.39; 0.62). Conclusions Our findings show that brachial FMD is inversely associated with future CVD events, with some indications for a stronger relation in diseased populations. Endothelial dysfunction may be considered relevant for classifying subjects in terms of CVD risk.
Single nucleotide polymorphisms (SNPs) involved in insulin resistance, weight regulation, lipid metabolism and inflammation in relation to metabolic syndrome: an epidemiological study
Povel, C.M. ; Boer, J.M.A. ; Onland-Moret, N. ; Dolle, M.E. ; Feskens, E.J.M. ; Schouw, Y.T. van der - \ 2012
Cardiovascular Diabetology 11 (2012)1. - ISSN 1475-2840
genome-wide association - c-reactive protein - coronary-artery-disease - mendelian randomization - genetic-variation - heart-disease - loci - risk - variants - traits
Background: Mechanisms involved in metabolic syndrome (MetS) development include insulin resistance, weight regulation, inflammation and lipid metabolism. Aim of this study is to investigate the association of single nucleotide polymorphisms (SNPs) involved in these mechanisms with MetS. Methods: In a random sample of the EPIC-NL study (n = 1886), 38 SNPs associated with waist circumference, insulin resistance, triglycerides, HDL cholesterol and inflammation in genome wide association studies (GWAS) were selected from the 50K IBC array and one additional SNP was measured with KASPar chemistry. The five groups of SNPs, each belonging to one of the metabolic endpoints mentioned above, were associated with MetS and MetS-score using Goeman's global test. For groups of SNPs significantly associated with the presence of MetS or MetS-score, further analyses were conducted. Results: The group of waist circumference SNPs was associated with waist circumference (P=0.03) and presence of MetS (P=0.03). Furthermore, the group of SNPs related to insulin resistance was associated with MetS score (P
A lipidomic analysis approach to evaluate the response to cholesterol-lowering food intake
Szymanska, E. ; Dorsten, F.A. van; Troost, J. ; Paliukhovich, I. ; Velzen, E.J.J. van; Hendriks, M.M.W.B. ; Trautwein, E.A. ; Duynhoven, J.P.M. van; Vreeken, R.J. ; Smilde, A.K. - \ 2012
Metabolomics 8 (2012)5. - ISSN 1573-3882 - p. 894 - 906.
coronary-artery-disease - plant sterols - mass-spectrometry - risk-factor - plasma - sphingomyelin - profiles - intervention - inflammation - metabolism
Plant sterols (PS) are well known to reduce serum levels of total cholesterol and LDL-cholesterol. Lipidomics potentially provides detailed information on a wide range of individual serum lipid metabolites, which may further add to our understanding of the biological effects of PS. In this study, lipidomics analysis was applied to serum samples from a placebo-controlled, parallel human intervention study (n = 97) of 4-week consumption of two PS-enriched, yoghurt drinks differing in fat content (based on 0.1% vs. 1.5% dairy fat). A comprehensive data analysis strategy was developed and implemented to assess and compare effects of two different PS-treatments and placebo treatment. The combination of univariate and multivariate data analysis approaches allowed to show significant effects of PS intake on the serum lipidome, and helped to distinguish them from fat content and non-specific effects. The PS-enriched 0.1% dairy fat yoghurt drink had a stronger impact on the lipidome than the 1.5% dairy fat yoghurt drink, despite similar LDL-cholesterol lowering effects. The PS-enriched 0.1% dairy fat yoghurt drink reduced levels of several sphingomyelins which correlated well with the reduction in LDL-cholesterol and can be explained by co-localization of sphingomyelins and cholesterol on the surface of LDL lipoprotein. Statistically significant reductions in serum levels of two lysophosphatidylcholines (LPC(16:1), LPC(20:1)) and cholesteryl arachidonate may suggest reduced inflammation and atherogenic potential. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11306-011-0384-2) contains supplementary material, which is available to authorized users.
Plasma Protein Profiling Reveals Protein Clusters Related to BMI and Insulin Levels in Middle-Aged Overweight Subjects
Dijk, S.J. van; Feskens, E.J.M. ; Heidema, A.G. ; Bos, M.B. ; Rest, O. van de; Geleijnse, J.M. ; Müller, M.R. ; Afman, L.A. - \ 2010
PLoS ONE 5 (2010)12. - ISSN 1932-6203 - 9 p.
c-reactive protein - coronary-artery-disease - plasminogen-activator inhibitor-1 - complement c3 - adipose-tissue - resistance atherosclerosis - cardiovascular health - multimarker approach - heart-disease - serum-levels
Background - Biomarkers that allow detection of the onset of disease are of high interest since early detection would allow intervening with lifestyle and nutritional changes before the disease is manifested and pharmacological therapy is required. Our study aimed to improve the phenotypic characterization of overweight but apparently healthy subjects and to identify new candidate profiles for early biomarkers of obesity-related diseases such as cardiovascular disease and type 2 diabetes. Methodology/Principal Findings - In a population of 56 healthy, middle-aged overweight subjects Body Mass Index (BMI), fasting concentration of 124 plasma proteins and insulin were determined. The plasma proteins are implicated in chronic diseases, inflammation, endothelial function and metabolic signaling. Random Forest was applied to select proteins associated with BMI and plasma insulin. Subsequently, the selected proteins were analyzed by clustering methods to identify protein clusters associated with BMI and plasma insulin. Similar analyses were performed for a second population of 20 healthy, overweight older subjects to verify associations found in population I. In both populations similar clusters of proteins associated with BMI or insulin were identified. Leptin and a number of pro-inflammatory proteins, previously identified as possible biomarkers for obesity-related disease, e.g. Complement 3, C Reactive Protein, Serum Amyloid P, Vascular Endothelial Growth Factor clustered together and were positively associated with BMI and insulin. IL-3 and IL-13 clustered together with Apolipoprotein A1 and were inversely associated with BMI and might be potential new biomarkers. Conclusion/ Significance - We identified clusters of plasma proteins associated with BMI and insulin in healthy populations. These clusters included previously reported biomarkers for obesity-related disease and potential new biomarkers such as IL-3 and IL-13. These plasma protein clusters could have potential applications for improved phenotypic characterization of volunteers in nutritional intervention studies or as biomarkers in the early detection of obesity-linked disease development and progression
The regular consumption of a polyphenol-rich apple doet not influence endothelial function: a randomised double-blind trial in hypercholesterolemic adults
Auclair, S. ; Chironi, G. ; Milenkovic, D. ; Hollman, P.C.H. ; Renard, C.M. ; Megnien, J.L. ; Gariepy, J. ; Paul, J.L. ; Simon, A. ; Scalbert, A. - \ 2010
European Journal of Clinical Nutrition 64 (2010). - ISSN 0954-3007 - p. 1158 - 1165.
coronary-artery-disease - healthy-young adults - cardiovascular-disease - vascular function - flavonoid intake - postmenopausal women - antioxidant capacity - dependent dilation - oxidative stress - phenolic-acids
Background/objectives: Epidemiological studies suggest that apple consumption is associated with a reduction in cardiovascular disease risk. Apple polyphenols may contribute to explain these effects. Endothelial dysfunction has been associated with early stage of atherosclerosis and polyphenols from various dietary sources have been shown to reverse it. The aim of the present study was to investigate the effect of the consumption of a polyphenol-rich apple on endothelial function. Subjects/methods: In all, 30 hypercholesterolemic volunteers were included in a double-blind, randomized crossover trial. They successively consumed 40¿g of two lyophilized apples, polyphenol-rich and polyphenol-poor, providing respectively 1.43 and 0.21¿g polyphenols per day during two 4-week periods separated by a 4-week washout period. Results: Brachial artery flow-mediated vasodilation (FMD) was assessed at the beginning and at the end of each intervention period. FMD did not differ between the polyphenol-rich and the polyphenol-poor apples, neither did the other cardiovascular disease risk factors (plasma lipids, homocysteine, antioxidant capacity). Conclusions: These data suggest that over a 4-week period, the consumption of a polyphenol-rich apple does not improve vascular function in hypercholesterolemic patients.
Association of polymorphism in the receptor for advanced glycation end products (RAGE) gene with circulating RAGE levels
Gaens, K.H. ; Ferreira, I. ; Kallen, C.J. ; Greevenbroek, M.M. ; Blaak, E.E. ; Feskens, E.J.M. ; Dekker, J.M. ; Nijpels, G. ; Heine, R.J. ; Hart, L.M. t; Groot, P.G. ; Stehouwer, C.D. ; Schalkwijk, C.G. - \ 2009
Journal of Clinical Endocrinology and Metabolism 94 (2009)12. - ISSN 0021-972X - p. 5174 - 5180.
coronary-artery-disease - low-grade inflammation - soluble form - gly82ser polymorphism - diabetic-retinopathy - cardiovascular-disease - splice variants - serum-levels - endproducts - codam
Objective: The receptor for advanced glycation end products (RAGE)-ligand interaction has been linked to vascular complications. The family of soluble forms of RAGE (sRAGE) consists of splice variants and proteolytically cleaved and shed forms of RAGE. sRAGE may be a reflection of cell-bound RAGE. Because genetic variation in the RAGE gene may be associated with individual differences in sRAGE concentration and outcome, we investigated whether RAGE single-nucleotide polymorphisms (SNPs) were associated with circulating levels of sRAGE. Methods: Nine SNPs, covering the common RAGE gene variation, were genotyped in a Dutch cohort of subjects with normal glucose metabolism (n = 301), impaired glucose metabolism (n = 127), and type 2 diabetes mellitus (n = 146). We used linear regression analyses adjusted for age, sex, and glucose metabolism status to compare sRAGE levels across genotypes. Results: SNP rs2060700 (Gly82Ser) showed an association with sRAGE levels. Specifically, after adjustments for age, sex, and glucose metabolism, subjects with CT genotype had –527 pg/ml (95% confidence interval –724 to –330, P <0.001) lower sRAGE levels compared with the CC genotype (age, sex, and glucose metabolism adjusted mean ± SE values of 836 ± 99 and 1369 ± 26 pg/ml, respectively, P <0.001). These results were confirmed in a subsample of a second cohort study of subjects with CT (n = 37) and CC genotype (n = 37). Immunoblotting using antibodies against amino acids 39-55 and 100-116 of RAGE also showed a similar decrease of sRAGE levels in the CT genotypes. No other SNPs showed an association with sRAGE levels. In addition, no associations between SNPs and the advanced glycation end products N-(carboxymethyl)lysine and N-(carboxyethyl)lysine were found. Conclusion: The CC genotype of SNP rs2070600 (Gly82Ser) was strongly associated with higher sRAGE levels in a Dutch population. The mechanism by which Gly82Ser polymorphism alters the sRAGE levels remains to be elucidated.
A multiple testing approach to high-dimensional association studies with an application to the detection of associations between risk factors of heart disease and genetic polymorphisms
Ferreira, J.A. ; Berkhof, J. ; Souverein, O.W. ; Zwinderman, K. - \ 2009
Statistical Applications in Genetics and Molecular Biology 8 (2009)1. - ISSN 1544-6115
false discovery rate - coronary-artery-disease - myocardial-infarction - cholesterol levels - protein - variant
We present an approach to association studies involving a dozen or so 'response' variables and a few hundred 'explanatory' variables which emphasizes transparency, simplicity, and protection against spurious results. The methods proposed are largely non-parametric, and they are systematically rounded-off by the Benjamini-Hochberg method of multiple testing. An application to the detection of associations between risk factors of heart disease and genetic polymorphisms using the REGRESS dataset provides ample illustration of our approach. Special attention is paid to book-keeping and information-management aspects of data analysis, which allow the creation of an informative and reasonably digestible 'map of relationships'-the end-product of an association study as far as statistics is concerned.
Autonomic dysfunction: a link between depression and cardiovascular mortality? The FINE Study
Kamphuis, M.H. ; Geerlings, M.I. ; Dekker, J.M. ; Giampaoli, S. ; Nissinen, A. ; Grobbee, D.E. ; Kromhout, D. - \ 2007
European Journal of Cardiovascular Prevention and Rehabilitation 14 (2007)6. - ISSN 1741-8267 - p. 796 - 802.
heart-rate-variability - coronary-artery-disease - elderly-men - myocardial-infarction - nervous-system - qt-interval - plasma norepinephrine - psychosocial factors - major depression - symptoms
Background: Depression is associated with an increased risk of cardiovascular diseases (CVD) in vascular patients as well as in the general population. We investigated whether autonomic dysfunction could explain this relationship. Design: The Finland, Italy and The Netherlands Elderly (FINE) Study is a prospective cohort study. Methods: Depressive symptoms were measured with the Zung Self-rating Depression Scale in 870 men, aged 70-90 years, free of CVD and diabetes in 1990. Resting heart rate was determined from a 15-30-s resting electrocardiogram in The Netherlands and Italy and as pulse rate in Finland. In addition, in The Netherlands, heart-rate variability (HRV) and QTc interval were determined. Results: At baseline, depressive symptoms were associated with an increase in resting heart rate, and nonsignificantly with low HRV and prolonged QTc interval. After 10 years of follow-up, 233 (27%) men died from CVD. Prospectively, an increase in resting heart rate with 1 SD was associated with an increased risk of cardiovascular mortality [hazard ratio (HR), 1.22; 95% confidence interval (CI), 1.08-1.38]. In addition, low HRV (HR, 0.78; 95% CI, 0.61-1.01) and prolonged QTc interval (HR, 1.28; 95% CI, 1.06-1.53) per SD were associated with cardiovascular mortality. The increased risk of depressive symptoms for cardiovascular mortality (HR, 1.38; 95% CI, 1.21-1.58) did not change after adjustments for several indicators of autonomic dysfunction. Conclusion: This study suggests that mild depressive symptoms are associated with autonomic dysfunction in elderly men. The increased risk of cardiovascular mortality with increasing magnitude of depressive symptoms could, however, not be explained by autonomic dysfunction.
PPAR - and dyslipidemia
Duval, C.N.C. ; Müller, M.R. ; Kersten, A.H. - \ 2007
Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids 1771 (2007)8. - ISSN 1388-1981 - p. 961 - 971.
proliferator-activated-receptor - coronary-artery-disease - low-density-lipoprotein - apolipoprotein-c-iii - rev-erb-alpha - diabetes atherosclerosis intervention - reverse cholesterol transport - angiopoietin-like protein-4 - chylomicron-like emulsions - coenzyme
Dyslipidemia is defined by abnormal levels of plasma lipoproteins. Several different types of dyslipidemia can be distinguished. An important group of drugs used in the treatment of dyslipidemia are the fibrates. Fibrates serve as agonists for the peroxisome proliferator-activated receptor alpha (PPAR¿), a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. By binding to response elements mostly present in the promoter of target genes, PPAR¿ governs the expression of numerous genes involved in a variety of metabolic processes. Activation of PPAR¿ results in a reduction of plasma TG levels, which is achieved by: (1) induction of genes that decrease the availability of TG for hepatic VLDL secretion, and (2) induction of genes that promote lipoprotein lipase-mediated lipolysis of TG-rich plasma lipoproteins. The stimulatory effect of PPAR¿ on plasma HDL levels in humans, which is opposite to what is observed in mice, appears to be mainly mediated via increased production of APOA1 and APOA2, the apolipoprotein constituents of HDL. Apart from its major actions outlined above, PPAR¿ modulates lipoprotein metabolism in several other ways, mostly via direct up-regulation of specific PPAR¿ target genes. By taking into account novel insights into the metabolism of plasma lipoproteins and by considering the latest information on PPAR¿-dependent gene regulation, a fresh perspective on the molecular mechanisms underlying the plasma lipoprotein modulating effect of PPAR¿ is presented.
EPIC-Heart: The cardiovascular component of a prospective study of nutritional, lifestyle and biological factors in 520,000 middle-aged participants from 10 European countries
Danesh, J. ; Saracci, R. ; Berglund, G. ; Feskens, E.J.M. ; Overvad, K. ; Panico, S. ; Thompson, S. ; Fournier, A. ; Clavel-Chapelon, F. ; Canonico, M. ; Kaaks, R. ; Linseisen, J. ; Boeing, H. ; Pischon, T. ; Weikert, C. ; Olsen, A. ; Tjonneland, A. ; Johnsen, S.P. ; Jensen, M.K. ; Quiros, J.R. ; Gonzalez-Svatetz, C.A. ; Sanchez-Perez, M.J. ; Larranaga, N. ; Navarro Sanchez, C. ; Moreno Iribas, C. ; Bingham, S. ; Khaw, K.T. ; Wareham, N. ; Key, T. ; Roddam, A. ; Trichopoulou, A. ; Benetou, V. ; Trichopoulous, D. ; Masala, G. ; Sieri, S. ; Tumino, R. ; Sacerdote, C. ; Mattiello, A. ; Verschuren, W.M.M. ; Bueno de Mesquita, H.B. ; Grobbee, D.E. ; Schouw, Y.T. van der; Melander, O. ; Hallmans, G. ; Wennberg, P. ; Lund, E. ; Kumle, M. ; Skeie, G. ; Ferrari, P. ; Slimani, N. ; Norat, T. ; Riboli, E. - \ 2007
European Journal of Epidemiology 22 (2007)2. - ISSN 0393-2990 - p. 129 - 141.
coronary-artery-disease - dietary assessment methods - high blood-pressure - fat distribution - norfolk cohort - plasma-levels - cancer - risk - women - population
EPIC-Heart is the cardiovascular component of the European Prospective Investigation into Cancer and Nutrition (EPIC), a multi-centre prospective cohort study investigating the relationship between nutrition and major chronic disease outcomes. Its objective is to advance understanding about the separate and combined influences of lifestyle (especially dietary), environmental, metabolic and genetic factors in the development of cardiovascular diseases by making best possible use of the unusually informative database and biological samples in EPIC. Between 1992 and 2000, 519,978 participants (366,521 women and 153,457 men, mostly aged 35¿70 years) in 23 centres in 10 European countries commenced follow-up for cause- specific mortality, cancer incidence and major cardiovascular morbidity. Dietary information was collected with quantitative questionnaires or semi-quantitative food frequency questionnaires, including a 24-h dietary recall sub-study to help calibrate the dietary measurements. Information was collected on physical activity, tobacco smoking, alcohol consumption, occupational history, socio-economic status, and history of previous illnesses. Anthropometric measurements and blood pressure recordings were made in the majority of participants. Blood samples were taken from 385,747 individuals, from which plasma, serum, red cells, and buffy coat fractions were separated and aliquoted for long-term storage. By 2004, an estimated 10,000 incident fatal and non-fatal coronary and stroke events had been recorded. The first cycle of EPIC-Heart analyses will assess associations of coronary mortality with several prominent dietary hypotheses and with established cardiovascular risk factors. Subsequent analyses will extend this approach to non-fatal cardiovascular outcomes¿and to further dietary, biochemical and genetic factors.
Flavonoids and heart health: Proceedings of the ILSI North America Flavonoids Workshop may 31-june 1, 2005, Washington DC
Erdman, J.W. ; Balentine, D. ; Arab, L. ; Beecher, G. ; Dwyer, J.T. ; Folts, J. ; Harnly, J. ; Hollman, P.C.H. ; Keen, C.L. ; Mazza, G. ; Messina, M. ; Scalbert, A. ; Vita, J. ; Williamson, G. ; Burrows, J. - \ 2007
The Journal of Nutrition 137 (2007)3. - ISSN 0022-3166 - p. 718s - 737s.
low-density-lipoprotein - coronary-artery-disease - potentially anticarcinogenic flavonoids - environmental estrogenic compounds - estradiol-induced tumorigenesis - improves endothelial function - liquid-chromatographic method - catechol o-methyltransferase - ran
This article provides an overview of current research on flavonoids as presented during a workshop entitled, "Flavonoids and Heart Health," held by the ILSI North America Project Committee on Flavonoids in Washington, DC, May 31 and June 1, 2005. Because a thorough knowledge and understanding about the science of flavonoids and their effects on health will aid in establishing dietary recommendations for bioactive components such as flavonoids, a systematic review of the science of select flavonoid classes (i.e., flavonols, flavones, flavanones, isoflavones, flavan-3-ols, anthocyanins, and proanthocyanidins) was presented. The objectives of the workshop were to 1) present and discuss current research on flavonoid intake and the relation between flavonoids and heart health; 2) develop information that could lead to expert consensus on the state-of-the-science of dietary intake of flavonoids on heart health; and 3) summarize and prioritize the research needed to establish the relations between specific flavonoids and heart health. Presentations included the basics of the biology of flavonoids, including the types and distribution in foods, analytical methodologies used to determine the amounts in foods, the bioavailability, the consumption patterns and potential biomarkers of intake, risk assessment and safety evaluation, structure/function claims, and the proposed mechanism(s) of the relation between certain flavonoids and heart health endpoints. Data presented support the concept that certain flavonoids in the diet can be associated with significant health benefits, including heart health. Research gaps were identified to help advance the science.
High risk of cardiovascular disease in patients with type 1 diabetes mellitus in the UK, a cohort study using the General Practice Research Database
Soedamah-Muthu, S.S. ; Fuller, J.H. ; Mulnier, H.E. ; Raleigh, V.S. ; Lawrenson, R.A. ; Colhoun, H.M. - \ 2006
Diabetes Care 29 (2006)4. - ISSN 0149-5992 - p. 798 - 804.
coronary-artery-disease - cause-specific mortality - follow-up - pittsburgh epidemiology - vascular-disease - heart-disease - complications - mellitus - calcification - trial
OBJECTIVE—To estimate the absolute and relative risk of cardiovascular disease (CVD) in patients with type 1 diabetes in the U.K. RESEARCH DESIGN AND METHODS—Subjects with type 1 diabetes (n = 7,479) and five age- and sex-matched subjects without diabetes (n = 38,116) and free of CVD at baseline were selected from the General Practice Research Database (GPRD), a large primary care database representative of the U.K. population. Incident major CVD events, comprising myocardial infarction, acute coronary heart disease death, coronary revascularizations, or stroke, were captured for the period 1992–1999. RESULTS—The hazard ratio (HR) for major CVD was 3.6 (95% CI 2.9–4.5) in type 1 diabetic men compared with those without diabetes and 7.7 (5.5–10.7) in women. Increased HRs were found for acute coronary events (3.0 and 7.6 in type 1 diabetic men and women, respectively, versus nondiabetic subjects), coronary revascularizations (5.0 in men, 16.8 in women), and for stroke (3.7 in men, 4.8 in women). Type 1 diabetic men aged 45–55 years had an absolute CVD risk similar to that of men in the general population 10–15 years older, with an even greater difference in women. CONCLUSIONS—Despite advances in care, these data show that absolute and relative risks of CVD remain extremely high in patients with type 1 diabetes. Women with type 1 diabetes continue to experience greater relative risks of CVD than men compared with those without diabetes.
Acute effect of folic acid, betaine, and serine supplements on flow-mediated dilation after methionine loading: A randomized trial
Olthof, M.R. ; Bots, M.L. ; Katan, M.B. ; Verhoef, P. - \ 2006
PloS Clinical trials 1 (2006)1. - ISSN 1555-5887
coronary-artery-disease - vascular endothelial dysfunction - homocysteine-lowering therapy - placebo-controlled trial - ischemic-heart-disease - healthy-human subjects - saturated fatty-acids - plasma homocysteine - dependent vasodilation - cardiovascular events
Objectives: We investigated whether reducing post-methionine homocysteine concentrations via various treatments other than folic acid affects vascular function, as measured through flow-mediated dilation (FMD) of the brachial artery. High fasting and post-methionine homocysteine concentrations are associated with cardiovascular disease risk, but homocysteine might be a surrogate marker for low folate status. Design: This was a randomized, placebo-controlled, double-blind, crossover study. Setting: The study took place at Wageningen University in Wageningen in the Netherlands. Participants: Participants were 39 apparently healthy men and women, aged 50 - 70 y. Interventions: Participants ingested 10 mg of folic acid, 3 g of betaine, 5 g of serine, and placebo together with an oral methionine load. Each supplement was tested on two different days. Outcome Measures: On each of the eight treatment days, plasma homocysteine concentrations and FMD were measured before ( t = 0 h, fasting) and 6 h ( t = 6 h) after methionine loading. Results: The mean (+/- SD) fasting homocysteine concentrations averaged over the eight test days were 9.6 +/- 62.1 mu mol/l. Mean fasting FMD was 3.1 +/- 2.4 FMD%. A methionine load with placebo increased homocysteine concentrations by 17.2 +/- 9.3 mu mol/l at 6 h after loading, similar to the increase following methionine loading with folic acid. A methionine load together with betaine and with serine increased homocysteine by 10.4 +/- 2.8 mu mol/l ( p<0.001 relative to placebo) and by 12.1 +/- 8.2 mu mol/l ( p<0.001 relative to placebo), respectively. Methionine loading with placebo did not affect FMD, and neither did methionine loading with folic acid, betaine, or serine; differences relative to placebo were +0.7 FMD% (95% CI, - 0.6; 1.9), +0.2 FMD% (- 1.0; 1.3), and +0.3 FMD% ( - 0.8; 1.4), respectively. Conclusions: Experimentally induced acute changes in homocysteine concentrations did not affect FMD in healthy volunteers. This implies that potential adverse effects of high homocysteine concentrations on the cardiovascular system are not mediated through vascular function. However, homocysteine or folate may affect cardiovascular disease risk through other mechanisms.