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101. Longitudinal associations of the alternative and terminal pathways of complement activation with adiposity: The CODAM study

Author

Xin, Ying, Xin, Ying, Hertle, Elisabeth, van der Kallen, Carla J. H., Schalkwijk, Casper G., Stehouwer, Coen D. A., van Greevenbroek, Marleen M. J., Xin, Ying, Xin, Ying, Hertle, Elisabeth, van der Kallen, Carla J. H., Schalkwijk, Casper G., Stehouwer, Coen D. A., and van Greevenbroek, Marleen M. J.

Abstract

Objective: To investigate longitudinal associations of components of the alternative (C3, C3a, Bb, factor D [FD], factor H [FH], and properdin) and the terminal complement pathway (C5a, sC5b-9) with adiposity. Methods: A prospective human cohort study (n = 574 at baseline, n = 489 after 7 years follow-up) was analyzed. Generalized estimating equations were used to evaluate the longitudinal associations between complement components (standardized values) and adiposity (main outcome BMI [kg/m(2)]). Multiple linear regression models were used to investigate the associations between change in complement levels and change in BMI. Analyses were adjusted for age, sex, medication and lifestyle. Results: Over the 7-year period, baseline C3 was positively associated with BMI (beta = 1.72 [95% confidence interval (CI): 1.35; 2.09]). Positive associations were also observed for C3a (beta = 0.64 [0.31; 0.97]), FD (beta = 1.00 [0.59; 1.42]), FH (beta = 1.17 [0.82; 1.53 ]), and properdin (beta = 0.60 [0.28; 0.92]), but not for Bb, C5a or sC5b-9. Moreover, changes in C3 ((3= 0.52 [0.34; 0.71 ]) and FH (beta = 0.51 [0.32; 0.70]) were significantly associated with changes in BMI. Conclusions: The complement system, particularly activation of the alternative pathway, may be involved in development of adiposity. Whether individual aspects of alternative pathway activation have a causal role in human obesity, remains to be investigated. (C) 2017 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

Published
2018

102. Circulating Polyunsaturated Fatty Acids as Biomarkers for Dietary Intake across Subgroups: The CODAM and Hoorn Studies

Author

Wanders, Anne J., Wanders, Anne J., Alssema, Marjan, De Hoon, Sabine E. M., Feskens, Edith J. M., van Woudenbergh, Geertruida J., van der Kallen, Carla J., Zock, Peter L., Refsum, Helga, Drevon, Christian A., Elshorbagy, Amany, Schalkwijk, Casper G., Stehouwer, Coen D. A., Dekker, Jacqueline M., van Greevenbroek, Marleen M. J., Wanders, Anne J., Wanders, Anne J., Alssema, Marjan, De Hoon, Sabine E. M., Feskens, Edith J. M., van Woudenbergh, Geertruida J., van der Kallen, Carla J., Zock, Peter L., Refsum, Helga, Drevon, Christian A., Elshorbagy, Amany, Schalkwijk, Casper G., Stehouwer, Coen D. A., Dekker, Jacqueline M., and van Greevenbroek, Marleen M. J.

Abstract

Aims: To evaluate whether participant characteristics and way of expressing circulating fatty acids (FA) influence the strengths of associations between self-reported intake and circulating levels of linoleic acid (LA), alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Methods: Cross-sectional analyses were performed in pooled data from the CODAM (n = 469) and Hoorn (n = 702) studies. Circulating FA were measured by gas liquid chromatography and expressed as proportions (% of total FA) and concentrations (mu g/mL). Dietary intakes were calculated from a validated food frequency questionnaire. Effects of participant characteristics on associations between dietary and circulating FA were calculated using interaction analyses. Results: Standardized regression coefficients between dietary FA and proportions of circulating FA (% of total FA) were LA beta = 0.28, ALA beta = 0.13, EPA beta = 0.34, and DHA beta = 0.45. Body mass index (BMI), waist circumference, and presence of CVD influenced associations for LA; gender influenced LA, EPA, and DHA; alcohol intake influenced LA and DHA; and glucose tolerance status influenced ALA (p values interaction <0.05). Coefficients for circulating FA as concentrations were LA beta = 0.19, ALA beta = 0.10, EPA beta = 0.31, and DHA beta = 0.41. Conclusions: This study suggests that characteristics such as BMI, alcohol intake, and expressing circulating FA as proportions or concentrations, influence associations between dietary and circulating FA. (C) 2018 S. Karger AG, Basel

Published
2018

103. Blood Metabolomic Measures Associate With Present and Future Glycemic Control in Type 2 Diabetes

Author

't Hart, Leen M., 't Hart, Leen M., Vogelzangs, Nicole, Mook-Kanamori, Dennis O., Brahimaj, Adela, Nano, Jana, van der Heijden, Amber A. W. A., van Dijk, Ko Willems, Slieker, Roderick C., Steyerberg, Ewout W., Ikram, M. Arfan, Beekman, Marian, Boomsma, Dorret I., van Duijn, Cornelia M., Slagboom, P. Eline, Stehouwer, Coen D. A., Schalkwijk, Casper G., Arts, Ilja C. W., Dekker, Jacqueline M., Dehghan, Abbas, Muka, Taulant, van der Kallen, Carla J. H., Nijpels, Giel, van Greevenbroek, Marleen M. J., 't Hart, Leen M., 't Hart, Leen M., Vogelzangs, Nicole, Mook-Kanamori, Dennis O., Brahimaj, Adela, Nano, Jana, van der Heijden, Amber A. W. A., van Dijk, Ko Willems, Slieker, Roderick C., Steyerberg, Ewout W., Ikram, M. Arfan, Beekman, Marian, Boomsma, Dorret I., van Duijn, Cornelia M., Slagboom, P. Eline, Stehouwer, Coen D. A., Schalkwijk, Casper G., Arts, Ilja C. W., Dekker, Jacqueline M., Dehghan, Abbas, Muka, Taulant, van der Kallen, Carla J. H., Nijpels, Giel, and van Greevenbroek, Marleen M. J.

Abstract

Objective: We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy.Methods: A total of 162 metabolomic measures were analyzed using a nuclear magnetic resonance-based method in people with T2D from four cohort studies (n = 2641) and one replication cohort (n = 395). Linear and logistic regression analyses with adjustment for potential confounders, followed by meta-analyses, were performed to analyze associations with hemoglobin A1c levels, six glucose-lowering drug categories, and insulin initiation during a 7-year follow-up period (n = 698).Results: After Bonferroni correction, 26 measures were associated with insufficient glycemic control (HbA1c >53 mmol/mol). The strongest association was with glutamine (OR, 0.66; 95% CI, 0.61 to 0.73; P = 7.6 x 10(-19)). In addition, compared with treatment-naive patients, 31 metabolomic measures were associated with glucose-lowering drug use (representing various metabolite categories; PConclusion: Blood metabolomic measures were associated with present and future glycemic control and might thus provide relevant cues to identify those at increased risk of treatment failure.

Published
2018

104. Classical Pathway of Complement Activation: Longitudinal Associations of C1q and C1-INH With Cardiovascular Outcomes: The CODAM Study (Cohort on Diabetes and Atherosclerosis Maastricht)Brief Report

Author

Hertle, Elisabeth, Hertle, Elisabeth, Arts, Ilja C. W., van der Kallen, Carla J. H., Feskens, Edith J. M., Schalkwijk, Casper G., Stehouwer, Coen D. A., van Greevenbroek, Marleen M. J., Hertle, Elisabeth, Hertle, Elisabeth, Arts, Ilja C. W., van der Kallen, Carla J. H., Feskens, Edith J. M., Schalkwijk, Casper G., Stehouwer, Coen D. A., and van Greevenbroek, Marleen M. J.

Abstract

Objective The classical complement pathway has been assigned both protective and pathological effects in cardiovascular disease (CVD), but human data are lacking. We determined the associations of the pattern recognition factor C1q and the regulator C1-INH (C1-inhibitor) with incident CVD, carotid intima-media thickness, endothelial dysfunction, and low-grade inflammation. Approach and Results Baseline concentrations of C1q and C1-INH were measured in the CODAM study (Cohort on Diabetes and Atherosclerosis Maastricht; n=574; 61% men; age, 607 years). The 7-year incidence of CVD in participants free of CVD at baseline was evaluated using logistic regression analyses (n=342; 73 cases). The lowest incidence of CVD was observed in the middle tertile of C1q (T-low compared with T-middle: odds ratio, 2.38 [95% confidence interval, 1.14-4.95]; T-high compared with T-middle: odds ratio, 1.96 [95% confidence interval, 0.94-4.07]). C1-INH was not associated with CVD. During the 7-year follow-up period, C1q and C1-INH were not, or inconsistently, associated with carotid intima-media thickness or with biomarker scores reflecting endothelial dysfunction and low-grade inflammation. Conclusions Our results suggest a nonlinear association between C1q and incident CVD. This supports the concept that early steps in classical pathway activation may have both protective and pathological effects on human CVD.

Published
2018

105. Disease variants alter transcription factor levels and methylation of their binding sites

Author

Bonder, Marc Jan, Luijk, René, Zhernakova, Daria V, Moed, Matthijs, Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Dijk, Freerk, van Galen, Michiel, Bot, Jan, Slieker, Roderick C, Jhamai, P Mila, Verbiest, Michael, Suchiman, H Eka D, Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Arindrarto, Wibowo, Kielbasa, Szymon M, Jonkers, Iris, van 't Hof, Peter, Nooren, Irene, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Zhernakova, Alexandra, Tigchelaar, Ettje F, Swertz, Morris A, Hofman, Albert, Uitterlinden, André G, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, Stehouwer, Coen D A, van der Kallen, Carla J H, Schalkwijk, Casper G, van den Berg, Leonard H, van Zwet, Erik W, Mei, Hailiang, Li, Yang, Lemire, Mathieu, Hudson, Thomas J, Slagboom, P Eline, Wijmenga, Cisca, Veldink, Jan H, van Greevenbroek, Marleen M J, van Duijn, Cornelia M, Boomsma, Dorret I, Isaacs, Aaron, and BIOS Consortium

Subjects
Journal Article
Abstract

Most disease-associated genetic variants are noncoding, making it challenging to design experiments to understand their functional consequences. Identification of expression quantitative trait loci (eQTLs) has been a powerful approach to infer the downstream effects of disease-associated variants, but most of these variants remain unexplained. The analysis of DNA methylation, a key component of the epigenome, offers highly complementary data on the regulatory potential of genomic regions. Here we show that disease-associated variants have widespread effects on DNA methylation in trans that likely reflect differential occupancy of trans binding sites by cis-regulated transcription factors. Using multiple omics data sets from 3,841 Dutch individuals, we identified 1,907 established trait-associated SNPs that affect the methylation levels of 10,141 different CpG sites in trans (false discovery rate (FDR) < 0.05). These included SNPs that affect both the expression of a nearby transcription factor (such as NFKB1, CTCF and NKX2-3) and methylation of its respective binding site across the genome. Trans methylation QTLs effectively expose the downstream effects of disease-associated variants.

Published
2017

107. Subcutaneous Adipose Tissue and Systemic Inflammation Are Associated With Peripheral but Not Hepatic Insulin Resistance in Humans.

Author

van der Kolk, Birgitta W., Kalafati, Marianthi, Adriaens, Michiel, Greevenbroek, Marleen M. J. van, Vogelzangs, Nicole, Saris, Wim H. M., Astrup, Arne, Valsesia, Armand, Langin, Dominique, van der Kallen, Carla J. H., Eussen, Simone J. P. M., Schalkwijk, Casper G., Stehouwer, Coen D. A., Goossens, Gijs H., Arts, Ilja C. W., Jocken, Johan W. E., Evelo, Chris T., Blaak, Ellen E., and van Greevenbroek, Marleen M J

Subjects
INSULIN resistance, ADIPOSE tissues, ABDOMINAL adipose tissue, ETIOLOGY of diseases, GLUCOSE tolerance tests
Abstract

Obesity-related insulin resistance (IR) may develop in multiple organs, representing various etiologies for cardiometabolic diseases. We identified abdominal subcutaneous adipose tissue (ScAT) transcriptome profiles in liver or muscle IR by means of RNA sequencing in overweight or obese participants of the Diet, Obesity, and Genes (DiOGenes) (NCT00390637, ClinicalTrials.gov) cohort (n = 368). Tissue-specific IR phenotypes were derived from a 5-point oral glucose tolerance test. Hepatic and muscle IR were characterized by distinct abdominal ScAT transcriptome profiles. Genes related to extracellular remodeling were upregulated in individuals with primarily hepatic IR, while genes related to inflammation were upregulated in individuals with primarily muscle IR. In line with this, in two independent cohorts, the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) (n = 325) and the Maastricht Study (n = 685), an increased systemic low-grade inflammation profile was specifically related to muscle IR but not to liver IR. We propose that increased ScAT inflammatory gene expression may translate into an increased systemic inflammatory profile, linking ScAT inflammation to the muscle IR phenotype. These distinct IR phenotypes may provide leads for more personalized prevention of cardiometabolic diseases. [ABSTRACT FROM AUTHOR]

Published
2019
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108. High dietary glycemic load is associated with higher concentrations of urinary advanced glycation endproducts: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) Study.

Author

Maasen, Kim, van Greevenbroek, Marleen M J, Scheijen, Jean L J M, van der Kallen, Carla J H, Stehouwer, Coen D A, and Schalkwijk, Casper G

Subjects
ALDEHYDES, AMINO acids, ATHEROSCLEROSIS, CONFIDENCE intervals, DIABETES, FASTING, CARBOHYDRATE content of food, GLYCEMIC index, LIQUID chromatography, LONGITUDINAL method, LYSINE, MASS spectrometry, QUESTIONNAIRES, MULTIPLE regression analysis, LIFESTYLES, CROSS-sectional method, ADVANCED glycation end-products
Abstract

Background Advanced glycation endproducts (AGEs) and their precursors (dicarbonyls) are associated with the progression of diseases such as diabetes and cardiovascular disease. Plasma concentrations of dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) are increased after an oral glucose load indicating that consumption of diets high in carbohydrates may induce the endogenous formation of dicarbonyls and AGEs. Objective To examine the associations of dietary glycemic index (GI) and glycemic load (GL) with concentrations of dicarbonyls and AGEs in plasma and urine. Methods Cross-sectional analyses were performed in a human observational cohort [Cohort on Diabetes and Atherosclerosis Maastricht (CODAM), n  = 494, 59 ± 7 y, 25% type 2 diabetes]. GI and GL were derived from FFQs. Dicarbonyls and AGEs were measured in the fasting state by ultra-performance liquid chromatography-tandem MS. MGO, GO, and 3-DG and protein-bound Nε-(carboxymethyl)lysine (CML), Nε-(1-carboxyethyl)lysine (CEL), and pentosidine were measured in plasma. Free forms of CML, CEL, and Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were measured in both plasma and urine. Multiple linear regression was performed with dicarbonyls and AGEs as dependent variables, and dietary GI or GL as main independent variables (all standardized). Models were adjusted for health and lifestyle factors, dietary factors, and reciprocally for GI and GL. As this was an explorative study, we did not adjust for multiple testing. Results GI was not associated with any of the dicarbonyls or AGEs. GL was positively associated with free urinary MG-H1 (β = 0.34; 95% CI: 0.12, 0.55). Furthermore, GL was positively associated with free plasma MG-H1 and free urinary CML (β = 0.23; 95% CI: 0.02, 0.43; and β = 0.28; 95% CI: 0.06, 0.50), but these associations were not independent of dietary AGE intake. Conclusions A habitual diet higher in GL is associated with higher concentrations of free urinary MG-H1. This urinary AGE is most likely a reflection of AGE accumulation and degradation in tissues, where they may be involved in tissue dysfunction. [ABSTRACT FROM AUTHOR]

Published
2019
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109. Identification of context-dependent expression quantitative trait loci in whole blood

Author

Zhernakova, Daria V, Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Galen, Michiel, Arindrarto, Wibowo, van 't Hof, Peter, Mei, Hailiang, van Dijk, Freerk, Westra, Harm-Jan, Bonder, Marc Jan, van Rooij, Jeroen, Verkerk, Marijn, Jhamai, P Mila, Moed, Matthijs, Kielbasa, Szymon M, Bot, Jan, Nooren, Irene, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, Stehouwer, Coen D A, van der Kallen, Carla J H, Schalkwijk, Casper G, Zhernakova, Alexandra, Li, Yang, Tigchelaar, Ettje F, de Klein, Niek, Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H, Hofman, Albert, Uitterlinden, André G, van Greevenbroek, Marleen M J, Veldink, Jan H, Boomsma, Dorret I, van Duijn, Cornelia M, Wijmenga, Cisca, Slagboom, P Eline, Swertz, Morris A, Isaacs, Aaron, van Meurs, Joyce B J, Jansen, Rick, Heijmans, Bastiaan T, 't Hoen, Peter A C, Franke, Lude, Zhernakova, Daria V, Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Galen, Michiel, Arindrarto, Wibowo, van 't Hof, Peter, Mei, Hailiang, van Dijk, Freerk, Westra, Harm-Jan, Bonder, Marc Jan, van Rooij, Jeroen, Verkerk, Marijn, Jhamai, P Mila, Moed, Matthijs, Kielbasa, Szymon M, Bot, Jan, Nooren, Irene, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, Stehouwer, Coen D A, van der Kallen, Carla J H, Schalkwijk, Casper G, Zhernakova, Alexandra, Li, Yang, Tigchelaar, Ettje F, de Klein, Niek, Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H, Hofman, Albert, Uitterlinden, André G, van Greevenbroek, Marleen M J, Veldink, Jan H, Boomsma, Dorret I, van Duijn, Cornelia M, Wijmenga, Cisca, Slagboom, P Eline, Swertz, Morris A, Isaacs, Aaron, van Meurs, Joyce B J, Jansen, Rick, Heijmans, Bastiaan T, 't Hoen, Peter A C, and Franke, Lude

Published
2017

110. Identification of context-dependent expression quantitative trait loci in whole blood

Author

Zhernakova, Dania V., Zhernakova, Dania V., Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Galen, Michiel, Arindrarto, Wibowo, van 't Hof, Peter, Mei, Hailiang, van Dijk, Freerk, Westra, Harm-Jan, Bonder, Marc Jan, van Rooij, Jeroen, Verkerk, Marijn, Jhamai, P. Mila, Moed, Matthijs, Kielbasa, Szymon M., Bot, Jan, Nooren, Irene, Pool, Rene, van Dongen, Jenny, Hottenga, Jouke J., Stehouwer, Coen D. A., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Alexandra, Li, Yang, Tigchelaar, Ettje F., de Klein, Niek, Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H., Hofman, Albert, Uitterlinden, Andre G., van Greevenbroek, Marleen M. J., Veldink, Jan H., Boomsma, Dorret I., van Duijn, Cornelia M., Wijmenga, Cisca, Slagboom, P. Eline, Swertz, Morris A., Isaacs, Aaron, van Meurs, Joyce B. J., Jansen, Rick, Heijmans, Bastiaan T., 't Hoen, Peter A. C., Franke, Lude, Zhernakova, Dania V., Zhernakova, Dania V., Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Galen, Michiel, Arindrarto, Wibowo, van 't Hof, Peter, Mei, Hailiang, van Dijk, Freerk, Westra, Harm-Jan, Bonder, Marc Jan, van Rooij, Jeroen, Verkerk, Marijn, Jhamai, P. Mila, Moed, Matthijs, Kielbasa, Szymon M., Bot, Jan, Nooren, Irene, Pool, Rene, van Dongen, Jenny, Hottenga, Jouke J., Stehouwer, Coen D. A., van der Kallen, Carla J. H., Schalkwijk, Casper G., Zhernakova, Alexandra, Li, Yang, Tigchelaar, Ettje F., de Klein, Niek, Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H., Hofman, Albert, Uitterlinden, Andre G., van Greevenbroek, Marleen M. J., Veldink, Jan H., Boomsma, Dorret I., van Duijn, Cornelia M., Wijmenga, Cisca, Slagboom, P. Eline, Swertz, Morris A., Isaacs, Aaron, van Meurs, Joyce B. J., Jansen, Rick, Heijmans, Bastiaan T., 't Hoen, Peter A. C., and Franke, Lude

Abstract

Genetic risk factors often localize to noncoding regions of the genome with unknown effects on disease etiology1,2. Expression quantitative trait loci (eQTLs) help to explain the regulatory mechanisms underlying these genetic associations(3-6). Knowledge of the context that determines the nature and strength of eQTLs may help identify cell types relevant to pathophysiology and the regulatory networks underlying disease(7-17). Here we generated peripheral blood RNA-seq data from 2,116 unrelated individuals and systematically identified context-dependent eQTLs using a hypothesis-free strategy that does not require previous knowledge of the identity of the modifiers. Of the 23,060 significant cis-regulated genes (false discovery rate (FDR)

Published
2017

111. Disease variants alter transcription factor levels and methylation of their binding sites

Author

Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Neurogenetica, Bonder, Marc Jan, Luijk, René, Zhernakova, Daria V, Moed, Matthijs, Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Dijk, Freerk, van Galen, Michiel, Bot, Jan, Slieker, Roderick C, Jhamai, P Mila, Verbiest, Michael, Suchiman, H Eka D, Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Arindrarto, Wibowo, Kielbasa, Szymon M, Jonkers, Iris, van 't Hof, Peter, Nooren, Irene, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Zhernakova, Alexandra, Tigchelaar, Ettje F, Swertz, Morris A, Hofman, Albert, Uitterlinden, André G, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, Stehouwer, Coen D A, van der Kallen, Carla J H, Schalkwijk, Casper G, van den Berg, Leonard H, van Zwet, Erik W, Mei, Hailiang, Li, Yang, Lemire, Mathieu, Hudson, Thomas J, Slagboom, P Eline, Wijmenga, Cisca, Veldink, Jan H, van Greevenbroek, Marleen M J, van Duijn, Cornelia M, Boomsma, Dorret I, Isaacs, Aaron, BIOS Consortium, Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Neurogenetica, Bonder, Marc Jan, Luijk, René, Zhernakova, Daria V, Moed, Matthijs, Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Dijk, Freerk, van Galen, Michiel, Bot, Jan, Slieker, Roderick C, Jhamai, P Mila, Verbiest, Michael, Suchiman, H Eka D, Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Arindrarto, Wibowo, Kielbasa, Szymon M, Jonkers, Iris, van 't Hof, Peter, Nooren, Irene, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Zhernakova, Alexandra, Tigchelaar, Ettje F, Swertz, Morris A, Hofman, Albert, Uitterlinden, André G, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, Stehouwer, Coen D A, van der Kallen, Carla J H, Schalkwijk, Casper G, van den Berg, Leonard H, van Zwet, Erik W, Mei, Hailiang, Li, Yang, Lemire, Mathieu, Hudson, Thomas J, Slagboom, P Eline, Wijmenga, Cisca, Veldink, Jan H, van Greevenbroek, Marleen M J, van Duijn, Cornelia M, Boomsma, Dorret I, Isaacs, Aaron, and BIOS Consortium

Published
2017

112. Identification of context-dependent expression quantitative trait loci in whole blood

Author

Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Neurogenetica, Zhernakova, Daria V, Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Galen, Michiel, Arindrarto, Wibowo, van 't Hof, Peter, Mei, Hailiang, van Dijk, Freerk, Westra, Harm-Jan, Bonder, Marc Jan, van Rooij, Jeroen, Verkerk, Marijn, Jhamai, P Mila, Moed, Matthijs, Kielbasa, Szymon M, Bot, Jan, Nooren, Irene, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, Stehouwer, Coen D A, van der Kallen, Carla J H, Schalkwijk, Casper G, Zhernakova, Alexandra, Li, Yang, Tigchelaar, Ettje F, de Klein, Niek, Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H, Hofman, Albert, Uitterlinden, André G, van Greevenbroek, Marleen M J, Veldink, Jan H, Boomsma, Dorret I, van Duijn, Cornelia M, Wijmenga, Cisca, Slagboom, P Eline, Swertz, Morris A, Isaacs, Aaron, van Meurs, Joyce B J, Jansen, Rick, Heijmans, Bastiaan T, 't Hoen, Peter A C, Franke, Lude, Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Neurogenetica, Zhernakova, Daria V, Deelen, Patrick, Vermaat, Martijn, van Iterson, Maarten, van Galen, Michiel, Arindrarto, Wibowo, van 't Hof, Peter, Mei, Hailiang, van Dijk, Freerk, Westra, Harm-Jan, Bonder, Marc Jan, van Rooij, Jeroen, Verkerk, Marijn, Jhamai, P Mila, Moed, Matthijs, Kielbasa, Szymon M, Bot, Jan, Nooren, Irene, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, Stehouwer, Coen D A, van der Kallen, Carla J H, Schalkwijk, Casper G, Zhernakova, Alexandra, Li, Yang, Tigchelaar, Ettje F, de Klein, Niek, Beekman, Marian, Deelen, Joris, van Heemst, Diana, van den Berg, Leonard H, Hofman, Albert, Uitterlinden, André G, van Greevenbroek, Marleen M J, Veldink, Jan H, Boomsma, Dorret I, van Duijn, Cornelia M, Wijmenga, Cisca, Slagboom, P Eline, Swertz, Morris A, Isaacs, Aaron, van Meurs, Joyce B J, Jansen, Rick, Heijmans, Bastiaan T, 't Hoen, Peter A C, and Franke, Lude

Published
2017

113. Age-related accrual of methylomic variability is linked to fundamental ageing mechanisms

Author

Slieker, Roderick C, van Iterson, Maarten, Luijk, René, Beekman, Marian, Zhernakova, Daria V, Moed, Matthijs H, Mei, Hailiang, van Galen, Michiel, Deelen, Patrick, Bonder, Marc Jan, Zhernakova, Alexandra, Uitterlinden, André G, Tigchelaar, Ettje F, Stehouwer, Coen D A, Schalkwijk, Casper G, van der Kallen, Carla J H, Hofman, Albert, van Heemst, Diana, de Geus, Eco J, van Dongen, Jenny, Deelen, Joris, van den Berg, Leonard H, van Meurs, Joyce, Jansen, Rick, 't Hoen, Peter A C, Franke, Lude, Wijmenga, Cisca, Veldink, Jan H, Swertz, Morris A, van Greevenbroek, Marleen M J, van Duijn, Cornelia M, Boomsma, Dorret I, Slagboom, P Eline, Heijmans, Bastiaan T, BIOS consortium, Slieker, Roderick C, van Iterson, Maarten, Luijk, René, Beekman, Marian, Zhernakova, Daria V, Moed, Matthijs H, Mei, Hailiang, van Galen, Michiel, Deelen, Patrick, Bonder, Marc Jan, Zhernakova, Alexandra, Uitterlinden, André G, Tigchelaar, Ettje F, Stehouwer, Coen D A, Schalkwijk, Casper G, van der Kallen, Carla J H, Hofman, Albert, van Heemst, Diana, de Geus, Eco J, van Dongen, Jenny, Deelen, Joris, van den Berg, Leonard H, van Meurs, Joyce, Jansen, Rick, 't Hoen, Peter A C, Franke, Lude, Wijmenga, Cisca, Veldink, Jan H, Swertz, Morris A, van Greevenbroek, Marleen M J, van Duijn, Cornelia M, Boomsma, Dorret I, Slagboom, P Eline, Heijmans, Bastiaan T, and BIOS consortium

Published
2016

114. Blood lipids influence DNA methylation in circulating cells

Author

Dekkers, Koen F, van Iterson, Maarten, Slieker, Roderick C, Moed, Matthijs H, Bonder, Marc Jan, van Galen, Michiel, Mei, Hailiang, Zhernakova, Daria V, van den Berg, Leonard H, Deelen, Joris, van Dongen, Jenny, van Heemst, Diana, Hofman, Albert, Hottenga, Jouke J, van der Kallen, Carla J H, Schalkwijk, Casper G, Stehouwer, Coen D A, Tigchelaar, Ettje F, Uitterlinden, André G, Willemsen, Gonneke, Zhernakova, Alexandra, Franke, Lude, 't Hoen, Peter A C, Jansen, Rick, van Meurs, Joyce, Boomsma, Dorret I, van Duijn, Cornelia M, van Greevenbroek, Marleen M J, Veldink, Jan H, Wijmenga, Cisca, van Zwet, Erik W, Slagboom, P Eline, Jukema, J Wouter, Heijmans, Bastiaan T, BIOS Consortium, Dekkers, Koen F, van Iterson, Maarten, Slieker, Roderick C, Moed, Matthijs H, Bonder, Marc Jan, van Galen, Michiel, Mei, Hailiang, Zhernakova, Daria V, van den Berg, Leonard H, Deelen, Joris, van Dongen, Jenny, van Heemst, Diana, Hofman, Albert, Hottenga, Jouke J, van der Kallen, Carla J H, Schalkwijk, Casper G, Stehouwer, Coen D A, Tigchelaar, Ettje F, Uitterlinden, André G, Willemsen, Gonneke, Zhernakova, Alexandra, Franke, Lude, 't Hoen, Peter A C, Jansen, Rick, van Meurs, Joyce, Boomsma, Dorret I, van Duijn, Cornelia M, van Greevenbroek, Marleen M J, Veldink, Jan H, Wijmenga, Cisca, van Zwet, Erik W, Slagboom, P Eline, Jukema, J Wouter, Heijmans, Bastiaan T, and BIOS Consortium

Published
2016

115. Blood lipids influence DNA methylation in circulating cells

Author

Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Neurogenetica, Dekkers, Koen F, van Iterson, Maarten, Slieker, Roderick C, Moed, Matthijs H, Bonder, Marc Jan, van Galen, Michiel, Mei, Hailiang, Zhernakova, Daria V, van den Berg, Leonard H, Deelen, Joris, van Dongen, Jenny, van Heemst, Diana, Hofman, Albert, Hottenga, Jouke J, van der Kallen, Carla J H, Schalkwijk, Casper G, Stehouwer, Coen D A, Tigchelaar, Ettje F, Uitterlinden, André G, Willemsen, Gonneke, Zhernakova, Alexandra, Franke, Lude, 't Hoen, Peter A C, Jansen, Rick, van Meurs, Joyce, Boomsma, Dorret I, van Duijn, Cornelia M, van Greevenbroek, Marleen M J, Veldink, Jan H, Wijmenga, Cisca, van Zwet, Erik W, Slagboom, P Eline, Jukema, J Wouter, Heijmans, Bastiaan T, BIOS Consortium, Projectafdeling ALS, Brain, Regenerative Medicine and Stem Cells, ZL Neuromusculaire Ziekten Medisch, Neurogenetica, Dekkers, Koen F, van Iterson, Maarten, Slieker, Roderick C, Moed, Matthijs H, Bonder, Marc Jan, van Galen, Michiel, Mei, Hailiang, Zhernakova, Daria V, van den Berg, Leonard H, Deelen, Joris, van Dongen, Jenny, van Heemst, Diana, Hofman, Albert, Hottenga, Jouke J, van der Kallen, Carla J H, Schalkwijk, Casper G, Stehouwer, Coen D A, Tigchelaar, Ettje F, Uitterlinden, André G, Willemsen, Gonneke, Zhernakova, Alexandra, Franke, Lude, 't Hoen, Peter A C, Jansen, Rick, van Meurs, Joyce, Boomsma, Dorret I, van Duijn, Cornelia M, van Greevenbroek, Marleen M J, Veldink, Jan H, Wijmenga, Cisca, van Zwet, Erik W, Slagboom, P Eline, Jukema, J Wouter, Heijmans, Bastiaan T, and BIOS Consortium

Published
2016

116. Discriminatory ability of simple OGTT-based beta cell function indices for prediction of prediabetes and type 2 diabetes: the CODAM study

Author

den Biggelaar, Louise J. C. J., primary, Sep, Simone J. S., additional, Eussen, Simone J. P. M., additional, Mari, Andrea, additional, Ferrannini, Ele, additional, van Greevenbroek, Marleen M. J., additional, van der Kallen, Carla J. H., additional, Schalkwijk, Casper G., additional, Stehouwer, Coen D. A., additional, and Dagnelie, Pieter C., additional

Published
2016
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117. Identification of context-dependent expression quantitative trait loci in whole blood

Author

Zhernakova, Daria V, primary, Deelen, Patrick, additional, Vermaat, Martijn, additional, van Iterson, Maarten, additional, van Galen, Michiel, additional, Arindrarto, Wibowo, additional, van 't Hof, Peter, additional, Mei, Hailiang, additional, van Dijk, Freerk, additional, Westra, Harm-Jan, additional, Bonder, Marc Jan, additional, van Rooij, Jeroen, additional, Verkerk, Marijn, additional, Jhamai, P Mila, additional, Moed, Matthijs, additional, Kielbasa, Szymon M, additional, Bot, Jan, additional, Nooren, Irene, additional, Pool, René, additional, van Dongen, Jenny, additional, Hottenga, Jouke J, additional, Stehouwer, Coen D A, additional, van der Kallen, Carla J H, additional, Schalkwijk, Casper G, additional, Zhernakova, Alexandra, additional, Li, Yang, additional, Tigchelaar, Ettje F, additional, de Klein, Niek, additional, Beekman, Marian, additional, Deelen, Joris, additional, van Heemst, Diana, additional, van den Berg, Leonard H, additional, Hofman, Albert, additional, Uitterlinden, André G, additional, van Greevenbroek, Marleen M J, additional, Veldink, Jan H, additional, Boomsma, Dorret I, additional, van Duijn, Cornelia M, additional, Wijmenga, Cisca, additional, Slagboom, P Eline, additional, Swertz, Morris A, additional, Isaacs, Aaron, additional, van Meurs, Joyce B J, additional, Jansen, Rick, additional, Heijmans, Bastiaan T, additional, 't Hoen, Peter A C, additional, and Franke, Lude, additional

Published
2016
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120. Plasma Levels of Advanced Glycation Endproducts N-is an element of-(carboxymethyl)lysine, N-is an element of-(carboxyethyl)lysine, and Pentosidine Are not Independently Associated With Cardiovascular Disease in Individuals With or Without Type 2 Diabetes: The Hoorn and CODAM Studies

Author

Hanssen, Nordin M. J., Engelen, Lian, Ferreira, Isabel, Scheijen, Jean L. J. M., Huijberts, Maya S., van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Dekker, Jacqueline M., Nijpels, Giel, Stehouwer, Coen D. A., Schalkwijk, Casper G., Interne Geneeskunde, Promovendi CD, MUMC+: MA Alg Interne Geneeskunde (9), MUMC+: MA Interne Geneeskunde (3), Epidemiologie, MUMC+: KIO Kemta (9), and RS: CARIM School for Cardiovascular Diseases

Abstract

Objective: Experimental and histological data suggest a role for advanced glycation end products (AGEs) in cardiovascular disease (CVD), particularly in type 2 diabetes (T2DM). However, the epidemiological evidence of an adverse association between AGEs and CVD remains inconclusive. We therefore investigated, in individuals with various degrees of glucose metabolism, the associations of plasma AGEs with prevalent CVD. Research Design and Methods: We measured plasma levels of protein-bound N-is an element of-(carboxymethyl)lysine (CML), N-is an element of-(carboxyethyl)lysine (CEL), and pentosidine, in participants from two Dutch cohort studies (n = 1291, mean age 64.7 +/- 8.3 years, 45% women), including 573 individuals with normal glucose metabolism, 304 with impaired glucose metabolism, and 414 with T2DM. In addition, we measured free CML, CEL, and 5-hydro-5-methylimidazolone in a subset of participants (n = 554). Data were analyzed with multiple logistic or linear regression analyses. Results: CEL (32 [interquartile range: 2540 vs 28 [22-35] nmol/mmol lysine]) and pentosidine (0.53 [0.43-0.67] vs 0.48 [0.40-0.59] nmol/mmol lysine) as well as free CEL (48 [39-62] vs 45 [36-56] nmol/L) and 5-hydro-5-methylimidazolone (141 [96-209] vs 116 [84-165] nmol/L) were higher in individuals with vs without CVD, whereas protein-bound CML was lower (33 [27-38] vs 34 [29-39] nmol/mmol lysine). However, these differences disappeared after adjustment for confounders. The associations did not differ consistently between individuals with and without T2DM. Conclusions: We found no independent adverse associations of plasma AGEs with CVD in individuals with normal glucose metabolism, impaired glucose metabolism, and T2DM.

Published
2013

122. BclI glucocorticoid receptor polymorphism in relation to cardiovascular variables: the Hoorn and CODAM studies

Author

van Moorsel, Dirk, primary, van Greevenbroek, Marleen M J, additional, Schaper, Nicolaas C, additional, Henry, Ronald M A, additional, Geelen, Charlotte C, additional, van Rossum, Elisabeth F C, additional, Nijpels, Giel, additional, 't Hart, Leen M, additional, Schalkwijk, Casper G, additional, van der Kallen, Carla J H, additional, Sauerwein, Hans P, additional, Dekker, Jacqueline M, additional, Stehouwer, Coen D A, additional, and Havekes, Bas, additional

Published
2015
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123. Establishing reference values for central blood pressure and its amplification in a general healthy population and according to cardiovascular risk factors

Author

Herbert, Annie, Cruickshank, John Kennedy, Laurent, Stephane, Boutouyrie, Pierre, Shimada, Kazuyuki, Kario, Kazuomi, Miyashita, Hiroshi, Eguchi, Kazuo, Kohara, Katsuhiko, Tabara, Yasuharu, Imai, Yutaka, Ito, Sadayoshi, Hashimoto, Junichiro, Uchiba, Kiyoshi, Suzuki, Hiromichi, Takenaka, Tsuneo, Takazawa, Kenji, Kino, Mineko, Yamashina, Akira, Tomiyama, Hirofumi, Dohi, Yasuaki, Takase, Hiroyuki, Jouven, Xavier, Empana, Jean, Pannier, Bruno, Thomas, Frederique, Prescott, Eva, Janner, Julie, McEniery, Carmel, Cockcroft, John, Wilkinson, Ian, Roman, Mary, Devereux, Richard, Teal, Valerie, Townsend, Raymond, Vermeersch, Sebastian, Rietzschel, Ernst, Van Bortel, Luc, De Buyzere, Marc, Segers, Patrick, Gillebert, Thierry, Wang, Ji-Guang, Li, Yan, Lazar, Jason, Salciccioli, Louis, Cunha, Pedro, Oliveira, Pedro, Cotter, Jorge, Vila, Isabel, Sousa, Nuno, Chirinos, Julio, Medina-Lezama, Josefina, Weber, Thomas, Rammer, Martin, O'Rourke, M F, Bernd, Eber, Lassnig, Elisabeth, Porodko, Michael, Ammer, Marcus, Wassertheurer, Siegfried, Adji, Audrey, Rosenkranz, Stefan, Punzengruber, Christian, Kvas, Erich, Dufouil, Carole, Tzourio, Christophe, Nijpels, Giel, Dekker, Jacqueline, Stehouwer, Coen D, Ferreira, Isabel, Twisk, Jos, Smulders, Yvo, Van De Laar, Roel J, Van Der Kallen, Carla J. H, Van Greevenbroek, Marleen M. J, Schalkwijk, Casper, Vlachopoulos, Charalambos, Aznaouridis, Constantinos, Terentes-Printzios, Dimitrios, Xaplanteris, Panos, Stefanadis, Christodoulos, Herbert, Annie, Cruickshank, John Kennedy, Laurent, Stephane, Boutouyrie, Pierre, Shimada, Kazuyuki, Kario, Kazuomi, Miyashita, Hiroshi, Eguchi, Kazuo, Kohara, Katsuhiko, Tabara, Yasuharu, Imai, Yutaka, Ito, Sadayoshi, Hashimoto, Junichiro, Uchiba, Kiyoshi, Suzuki, Hiromichi, Takenaka, Tsuneo, Takazawa, Kenji, Kino, Mineko, Yamashina, Akira, Tomiyama, Hirofumi, Dohi, Yasuaki, Takase, Hiroyuki, Jouven, Xavier, Empana, Jean, Pannier, Bruno, Thomas, Frederique, Prescott, Eva, Janner, Julie, McEniery, Carmel, Cockcroft, John, Wilkinson, Ian, Roman, Mary, Devereux, Richard, Teal, Valerie, Townsend, Raymond, Vermeersch, Sebastian, Rietzschel, Ernst, Van Bortel, Luc, De Buyzere, Marc, Segers, Patrick, Gillebert, Thierry, Wang, Ji-Guang, Li, Yan, Lazar, Jason, Salciccioli, Louis, Cunha, Pedro, Oliveira, Pedro, Cotter, Jorge, Vila, Isabel, Sousa, Nuno, Chirinos, Julio, Medina-Lezama, Josefina, Weber, Thomas, Rammer, Martin, O'Rourke, M F, Bernd, Eber, Lassnig, Elisabeth, Porodko, Michael, Ammer, Marcus, Wassertheurer, Siegfried, Adji, Audrey, Rosenkranz, Stefan, Punzengruber, Christian, Kvas, Erich, Dufouil, Carole, Tzourio, Christophe, Nijpels, Giel, Dekker, Jacqueline, Stehouwer, Coen D, Ferreira, Isabel, Twisk, Jos, Smulders, Yvo, Van De Laar, Roel J, Van Der Kallen, Carla J. H, Van Greevenbroek, Marleen M. J, Schalkwijk, Casper, Vlachopoulos, Charalambos, Aznaouridis, Constantinos, Terentes-Printzios, Dimitrios, Xaplanteris, Panos, and Stefanadis, Christodoulos

Abstract

Aims: Estimated central systolic blood pressure (cSBP) and amplification (Brachial SBP-cSBP) are non-invasive measures potentially prognostic of cardiovascular (CV) disease. No worldwide, multiple-device reference values are available. We aimed to establish reference values for a worldwide general population standardizing between the different available methods of measurement. How these values were significantly altered by cardiovascular risk factors (CVRFs) was then investigated. Methods and results: Existing data from population surveys and clinical trials were combined, whether published or not. Reference values of cSBP and amplification were calculatedas percentiles for 'Normal' (no CVRFs) and 'Reference' (any CVRFs) populations. We included 45 436 subjects out of 82 930 that were gathered from 77 studies of 53 centres. Included subjects were apparently healthy, not treated for hypertension or dyslipidaemia, and free from overt CV disease and diabetes. Values of cSBP and amplification were stratified by brachial blood pressure categories and age decade in turn, both being stratifiedbysex. Amplification decreased with age and more so in males than in females. Sex was the most powerful factor associated with amplification with 6.6 mmHg (5.8-7.4) higher amplification in males than in females. Amplification was marginally but significantly influenced by CVRFs, with smoking and dyslipidaemia decreasing amplification, but increased with increasing levels of blood glucose. Conclusion: Typical values of cSBP and amplification in a healthy population and a population free of traditional CVRFs are now available according to age, sex, and brachial BP, providing values included from different devices with a wide geographical representation. Amplification is significantly influenced by CVRFs, but differently in men and women.

Published
2014

124. Iron metabolism is prospectively associated with insulin resistance and glucose intolerance over a 7-year follow-up period: the CODAM study

Author

Wlazlo, Nick, primary, van Greevenbroek, Marleen M. J., additional, Ferreira, Isabel, additional, Jansen, Eugene H. J. M., additional, Feskens, Edith J. M., additional, van der Kallen, Carla J. H., additional, Schalkwijk, Casper G., additional, Bravenboer, Bert, additional, and Stehouwer, Coen D. A., additional

Published
2014
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125. Blood Metabolomic Measures Associate With Present and Future Glycemic Control in Type 2 Diabetes.

Author

't Hart, Leen M, Vogelzangs, Nicole, Mook-Kanamori, Dennis O, Brahimaj, Adela, Nano, Jana, van der Heijden, Amber A W A, Willems van Dijk, Ko, Slieker, Roderick C, Steyerberg, Ewout W, Ikram, M Arfan, Beekman, Marian, Boomsma, Dorret I, van Duijn, Cornelia M, Slagboom, P Eline, Stehouwer, Coen D A, Schalkwijk, Casper G, Arts, Ilja C W, Dekker, Jacqueline M, Dehghan, Abbas, Muka, Taulant, van der Kallen, Carla J H, Nijpels, Giel, and van Greevenbroek, Marleen M J

Abstract

We studied whether blood metabolomic measures in people with type 2 diabetes (T2D) are associated with insufficient glycemic control and whether this association is influenced differentially by various diabetes drugs. We then tested whether the same metabolomic profiles were associated with the initiation of insulin therapy.

Published
2018
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126. Multiple Inflammatory Biomarker Detection in a Prospective Cohort Study: A Cross-Validation between Well-Established Single-Biomarker Techniques and an Electrochemiluminescense-Based Multi-Array Platform

Author

van Bussel, Bas, Ferreira, Isabel, Van De Waarenburg, Marjo, Van Greevenbroek, Marleen M. J, Van Der Kallen, Carla J. H, Henry, Ronald, Feskens, Edith, Stehouwer, Coen D, Schalkwijk, Casper, van Bussel, Bas, Ferreira, Isabel, Van De Waarenburg, Marjo, Van Greevenbroek, Marleen M. J, Van Der Kallen, Carla J. H, Henry, Ronald, Feskens, Edith, Stehouwer, Coen D, and Schalkwijk, Casper

Abstract

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.

Published
2013

127. Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin: The Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study

Author

Wlazlo, Nick, Van Greevenbroek, Marleen M. J, Ferreira, Isabel, Jansen, Eugene, Feskens, Edith, Van Der Kallen, Carla J. H, Schalkwijk, Casper, Bravenboer, Bert, Stehouwer, Coen D, Wlazlo, Nick, Van Greevenbroek, Marleen M. J, Ferreira, Isabel, Jansen, Eugene, Feskens, Edith, Van Der Kallen, Carla J. H, Schalkwijk, Casper, Bravenboer, Bert, and Stehouwer, Coen D

Abstract

OBJECTIVE-Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism-related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin. RESEARCH DESIGN AND METHODS-Serum ferritin, transferrin, total iron, non- transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers. RESULTS-Serum ferritin (b = 1.00% increase in adipocyte IR per 10 mg/L [95% CI 0.66- 1.34]), transferrin (4.18% per 0.1 g/L [2.88-5.50] ), total iron (1.36% per mmol/L [0.61-2.12]), and NTBI (5.14% per mmol/L [1.88-8.52] ) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P < 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P < 0.01). CONCLUSIONS-The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM.

Published
2013

128. The diagnosis of non-alcoholic fatty liver disease

Author

Wlazlo, Nick, Van Greevenbroek, Marleen M. J, Ferreira, Isabel, Bravenboer, Bert, Stehouwer, Coen D, Wlazlo, Nick, Van Greevenbroek, Marleen M. J, Ferreira, Isabel, Bravenboer, Bert, and Stehouwer, Coen D

Published
2012

129. The association between the-374T/A polymorphism of the receptor for advanced glycation endproducts gene and blood pressure and arterial stiffness is modified by glucose metabolism status: The Hoorn and CoDAM studies

Author

Engelen, Lian, Ferreira, Isabel, Gaens, Katrien, Henry, Ronald, Dekker, Jacqueline, Nijpels, Giel, Heine, Robert J, Hart, Leen, Van Greevenbroek, Marleen M. J, Van Der Kallen, Carla J. H, Blaak, Ellen, Feskens, Edith, ten Cate, Hugo, Stehouwer, Coen D, Schalkwijk, Casper, Engelen, Lian, Ferreira, Isabel, Gaens, Katrien, Henry, Ronald, Dekker, Jacqueline, Nijpels, Giel, Heine, Robert J, Hart, Leen, Van Greevenbroek, Marleen M. J, Van Der Kallen, Carla J. H, Blaak, Ellen, Feskens, Edith, ten Cate, Hugo, Stehouwer, Coen D, and Schalkwijk, Casper

Abstract

Objectives: Receptor for advanced glycation endproducts (RAGE)-ligand interaction may lead to vascular complications. Genetic variation in RAGE has been shown to alter expression, activity of RAGE or both. We, therefore, investigated whether RAGE single-nucleotide polymorphisms (SNPs) and haplotypes were associated with vascular disease. Methods: Nine tag SNPs that cover the common RAGE gene variation were genotyped in 1291 individuals from two Dutch population-based cohort studies, aged 64.5 ± 8.6 years, with normal glucose metabolism (44%), impaired glucose metabolism (23%) or type 2 diabetes mellitus (33%). We used multiple regression analyses to compare prevalent cardiovascular disease and markers of atherosclerosis, blood pressure and arterial stiffness across genotypes, and examine effect modification by glucose metabolism status. Results: In unstratified analyses, no consistent associations between RAGE SNPs and prevalent cardiovascular disease and markers of atherosclerosis were found. However, the AA genotype of SNP rs1800624 (-374T/A) was consistently associated with lower SBP [-5.0 mmHg (95% confidence interval-10.4 to 0.3)] and DBP [-4.2 (-7.2 to-1.3)] , pulse pressure [-0.8 (-5.0 to 3.4)] as well as with less arterial stiffness [-0.56 SD (-1.04 to-0.09)] in individuals with normal glucose metabolism, but with higher SBP [6.2 (0.9-11.5)], DBP [2.1 (-0.7 to 5.0)] and pulse pressure [4.1 (-0.2 to 8.4)] in individuals with impaired glucose metabolism or type 2 diabetes mellitus (P for interaction ≤0.05 in all analyses). Similar results were found for a haplotype that includes the-374A allele. Conclusion: In individuals with normal glucose metabolism, the-374A allele of the RAGE gene is protectively associated with blood pressure and arterial stiffness, whereas in individuals with impaired glucose metabolism or type 2 diabetes mellitus, it is adversely associated with these variables. 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Published
2010

131. A Common Gene Variant in Glucokinase Regulatory Protein Interacts With Glucose Metabolism on Diabetic Dyslipidemia: the Combined CODAM and Hoorn Studies.

Author

Simons, Nynke, Dekker, Jacqueline M., van Greevenbroek, Marleen M. J., Nijpels, Giel, 't Hart, Leen M., van der Kallen, Carla J. H., Schalkwijk, Casper G., Schaper, Nicolaas C., Stehouwer, Coen D. A., and Brouwers, Martijn C. G. J.

Subjects
TYPE 2 diabetes, GLUCOKINASE, DYSLIPIDEMIA, ATHEROSCLEROSIS, TRIGLYCERIDES, ALLELES, BLOOD sugar, BODY weight, CARRIER proteins, GENETICS, GLYCOSYLATED hemoglobin, HIGH density lipoproteins, HYPERLIPIDEMIA, LIVER, LONGITUDINAL method, LOW density lipoproteins, REGRESSION analysis, TRANSFERASES, BODY mass index, WAIST circumference
Abstract

Objective: Small molecules that disrupt the binding between glucokinase and glucokinase regulatory protein (GKRP) are potential new glucose-lowering targets. They stimulate hepatic glucose disposal by increasing glucokinase activity in the liver. It can, however, be anticipated that increased hepatic glucokinase activity might be accompanied by the development of hypertriglyceridemia, particularly in type 2 diabetes. We examined whether the strength of association between rs1260326, a common, functional gene variant in GKRP, and plasma lipids is affected by glucose metabolism.Research Design and Methods: rs1260326 was genotyped in subjects with normal glucose metabolism (n = 497), subjects with impaired glucose metabolism (n = 256), and patients with type 2 diabetes (n = 351) in the combined Hoorn and Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) studies.Results: The strength of association between the rs1260326 minor T allele and plasma triglycerides increased from normal glucose metabolism to impaired glucose metabolism to type 2 diabetes (P for interaction = 0.002). The inverse relation between rs1260326 and plasma HDL cholesterol was again most prominent in type 2 diabetes (P for interaction = 0.004). Similar trends were observed when the Hoorn and CODAM cohorts were analyzed separately. Comparable results were obtained when glucose metabolism strata were replaced by continuous indices of glucose metabolism, i.e., HbA1c and fasting plasma glucose.Conclusions: These findings illustrate that common gene variants, such as rs1260326, can have substantial effect sizes when they are studied in specific populations, such as type 2 diabetes. Moreover, our results shed light on potential side effects of small molecule disruptors of the GKRP-glucokinase complex, especially when glucose control is suboptimal. [ABSTRACT FROM AUTHOR]

Published
2016
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133. Genetic and environmental influences interact with age and sex in shaping the human methylome.

Author

van Dongen, Jenny, Nivard, Michel G., Willemsen, Gonneke, Hottenga, Jouke-Jan, Helmer, Quinta, Dolan, Conor V., Ehli, Erik A., Davies, Gareth E., van Iterson, Maarten, Breeze, Charles E., Beck, Stephan, Eka Suchiman, H., Jansen, Rick, van Meurs, Joyce B., Heijmans, Bastiaan T., Eline Slagboom, P., Boomsma, Dorret I., Hoen, Peter A. C. 't, Pool, René, and van Greevenbroek, Marleen M. J.

Published
2016
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134. Multiple Inflammatory Biomarker Detection in a Prospective Cohort Study: A Cross-Validation between Well-Established Single-Biomarker Techniques and an Electrochemiluminescense-Based Multi-Array Platform

Author

van Bussel, Bas C. T., primary, Ferreira, Isabel, additional, van de Waarenburg, Marjo P. H., additional, van Greevenbroek, Marleen M. J., additional, van der Kallen, Carla J. H., additional, Henry, Ronald M. A., additional, Feskens, Edith J. M., additional, Stehouwer, Coen D. A., additional, and Schalkwijk, Casper G., additional

Published
2013
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135. The cross-sectional association between insulin resistance and circulating complement C3 is partly explained by plasma alanine aminotransferase, independent of central obesity and general inflammation (the CODAM study)

Author

van Greevenbroek, Marleen M. J., primary, Jacobs, Marjon, additional, van der Kallen, Carla J. H., additional, Vermeulen, Vicky M. M-J., additional, Jansen, Eugene H. J. M., additional, Schalkwijk, Casper G., additional, Ferreira, Isabel, additional, Feskens, Edith J. M., additional, and Stehouwer, Coen D. A., additional

Published
2010
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136. The association between the metabolic syndrome and peripheral, but not coronary, artery disease is partly mediated by endothelial dysfunction: the CODAM study

Author

Jacobs, Marjon, primary, van Greevenbroek, Marleen M. J., additional, van der Kallen, Carla J. H., additional, Ferreira, Isabel, additional, Blaak, Ellen E., additional, Feskens, Edith J. M., additional, Jansen, Eugène H. J. M., additional, Schalkwijk, Casper G., additional, and Stehouwer, Coen D. A., additional

Published
2010
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138. Parabolic relationship between plasma triacylglycerols and LDL-cholesterol in familial combined hyperlipidaemia: the multiple-type hyperlipidaemia explained?

Author

Brouwers, Martijn C. G. J., primary, de Graaf, Jacqueline, additional, van Greevenbroek, Marleen M. J., additional, Georgieva, Anna M., additional, van der Kallen, Carla J. H., additional, ter Avest, Ewoud, additional, Stehouwer, Coen D. A., additional, Stalenhoef, Anton F., additional, and de Bruin, Tjerk W. A., additional

Published
2008
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142. A Healthy Diet Is Associated with Less Endothelial Dysfunction and Less Low-Grade Inflammation over a 7-Year Period in Adults at Risk of Cardiovascular Disease.

Author

van Bussel, Bas C. T., Henry, Ronald M. A., Ferreira, Isabel, van Greevenbroek, Marleen M. J., van der Kallen, Carla J. H., Twisk, Jos W. R., Feskens, Edith J. M., Schalkwijk, Casper G., and Stehouwer, Coen D. A.

Subjects
DIET research, ENDOTHELIUM diseases, CARDIOVASCULAR disease prevention, CARDIOVASCULAR diseases risk factors, DIET in disease, INFLAMMATION
Abstract

Background: A healthy diet rich in fish, fruit, and vegetables, but moderate in alcohol and low in dairy products and meat, has been associated with a lower rate of incident cardiovascular disease (CVD). The underlying mechanisms, however, remain unclear. Endothelial dysfunction and low-grade inflammation play important roles in CVD. A healthy diet might modify these phenomena. Objective: We investigated the associations between the above food groups and overall biomarker scores of endothelial dysfunction and low-grade inflammation in a 7-y longitudinal study. Methods: Using longitudinal data from 557 participants at increased CVD risk from the CODAM (Cohort on Diabetes and Atherosclerosis Maastricht) Study, we assessed diet intake by food-frequency questionnaire and measured plasma biomarkers of endothelial dysfunction [von Willebrand factor, soluble vascular cell adhesion molecule 1, soluble endothelial selectin, soluble thrombomodulin, soluble intercellular adhesion molecule 1 (sICAM-1)] and low-grade inflammation [C-reactive protein, serum amyloid A, interleukin (IL)-6, IL-8, tumor necrosis factor a, and sICAM-1]. At baseline, participants were aged 59.6 ± 6.9 y. Measurements were performed then and after 7 y. Biomarkers were combined into overall scores (sum of z scores; higher scores indicating worse function). Longitudinal data were analyzed with generalized estimating equations and adjusted for sex, age, glucose metabolism, energy intake, body mass index, physical activity, alcohol consumption, and smoking. Results: Higher consumption of fish (per 100 g/wk), but not total consumption of vegetables, fruit, alcohol-containing beverages, dairy products, or meat, was associated with a lower overall endothelial dysfunction score over 7 y (β: 20.027; 95% CI: 20.051, 20.004). No associations were observed with the overall low-grade inflammation score. Further food component analyses indicated that consumption of more lean fish (per 100 g/wk) and raw vegetables (per 100 g/d), and fewer high-fat dairy products (per 100 g/d) was associated with less endothelial dysfunction [(β: -0.038; 95% CI: -0.072, -0.005), (β: -0.095; 95% CI: -0.191, 0.000), and (β: -0.070; 95% CI: -0.131, -0.009), respectively]. Consumption of more fresh fruit (per 100 g/d), wine (per 100 mL/wk), and poultry (per 100 g/d), and fewer high-fat dairy products (per 100 g/d) was associated with less low-grade inflammation [(b: 20.074; 95% CI: 20.133, 20.015), (β: -0.006; 95% CI: -0.013, 0.001), (β: -0.247; 95% CI: -0.479, -0.014), and (β: -0.100; 95% CI: 20.182, 20.019), respectively]. Conclusion: These data suggest that the dietary modification of endothelial dysfunction and low-grade inflammation, processes that are important in atherothrombosis, is possible. [ABSTRACT FROM AUTHOR]

Published
2015
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143. Complement Factor 3 Is Associated With Insulin Resistance and With Incident Type 2 Diabetes Over a 7-Year Follow-up Period: The CODAM Study.

Author

Wlazlo, Nick, van Greevenbroek, Marleen M. J., Ferreira, Isabel, Feskens, Edith J. M., van der Kallen, Carla J. H., Schalkwijk, Casper G., Bravenboer, Bert, and Stehouwer, Coen D. A.

Subjects
*INSULIN resistance, *TYPE 2 diabetes risk factors, *GLUCOSE tolerance tests, *HOMEOSTASIS, *FAT cells, *METABOLIC disorders
Abstract

OBJECTIVE Immune dysregulation can affect insulin resistance (IR) and b-cell function and hence contribute to development of type 2 diabetes mellitus (T2DM). The complement system, as a regulator of immune and in flammatory homeostasis, may be a relevant contributor therein. However, longitudinal studies focusing on complement as a determinant of T2DMand IR are scarce. Therefore, we prospectively investigated the association of plasma complement factor 3 (C3) with (estimates of) IR in muscle, liver, and adipocytes, as well as with glucose tolerance, including incident T2DM. RESEARCH DESIGN AND METHODS Fasting C3, nonesterified fatty acids, glucose, and insulin (the latter two during oral glucose tolerance tests) were measured at baseline (n = 545) and after 7 years of follow-up (n = 394) in a prospective cohort study. RESULTS Over the 7-year period, C3 levels (per 0.1 g/L) were longitudinally associated with higher homeostasis model assessment of IR (HOMA2-IR; β = 15.2%[95% CI 12.9-17.6]), hepatic IR (β = 6.1%[95% CI 4.7-7.4]), adipocyte IR (β = 16.0% [95%CI 13.0-19.1]), fasting glucose (β = 1.8% [95% CI 1.2-2.4]), 2-h glucose (β = 5.2% [95% CI 3.7-6.7]), and area under the curve for glucose (β = 3.6% [95% CI 2.7-4.6]). In addition, greater changes in C3 (per 0.1 g/L) were associated with greater changes in HOMA2-IR (β = 0.08 [95% CI 0.02-0.15]) and greater changes in hepatic IR (β = 0.87 [95% CI 0.12-1.61]) over 7 years, but not glucose tolerance. Moreover, baseline C3 was associated with the 7-year incidence of T2DM (odds ratio 1.5 [95% CI 1.1-2.0]). CONCLUSIONS Changes in C3 were associated with changes in several measures of IR and may reflect progression of metabolic dysregulation, which eventually leads to abnormalities in glucose tolerance and T2DM. [ABSTRACT FROM AUTHOR]

Published
2014
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144. Genetically defined elevated homocysteine levels do not result in widespread changes of DNA methylation in leukocytes

Author

Mandaviya, Pooja R., Aïssi, Dylan, Kühnel, Brigitte, Marioni, Riccardo E., Truong, Vinh, Stolk, Lisette, Beekman, Marian, Bonder, Marc Jan, Franke, Lude, Gieger, Christian, Huan, Tianxiao, Ikram, M. Arfan, Kunze, Sonja, Liang, Liming, Lindemans, Jan, Liu, Chunyu, McRae, Allan F., Mendelson, Michael M., Müller-Nurasyid, Martina, Peters, Annette, Slagboom, P. Eline, Starr, John M., Trégouët, David-Alexandre, Uitterlinden, André G., van Greevenbroek, Marleen M. J., van Heemst, Diana, van Iterson, Maarten, Wells, Philip S., Yao, Chen, Deary, Ian J., Gagnon, France, Heijmans, Bastiaan T., Levy, Daniel, Morange, Pierre-Emmanuel, Waldenberger, Melanie, Heil, Sandra G., van Meurs, Joyce B. J., and Joehanes, Roby

Subjects
Biology and life sciences, Cell biology, Chromosome biology, Chromatin, Chromatin modification, DNA methylation, Genetics, Epigenetics, Gene expression, DNA, DNA modification, Biochemistry, Nucleic acids, Physical Sciences, Chemistry, Chemical Reactions, Methylation, Mathematical and Statistical Techniques, Statistical Methods, Meta-Analysis, Mathematics, Statistics (Mathematics), Biology and Life Sciences, Molecular Genetics, Molecular Biology, Genetic Loci, Cell Biology, Cellular Types, Animal Cells, Blood Cells, White Blood Cells, Immune Cells, Immunology, Medicine and Health Sciences, Chromosome Biology, Chromosomes, Autosomes, Chromosome Pairs, Social Sciences, Sociology, Consortia
Abstract

Background: DNA methylation is affected by the activities of the key enzymes and intermediate metabolites of the one-carbon pathway, one of which involves homocysteine. We investigated the effect of the well-known genetic variant associated with mildly elevated homocysteine: MTHFR 677C>T independently and in combination with other homocysteine-associated variants, on genome-wide leukocyte DNA-methylation. Methods: Methylation levels were assessed using Illumina 450k arrays on 9,894 individuals of European ancestry from 12 cohort studies. Linear-mixed-models were used to study the association of additive MTHFR 677C>T and genetic-risk score (GRS) based on 18 homocysteine-associated SNPs, with genome-wide methylation. Results: Meta-analysis revealed that the MTHFR 677C>T variant was associated with 35 CpG sites in cis, and the GRS showed association with 113 CpG sites near the homocysteine-associated variants. Genome-wide analysis revealed that the MTHFR 677C>T variant was associated with 1 trans-CpG (nearest gene ZNF184), while the GRS model showed association with 5 significant trans-CpGs annotated to nearest genes PTF1A, MRPL55, CTDSP2, CRYM and FKBP5. Conclusions: Our results do not show widespread changes in DNA-methylation across the genome, and therefore do not support the hypothesis that mildly elevated homocysteine is associated with widespread methylation changes in leukocytes., Version of Record

Published
2017
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145. Iron MetabolismIs Associated With Adipocyte Insulin Resistance and Plasma Adiponectin.

Author

WLAZLO, NICK, VAN GREEVENBROEK, MARLEEN M. J., FERREIRA, ISABEL, JANSEN, EUGENE H. J. M., FESKENS, EDITH J. M., VAN DER KALLEN, CARLA J. H., SCHALKWIJK, CASPER G., BRAVENBOER, BERT, and STEHOUWER, COEN D. A.

Subjects
*INSULIN resistance, *TYPE 2 diabetes, *FAT cells, *DIABETES complications, *TRANSFERRIN, *IRON metabolism
Abstract

OBJECTIVE--Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism--related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin. RESEARCH DESIGN AND METHODS--Serum ferritin, transferrin, total iron, non- transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers. RESULTS--Serum ferritin (β = 1.00% increase in adipocyte IR per 10 µg/L [95% CI 0.66- 1.34]), transferrin (4.18% per 0.1 g/L [2.88-5.50]), total iron (1.36% per µmol/L [0.61-2.12]), and NTBI (5.14% per µmol/L [1.88-8.52]) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P <0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P <0.01). CONCLUSIONS--The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM. [ABSTRACT FROM AUTHOR]

Published
2013
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146. Iron metabolism is associated with adipocyte insulin resistance and plasma adiponectin: the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study.

Author

Wlazlo N, van Greevenbroek MM, Ferreira I, Jansen EH, Feskens EJ, van der Kallen CJ, Schalkwijk CG, Bravenboer B, Stehouwer CD, Wlazlo, Nick, van Greevenbroek, Marleen M J, Ferreira, Isabel, Jansen, Eugene H J M, Feskens, Edith J M, van der Kallen, Carla J H, Schalkwijk, Casper G, Bravenboer, Bert, and Stehouwer, Coen D A

Abstract

Objective: Adipocyte insulin resistance (IR) is a key feature early in the pathogenesis of type 2 diabetes mellitus (T2DM), and although scarce, data in the literature suggest a direct role for iron and iron metabolism-related factors in adipose tissue function and metabolism. Serum ferritin and transferrin were shown to be associated with muscle insulin resistance (IR) and T2DM, but little is known about the role of iron metabolism on adipose tissue. We therefore investigated whether markers of iron metabolism were associated with adipocyte IR and plasma adiponectin.Research Design and Methods: Serum ferritin, transferrin, total iron, non-transferrin-bound iron (NTBI), transferrin saturation, and plasma adiponectin were determined in 492 individuals. Adipocyte IR was defined by the product of fasting insulin and nonesterified fatty acids (NEFAs). Using linear regression analyses, we investigated the difference in adipocyte IR or adiponectin (in %) according to differences in iron metabolism markers.Results: Serum ferritin (β = 1.00% increase in adipocyte IR per 10 μg/L [95% CI 0.66-1.34]), transferrin (4.18% per 0.1 g/L [2.88-5.50]), total iron (1.36% per μmol/L [0.61-2.12]), and NTBI (5.14% per μmol/L [1.88-8.52]) were associated with adipocyte IR after adjustment for several covariates, including inflammatory markers. All markers of iron metabolism were also associated with NEFAs (all P < 0.01). In addition, ferritin and transferrin were inversely associated with adiponectin (both P < 0.01).Conclusions: The observed associations of several markers of iron metabolism with adipocyte IR and adiponectin suggest that factors related to iron and iron metabolism may contribute to adipocyte IR early in the pathogenesis of T2DM. [ABSTRACT FROM AUTHOR]

Published
2013
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147. Increased arterial stiffness in familial combined hyperlipidemia.

Author

Brouwers MC, Reesink KD, van Greevenbroek MM, Meinders JM, van der Kallen CJ, Schaper N, Hoeks AP, Stehouwer CD, Brouwers, Martijn C G J, Reesink, Koen D, van Greevenbroek, Marleen M J, Meinders, Jan M, van der Kallen, Carla J H, Schaper, Nicolaas, Hoeks, Arnold P G, and Stehouwer, Coen D A

Published
2009
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148. Effects of interacting networks of cardiovascular risk genes on the risk of type 2 diabetes mellitus (the CODAM study).

Author

van Greevenbroek, Marleen M. J., Jian Zhang, van der Kallen, Carla J. H., Schiffers, Paul M. H., Feskens, Edith J. M., and de Bruin, Tjerk W. A.

Subjects
*CARDIOVASCULAR diseases, *GENETIC polymorphisms, *TYPE 2 diabetes, *DIABETES, *GENES, *MEDICAL genetics
Abstract

Background: Genetic dissection of complex diseases requires innovative approaches for identification of disease-predisposing genes. A well-known example of a human complex disease with a strong genetic component is Type 2 Diabetes Mellitus (T2DM). Methods: We genotyped normal-glucose-tolerant subjects (NGT; n = 54), subjects with an impaired glucose metabolism (IGM; n = 111) and T2DM (n = 142) subjects, in an assay (designed by Roche Molecular Systems) for detection of 68 polymorphisms in 36 cardiovascular risk genes. Using the single-locus logistic regression and the so-called haplotype entropy, we explored the possibility that (1) common pathways underlie development of T2DM and cardiovascular disease -- which would imply enrichment of cardiovascular risk polymorphisms in "pre-diabetic" (IGM) and diabetic (T2DM) populations- and (2) that gene-gene interactions are relevant for the effects of risk polymorphisms. Results: In single-locus analyses, we showed suggestive association with disturbed glucose metabolism (i.e. subjects who were either IGM or had T2DM), or with T2DM only. Moreover, in the haplotype entropy analysis, we identified a total of 14 pairs of polymorphisms (with a false discovery rate of 0.125) that may confer risk of disturbed glucose metabolism, or T2DM only, as members of interacting networks of genes. We substantiated gene-gene interactions by showing that these interacting networks can indeed identify potential "disease-predisposing allele-combinations". Conclusion: Gene-gene interactions of cardiovascular risk polymorphisms can be detected in prediabetes and T2DM, supporting the hypothesis that common pathways may underlie development of T2DM and cardiovascular disease. Thus, a specific set of risk polymorphisms, when simultaneously present, increases the risk of disease and hence is indeed relevant in the transfer of risk. [ABSTRACT FROM AUTHOR]

Published
2008
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149. The circulating PBEF/NAMPT/visfatin level is associated with a beneficial blood lipid profile.

Author

Ping Wang, van Greevenbroek, Marleen M. J., Bouwman, Freek G., Brouwers, Martijn C. G. J., van der Kallen, Carla J. H., Smit, Egbert, Keijer, Jaap, and Mariman, Edwin C. M.

Subjects
B cells, FAT cells, TRANSFERASES, ENZYMES, INSULIN
Abstract

Visfatin with the official gene name pre-B cell colony-enhancing factor 1 (PBEF) and the protein name nicotinamide phosphoribosyltransferase (NAMPT) is a recently discovered adipocyte-secreted protein that was shown by some to be associated with visceral fat and insulin resistance. To explore the link between PBEF/NAMPT/visfatin and lipid metabolism, we analyzed the relation of its plasma level with several parameters of adiposity, insulin resistance and the circulating blood lipid profile in a group of general population ( n = 40) and a group of subjects who are genetically predisposed to insulin resistance and hyperlipidemia ( n = 35). In both groups and pooled cohort, PBEF/NAMPT/visfatin lacked association with whole body adiposity, but correlated positively with HDL-cholesterol and negatively with triglycerides. The data suggested a negative correlation of the PBEF level with visceral fat and insulin resistance. But this negative correlation completely disappeared after adjustment for lipid profile. We concluded that circulating PBEF/NAMPT/visfatin level is an indicator of beneficial lipid profile in non-diabetic Caucasian subjects. The relation to lipid metabolism does not depend on visceral obesity and insulin resistance, but may be linked to its enzymatic function in NAD metabolism. [ABSTRACT FROM AUTHOR]

Published
2007
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150. Heritability and genetic loci of fatty liver in familial combined hyperlipidemia

Author

Brouwers, Martijn C. G. J., Cantor, Rita M., Kono, Naoko, Yoon, Jeong lim, van der Kallen, Carla J. H., Bilderbeek-Beckers, Monique A. L., van Greevenbroek, Marleen M. J., Lusis, Aldons J., and de Bruin, Tjerk W. A.

Abstract

VLDL overproduction, a process that is driven by an excess amount of hepatic fat, is a well-documented feature of familial combined hyperlipidemia (FCHL). The aims of this study were to investigate whether fatty liver, measured with ultrasound and as plasma alanine aminotransferase (ALT) levels, develops against a genetic background in FCHL and to identify chromosomal loci that are linked to these traits. In total, 157 FCHL family members and 20 spouses participated in this study. Radiological evidence of fatty liver was more prevalent not only in FCHL probands (40%) but also in their relatives (35%) compared with spouses (15%) (P < 0.05). Heritability calculations revealed that 20–36% of the variability in ALT levels could be attributed to genetic factors. Nonparametric quantitative trait locus (QTL) analysis revealed three significant (P < 0.001) loci with either the ultrasound or the ALT trait in the male sample: 1q42.3, 7p12-21, and 22p13-q11; none was found in the female sample or the entire group. Of these QTLs, the 7p region was consistent over time, because reanalysis with ALT levels that were determined during a visit 5 years earlier yielded similar results. This study shows that fatty liver is a heritable aspect of FCHL. Replication of particularly the 7p region is awaited.

Published
2006

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