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2. Disease severity-based subgrouping of type 2 diabetes does not parallel differences in quality of life: the Maastricht Study

Author

Werkman, Nikki C. C., García-Sáez, Gema, Nielen, Johannes T. H., Tapia-Galisteo, Jose, Somolinos-Simón, Francisco J., Hernando, Maria E., Wang, Junfeng, Jiu, Li, Goettsch, Wim G., van der Kallen, Carla J. H., Koster, Annemarie, Schalkwijk, Casper G., de Vries, Hein, de Vries, Nanne K., Eussen, Simone J. P. M., Driessen, Johanna H. M., and Stehouwer, Coen D. A.

Published
2024
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4. (Pre)diabetes and a higher level of glycaemic measures are continuously associated with corneal neurodegeneration assessed by corneal confocal microscopy: the Maastricht Study

Author

Mokhtar, Sara B. A., van der Heide, Frank C. T., Oyaert, Karel A. M., van der Kallen, Carla J. H., Berendschot, Tos T. J. M., Scarpa, Fabio, Colonna, Alessia, de Galan, Bastiaan E., van Greevenbroek, Marleen M. J., Dagnelie, Pieter C., Schalkwijk, Casper G., Nuijts, Rudy M. M. A., Schaper, Nicolaas C., Kroon, Abraham A., Schram, Miranda T., Webers, Carroll A. B., and Stehouwer, Coen D. A.

Published
2023
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6. Alcohol consumption and microvascular dysfunction: a J-shaped association: The Maastricht Study

Author

van der Heide, Frank C. T., Eussen, Simone J. P. M., Houben, Alfons J. H. M., Henry, Ronald M. A., Kroon, Abraham A., van der Kallen, Carla J. H., Dagnelie, Pieter C., van Dongen, Martien C. J. M., Berendschot, Tos T. J. M., Schouten, Jan S. A. G., Webers, Carroll A. B., van Greevenbroek, Marleen M. J., Wesselius, Anke, Schalkwijk, Casper G., Koster, Annemarie, Jansen, Jacobus F. A., Backes, Walter H., Beulens, Joline W. J., and Stehouwer, Coen D. A.

Published
2023
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7. Lower heart rate variability, an index of worse autonomic function, is associated with worse beta cell response to a glycemic load in vivo—The Maastricht Study

Author

Rinaldi, Elisabetta, van der Heide, Frank CT, Bonora, Enzo, Trombetta, Maddalena, Zusi, Chiara, Kroon, Abraham A, Schram, Miranda T, van der Kallen, Carla JH, Wesselius, Anke, Bonadonna, Riccardo, Mari, Andrea, Schalkwijk, Casper G, van Greevenbroek, Marleen MJ, and Stehouwer, Coen DA

Published
2023
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8. Associations between plasma sulfur amino acids and specific fat depots in two independent cohorts: CODAM and The Maastricht Study

Author

Tore, Elena C., Elshorbagy, Amany K., Bakers, Frans C. H., Brouwers, Martijn C. G. J., Dagnelie, Pieter C., Eussen, Simone J. P. M., Jansen, Jacobus F. A., Kooi, M. Eline, Kusters, Yvo H. A. M., Meex, Steven J. R., Olsen, Thomas, Refsum, Helga, Retterstøl, Kjetil, Schalkwijk, Casper G., Stehouwer, Coen D. A., Vinknes, Kathrine J., and van Greevenbroek, Marleen M. J.

Published
2023
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10. Dimorphic Mechanisms of Fragility in Diabetes Mellitus: the Role of Reduced Collagen Fibril Deformation

Author

Wölfel, Eva M, Schmidt, Felix N, vom Scheidt, Annika, Siebels, Anna K, Wulff, Birgit, Mushumba, Herbert, Ondruschka, Benjamin, Püschel, Klaus, Scheijen, Jean, Schalkwijk, Casper G, Vettorazzi, Eik, Jähn‐Rickert, Katharina, Gludovatz, Bernd, Schaible, Eric, Amling, Michael, Rauner, Martina, Hofbauer, Lorenz C, Zimmermann, Elizabeth A, and Busse, Björn

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Diabetes, Autoimmune Disease, Women's Health, Prevention, Aetiology, 2.1 Biological and endogenous factors, Metabolic and endocrine, Male, Humans, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Glycation End Products, Advanced, Bone and Bones, Collagen, advanced glycation end-products, bone quality, collagen deformation, cortical bone, diabetes mellitus, Biological Sciences, Engineering, Medical and Health Sciences, Anatomy & Morphology, Biological sciences, Biomedical and clinical sciences
Abstract

Diabetes mellitus (DM) is an emerging metabolic disease, and the management of diabetic bone disease poses a serious challenge worldwide. Understanding the underlying mechanisms leading to high fracture risk in DM is hence of particular interest and urgently needed to allow for diagnosis and treatment optimization. In a case-control postmortem study, the whole 12th thoracic vertebra and cortical bone from the mid-diaphysis of the femur from male individuals with type 1 diabetes mellitus (T1DM) (n = 6; 61.3 ± 14.6 years), type 2 diabetes mellitus (T2DM) (n = 11; 74.3 ± 7.9 years), and nondiabetic controls (n = 18; 69.3 ± 11.5) were analyzed with clinical and ex situ imaging techniques to explore various bone quality indices. Cortical collagen fibril deformation was measured in a synchrotron setup to assess changes at the nanoscale during tensile testing until failure. In addition, matrix composition was analyzed including determination of cross-linking and non-crosslinking advanced glycation end-products like pentosidine and carboxymethyl-lysine. In T1DM, lower fibril deformation was accompanied by lower mineralization and more mature crystalline apatite. In T2DM, lower fibril deformation concurred with a lower elastic modulus and tendency to higher accumulation of non-crosslinking advanced glycation end-products. The observed lower collagen fibril deformation in diabetic bone may be linked to altered patterns mineral characteristics in T1DM and higher advanced glycation end-product accumulation in T2DM. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Published
2020

19. Sedentary behaviour and physical activity are associated with biomarkers of endothelial dysfunction and low-grade inflammation—relevance for (pre)diabetes: The Maastricht Study

Author

Vandercappellen, Evelien J., Koster, Annemarie, Savelberg, Hans H. C. M., Eussen, Simone J. P. M., Dagnelie, Pieter C., Schaper, Nicolaas C., Schram, Miranda T., van der Kallen, Carla J. H., van Greevenbroek, Marleen M. J., Wesselius, Anke, Schalkwijk, Casper G., Kroon, Abraham A., Henry, Ronald M. A., and Stehouwer, Coen D. A.

Published
2022
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20. (Pre)diabetes, glycemia, and daily glucose variability are associated with retinal nerve fiber layer thickness in The Maastricht Study

Author

van der Heide, Frank C. T., Foreman, Yuri D., Franken, Iris W. M., Henry, Ronald M. A., Kroon, Abraham A., Dagnelie, Pieter C., Eussen, Simone J. P. M., Berendschot, Tos T. J. M., Schouten, Jan S. A. G., Webers, Carroll A. B., Schram, Miranda T., van der Kallen, Carla J. H., van Greevenbroek, Marleen M. J., Wesselius, Anke, Schalkwijk, Casper G., Schaper, Nicolaas C., Brouwers, Martijn C. G. J., and Stehouwer, Coen D. A.

Published
2022
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22. DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation

Author

Richard, Melissa A, Huan, Tianxiao, Ligthart, Symen, Gondalia, Rahul, Jhun, Min A, Brody, Jennifer A, Irvin, Marguerite R, Marioni, Riccardo, Shen, Jincheng, Tsai, Pei-Chien, Montasser, May E, Jia, Yucheng, Syme, Catriona, Salfati, Elias L, Boerwinkle, Eric, Guan, Weihua, Mosley, Thomas H, Bressler, Jan, Morrison, Alanna C, Liu, Chunyu, Mendelson, Michael M, Uitterlinden, André G, van Meurs, Joyce B, Consortium, BIOS, Heijmans, Bastiaan T, Hoen, Peter AC ’t, van Meurs, Joyce, Isaacs, Aaron, Jansen, Rick, Franke, Lude, Boomsma, Dorret I, Pool, René, van Dongen, Jenny, Hottenga, Jouke J, van Greevenbroek, Marleen MJ, Stehouwer, Coen DA, van der Kallen, Carla JH, Schalkwijk, Casper G, Wijmenga, Cisca, Zhernakova, Alexandra, Tigchelaar, Ettje F, Slagboom, P Eline, Beekman, Marian, Deelen, Joris, van Heemst, Diana, Veldink, Jan H, van den Berg, Leonard H, van Duijn, Cornelia M, Hofman, Albert, Jhamai, P Mila, Verbiest, Michael, Suchiman, H Eka D, Verkerk, Marijn, van der Breggen, Ruud, van Rooij, Jeroen, Lakenberg, Nico, Mei, Hailiang, van Iterson, Maarten, van Galen, Michiel, Bot, Jan, van ’t Hof, Peter, Deelen, Patrick, Nooren, Irene, Moed, Matthijs, Vermaat, Martijn, Zhernakova, Dasha V, Luijk, René, Bonder, Marc Jan, van Dijk, Freerk, Arindrarto, Wibowo, Kielbasa, Szymon M, Swertz, Morris A, van Zwet, Erik W, Franco, Oscar H, Zhang, Guosheng, Li, Yun, Stewart, James D, Bis, Joshua C, Psaty, Bruce M, Chen, Yii-Der Ida, Kardia, Sharon LR, Zhao, Wei, Turner, Stephen T, Absher, Devin, Aslibekyan, Stella, Starr, John M, McRae, Allan F, Hou, Lifang, Just, Allan C, Schwartz, Joel D, Vokonas, Pantel S, Menni, Cristina, Spector, Tim D, Shuldiner, Alan, Damcott, Coleen M, Rotter, Jerome I, Palmas, Walter, Liu, Yongmei, and Paus, Tomáš

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Biotechnology, Aetiology, 2.1 Biological and endogenous factors, Aged, Blood Pressure, CpG Islands, Cross-Sectional Studies, DNA Methylation, Epigenesis, Genetic, Genetic Variation, Genome-Wide Association Study, Humans, Mendelian Randomization Analysis, Middle Aged, Nerve Tissue Proteins, Quantitative Trait Loci, Tetraspanins, BIOS Consortium, DNA methylation, Mendelian randomization, blood pressure, epigenome-wide association study, gene expression, sequence variation, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p  30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.

Published
2017

23. Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study

Author

van Gennip, April C. E., primary, Gupta, Monideepa D., additional, Houben, Alfons J. H. M., additional, Berendschot, Tos T. J. M., additional, Webers, Carroll A. B., additional, van Greevenbroek, Marleen M. J., additional, van der Kallen, Carla J. H., additional, Koster, Annemarie, additional, Wesselius, Anke, additional, Eussen, Simone J. P. M., additional, Schalkwijk, Casper G., additional, de Galan, Bastiaan E., additional, Köhler, Sebastian, additional, Schram, Miranda T., additional, Stehouwer, Coen D. A., additional, and van Sloten, Thomas T., additional

Published
2024
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28. Dietary intake of dicarbonyl compounds and changes in body weight over time in a large cohort of European adults

Author

Debras, Charlotte, Cordova, Reynalda, Mayén, Ana-Lucia, Maasen, Kim, Knaze, Viktoria, Eussen, Simone Jpm, Schalkwijk, Casper G., Huybrechts, Inge, Tjønneland, Anne, Halkjær, Jytte, Katzke, Verena, Bajracharya, Rashmita, Schulze, Matthias B., Masala, Giovanna, Pala, Valeria, Pasanisi, Fabrizio, Macciotta, Alessandra, Petrova, Dafina, Castañeda, Jazmin, Santiuste, Carmen, Amiano, Pilar, Moreno-Iribas, Conchi, Borné, Yan, Sonestedt, Emily, Johansson, Ingegerd, Esberg, Anders, Aglago, Elom Kouassivi, Jenab, Mazda, Freisling, Heinz, Debras, Charlotte, Cordova, Reynalda, Mayén, Ana-Lucia, Maasen, Kim, Knaze, Viktoria, Eussen, Simone Jpm, Schalkwijk, Casper G., Huybrechts, Inge, Tjønneland, Anne, Halkjær, Jytte, Katzke, Verena, Bajracharya, Rashmita, Schulze, Matthias B., Masala, Giovanna, Pala, Valeria, Pasanisi, Fabrizio, Macciotta, Alessandra, Petrova, Dafina, Castañeda, Jazmin, Santiuste, Carmen, Amiano, Pilar, Moreno-Iribas, Conchi, Borné, Yan, Sonestedt, Emily, Johansson, Ingegerd, Esberg, Anders, Aglago, Elom Kouassivi, Jenab, Mazda, and Freisling, Heinz

Abstract

Dicarbonyl compounds are highly reactive precursors of Advanced Glycation End-products (AGEs), produced endogenously, present in certain foods, and formed during food processing. AGEs contribute to development of adverse metabolic outcomes but health effects of dietary dicarbonyls are largely unexplored. We investigated associations between three dietary dicarbonyl compounds, methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), and body-weight changes in European adults. Dicarbonyl intakes were estimated using food composition database from 263,095 EPIC-PANACEA participants with two body-weight assessments (median follow-up time=5.4y). Associations between dicarbonyls and 5-year body-weight changes were estimated using mixed linear regression models. Stratified analyses by sex, age, and baseline BMI were performed. Risk of becoming overweight/obese was assessed using multivariable-adjusted logistic regression. MGO intake was associated with 5-year body-weight gain of 0.089kg (per 1-SD increase, 95%CI=0.072, 0.107). 3-DG was inversely associated with body-weight change (-0.076kg, -0.094, -0.058). No significant association was observed for GO (0.018kg, -0.002, 0.037). In stratified analyses, GO was associated with body-weight gain among women and older participants (above median of 52.4y). MGO was associated with higher body-weight gain among older participants. 3-DG was inversely associated with body-weight gain among younger and normal-weight participants. MGO was associated with higher risk of becoming overweight/obese, while inverse associations were observed for 3-DG. No associations were observed for GO with overweight/obesity. Dietary dicarbonyls are inconsistently associated with body-weight change among European adults. Further research is needed to clarify the role of these food components in overweight and obesity, their underlying mechanisms, and potential public-health implications.

Published
2024
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29. Disease severity-based subgrouping of type 2 diabetes does not parallel differences in quality of life: the Maastricht Study

Author

Werkman, Nikki C C, García-Sáez, Gema, Nielen, Johannes T H, Tapia-Galisteo, Jose, Somolinos-Simón, Francisco J, Hernando, Maria E, Wang, Junfeng, Jiu, Li, Goettsch, Wim G, van der Kallen, Carla J H, Koster, Annemarie, Schalkwijk, Casper G, de Vries, Hein, de Vries, Nanne K, Eussen, Simone J P M, Driessen, Johanna H M, Stehouwer, Coen D A, Werkman, Nikki C C, García-Sáez, Gema, Nielen, Johannes T H, Tapia-Galisteo, Jose, Somolinos-Simón, Francisco J, Hernando, Maria E, Wang, Junfeng, Jiu, Li, Goettsch, Wim G, van der Kallen, Carla J H, Koster, Annemarie, Schalkwijk, Casper G, de Vries, Hein, de Vries, Nanne K, Eussen, Simone J P M, Driessen, Johanna H M, and Stehouwer, Coen D A

Abstract

Aims/hypothesis: Type 2 diabetes is a highly heterogeneous disease for which new subgroups (‘clusters’) have been proposed based on disease severity: moderate age-related diabetes (MARD), moderate obesity-related diabetes (MOD), severe insulin-deficient diabetes (SIDD) and severe insulin-resistant diabetes (SIRD). It is unknown how disease severity is reflected in terms of quality of life in these clusters. Therefore, we aimed to investigate the cluster characteristics and cluster-wise evolution of quality of life in the previously defined clusters of type 2 diabetes. Methods: We included individuals with type 2 diabetes from the Maastricht Study, who were allocated to clusters based on a nearest centroid approach. We used logistic regression to evaluate the cluster-wise association with diabetes-related complications. We plotted the evolution of HbA1c levels over time and used Kaplan–Meier curves and Cox regression to evaluate the cluster-wise time to reach adequate glycaemic control. Quality of life based on the Short Form 36 (SF-36) was also plotted over time and adjusted for age and sex using generalised estimating equations. The follow-up time was 7 years. Analyses were performed separately for people with newly diagnosed and already diagnosed type 2 diabetes. Results: We included 127 newly diagnosed and 585 already diagnosed individuals. Already diagnosed people in the SIDD cluster were less likely to reach glycaemic control than people in the other clusters, with an HR compared with MARD of 0.31 (95% CI 0.22, 0.43). There were few differences in the mental component score of the SF-36 in both newly and already diagnosed individuals. In both groups, the MARD cluster had a higher physical component score of the SF-36 than the other clusters, and the MOD cluster scored similarly to the SIDD and SIRD clusters. Conclusions/interpretation: Disease severity suggested by the clusters of type 2 diabetes is not entirely reflected in quality of life. In pa

Published
2024

30. Microvascular Dysfunction and Whole-Brain White Matter Connectivity: The Maastricht Study

Author

Cardiovasculaire Epi Team 7a, Circulatory Health, Cardiovasculaire Epi Team 5, Brain, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, MS Interne Geneeskunde, Beran, Magdalena, van Gennip, April C E, Stehouwer, Coen D A, Jansen, Jacobus F A, Gupta, Monideepa D, Houben, Alfons J H M, Berendschot, Tos T J M, Webers, Carroll A B, Wesselius, Anke, Schalkwijk, Casper G, Backes, Walter H, de Jong, Joost J A, van der Kallen, Carla J H, van Greevenbroek, Marleen M J, Köhler, Sebastian, Vonk, Jet M J, Geerlings, Mirjam I, Schram, Miranda T, van Sloten, Thomas T, Cardiovasculaire Epi Team 7a, Circulatory Health, Cardiovasculaire Epi Team 5, Brain, JC onderzoeksprogramma Cardiovasculaire Epidemiologie, MS Interne Geneeskunde, Beran, Magdalena, van Gennip, April C E, Stehouwer, Coen D A, Jansen, Jacobus F A, Gupta, Monideepa D, Houben, Alfons J H M, Berendschot, Tos T J M, Webers, Carroll A B, Wesselius, Anke, Schalkwijk, Casper G, Backes, Walter H, de Jong, Joost J A, van der Kallen, Carla J H, van Greevenbroek, Marleen M J, Köhler, Sebastian, Vonk, Jet M J, Geerlings, Mirjam I, Schram, Miranda T, and van Sloten, Thomas T

Published
2024

31. Disease severity-based subgrouping of type 2 diabetes does not parallel differences in quality of life: the Maastricht Study

Author

Afd Pharmacoepi & Clinical Pharmacology, PECP - Centre for Pharmaceutical Policy and Regulation, Sub Gen. Pharmacoepi and Clinical Pharm, Pharmacoepidemiology and Clinical Pharmacology, Werkman, Nikki C C, García-Sáez, Gema, Nielen, Johannes T H, Tapia-Galisteo, Jose, Somolinos-Simón, Francisco J, Hernando, Maria E, Wang, Junfeng, Jiu, Li, Goettsch, Wim G, van der Kallen, Carla J H, Koster, Annemarie, Schalkwijk, Casper G, de Vries, Hein, de Vries, Nanne K, Eussen, Simone J P M, Driessen, Johanna H M, Stehouwer, Coen D A, Afd Pharmacoepi & Clinical Pharmacology, PECP - Centre for Pharmaceutical Policy and Regulation, Sub Gen. Pharmacoepi and Clinical Pharm, Pharmacoepidemiology and Clinical Pharmacology, Werkman, Nikki C C, García-Sáez, Gema, Nielen, Johannes T H, Tapia-Galisteo, Jose, Somolinos-Simón, Francisco J, Hernando, Maria E, Wang, Junfeng, Jiu, Li, Goettsch, Wim G, van der Kallen, Carla J H, Koster, Annemarie, Schalkwijk, Casper G, de Vries, Hein, de Vries, Nanne K, Eussen, Simone J P M, Driessen, Johanna H M, and Stehouwer, Coen D A

Published
2024

32. Pyridoxamine Alleviates Cardiac Fibrosis and Oxidative Stress in Western Diet-Induced Prediabetic Rats.

Author

D'Haese, Sarah, Claes, Lisa, Jaeken, Eva, Deluyker, Dorien, Evens, Lize, Heeren, Ellen, Haesen, Sibren, Vastmans, Lotte, Lambrichts, Ivo, Wouters, Kristiaan, Schalkwijk, Casper G., Hansen, Dominique, Eijnde, BO, and Bito, Virginie

Subjects
TYPE 2 diabetes, GLUCOSE tolerance tests, BLOOD sugar, HEART fibrosis, HEART failure
Abstract

Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk for heart failure, yet preventive cardiac care is suboptimal in this population. Pyridoxamine (PM), a vitamin B6 analog, has been shown to exert protective effects in metabolic and cardiovascular diseases. In this study, we aimed to investigate whether PM limits adverse cardiac remodeling and dysfunction in rats who develop T2DM. Male rats received a standard chow diet or Western diet (WD) for 18 weeks to induce prediabetes. One WD group received additional PM (1 g/L) via drinking water. Glucose tolerance was assessed with a 1 h oral glucose tolerance test. Cardiac function was evaluated using echocardiography and hemodynamic measurements. Histology on left ventricular (LV) tissue was performed. Treatment with PM prevented the increase in fasting plasma glucose levels compared to WD-fed rats (p < 0.05). LV cardiac dilation tended to be prevented using PM supplementation. In LV tissue, PM limited an increase in interstitial collagen deposition (p < 0.05) seen in WD-fed rats. PM tended to decrease 3-nitrotyrosine and significantly lowered 4-hydroxynonenal content compared to WD-fed rats. We conclude that PM alleviates interstitial fibrosis and oxidative stress in the hearts of WD-induced prediabetic rats. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Phenotype prediction using biologically interpretable neural networks on multi-cohort multi-omics data.

Author

van Hilten, Arno, van Rooij, Jeroen, Heijmans, Bastiaan T., 't Hoen, Peter A. C., Meurs, Joyce van, Jansen, Rick, Franke, Lude, Boomsma, Dorret I., Pool, René, van Dongen, Jenny, Hottenga, Jouke J., van Greevenbroek, Marleen M. J., Stehouwer, Coen D. A., van der Kallen, Carla J. H., Schalkwijk, Casper G., Wijmenga, Cisca, Zhernakova, Sasha, Tigchelaar, Ettje F., Slagboom, P. Eline, and Beekman, Marian

Subjects
GENE expression, MULTIOMICS, PREDICTION models, NETWORK performance, INDIVIDUALIZED medicine
Abstract

Integrating multi-omics data into predictive models has the potential to enhance accuracy, which is essential for precision medicine. In this study, we developed interpretable predictive models for multi-omics data by employing neural networks informed by prior biological knowledge, referred to as visible networks. These neural networks offer insights into the decision-making process and can unveil novel perspectives on the underlying biological mechanisms associated with traits and complex diseases. We tested the performance, interpretability and generalizability for inferring smoking status, subject age and LDL levels using genome-wide RNA expression and CpG methylation data from the blood of the BIOS consortium (four population cohorts, Ntotal = 2940). In a cohort-wise cross-validation setting, the consistency of the diagnostic performance and interpretation was assessed. Performance was consistently high for predicting smoking status with an overall mean AUC of 0.95 (95% CI: 0.90–1.00) and interpretation revealed the involvement of well-replicated genes such as AHRR, GPR15 and LRRN3. LDL-level predictions were only generalized in a single cohort with an R2 of 0.07 (95% CI: 0.05–0.08). Age was inferred with a mean error of 5.16 (95% CI: 3.97–6.35) years with the genes COL11A2, AFAP1, OTUD7A, PTPRN2, ADARB2 and CD34 consistently predictive. For both regression tasks, we found that using multi-omics networks improved performance, stability and generalizability compared to interpretable single omic networks. We believe that visible neural networks have great potential for multi-omics analysis; they combine multi-omic data elegantly, are interpretable, and generalize well to data from different cohorts. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Retinal microvascular function and incidence and trajectories of clinically relevant depressive symptoms: the Maastricht Study.

Author

Gennip, April C. E. van, Gupta, Monideepa D., Houben, Alfons J. H. M., Berendschot, Tos T. J. M., Webers, Carroll A. B., Greevenbroek, Marleen M. J. van, Kallen, Carla J. H. van der, Koster, Annemarie, Wesselius, Anke, Eussen, Simone J. P. M., Schalkwijk, Casper G., Galan, Bastiaan E. de, Köhler, Sebastian, Schram, Miranda T., Stehouwer, Coen D. A., and Sloten, Thomas T. van

Abstract

Background Cerebral microvascular dysfunction may contribute to depression via disruption of brain structures involved in mood regulation, but evidence is limited. We investigated the association of retinal microvascular function, a proxy for microvascular function in the brain, with incidence and trajectories of clinically relevant depressive symptoms. Methods Longitudinal data are from The Maastricht Study of 5952 participants (59.9 ± 8.5 years/49.7% women) without clinically relevant depressive symptoms at baseline (2010–2017). Central retinal arteriolar equivalent and central retinal venular equivalent (CRAE and CRVE) and a composite score of flicker light-induced retinal arteriolar and venular dilation were assessed at baseline. We assessed incidence and trajectories of clinically relevant depressive symptoms (9-item Patient Health Questionnaire score ⩾10). Trajectories included continuously low prevalence (low, n = 5225 [87.8%]); early increasing, then chronic high prevalence (early-chronic, n = 157 [2.6%]); low, then increasing prevalence (late-increasing, n = 247 [4.2%]); and remitting prevalence (remitting, n = 323 [5.4%]). Results After a median follow-up of 7.0 years (range 1.0–11.0), 806 (13.5%) individuals had incident clinically relevant depressive symptoms. After full adjustment, a larger CRAE and CRVE were each associated with a lower risk of clinically relevant depressive symptoms (hazard ratios [HRs] per standard deviation [ s.d. ]: 0.89 [95% confidence interval (CI) 0.83–0.96] and 0.93 [0.86–0.99], respectively), while a lower flicker light-induced retinal dilation was associated with a higher risk of clinically relevant depressive symptoms (HR per s.d. : 1.10 [1.01–1.20]). Compared to the low trajectory, a larger CRAE was associated with lower odds of belonging to the early-chronic trajectory (OR: 0.83 [0.69–0.99]) and a lower flicker light-induced retinal dilation was associated with higher odds of belonging to the remitting trajectory (OR: 1.23 [1.07–1.43]). Conclusions These findings support the hypothesis that cerebral microvascular dysfunction contributes to the development of depressive symptoms. [ABSTRACT FROM AUTHOR]

Published
2024
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35. Placental Methylglyoxal in Preeclampsia: Vascular and Biomarker Implications.

Author

Vangrieken, Philippe, Al-Nasiry, Salwan, Remels, Alex H. V., Schiffers, Paul M. H., Janssen, Emma, Nass, Stefanie, Scheijen, Jean L. J. M., Spaanderman, Marc E. A., and Schalkwijk, Casper G.

Abstract

BACKGROUND: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction. METHODS: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored. RESULTS: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (−12%) and hypoxia-exposed placentas (−16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (−26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2. CONCLUSIONS: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia. [ABSTRACT FROM AUTHOR]

Published
2024
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39. Dietary intake of dicarbonyl compounds and changes in body weight over time in a large cohort of European adults

Author

Debras, Charlotte, primary, Cordova, Reynalda, additional, Mayén, Ana-Lucia, additional, Maasen, Kim, additional, Knaze, Viktoria, additional, Eussen, Simone J. P. M., additional, Schalkwijk, Casper G., additional, Huybrechts, Inge, additional, Tjønneland, Anne, additional, Halkjær, Jytte, additional, Katzke, Verena, additional, Bajracharya, Rashmita, additional, Schulze, Matthias B., additional, Masala, Giovanna, additional, Pala, Valeria, additional, Pasanisi, Fabrizio, additional, Macciotta, Alessandra, additional, Petrova, Dafina, additional, Castañeda, Jazmin, additional, Santiuste, Carmen, additional, Amiano, Pilar, additional, Moreno-Iribas, Conchi, additional, Borné, Yan, additional, Sonestedt, Emily, additional, Johansson, Ingegerd, additional, Esberg, Anders, additional, Aglago, Elom Kouassivi, additional, Jenab, Mazda, additional, and Freisling, Heinz, additional

Published
2024
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40. Correction: Methylglyoxal, a glycolysis side-product, induces Hsp90 glycation and YAP-mediated tumor growth and metastasis

Author

Nokin, Marie-Julie, primary, Durieux, Florence, additional, Peixoto, Paul, additional, Chiavarina, Barbara, additional, Peulen, Olivier, additional, Blomme, Arnaud, additional, Turtoi, Andrei, additional, Costanza, Brunella, additional, Smargiasso, Nicolas, additional, Baiwir, Dominique, additional, Scheijen, Jean L, additional, Schalkwijk, Casper G, additional, Leenders, Justine, additional, De Tullio, Pascal, additional, Bianchi, Elettra, additional, Thiry, Marc, additional, Uchida, Koji, additional, Spiegel, David A, additional, Cochrane, James R, additional, Hutton, Craig A, additional, De Pauw, Edwin, additional, Delvenne, Philippe, additional, Belpomme, Dominique, additional, Castronovo, Vincent, additional, and Bellahcène, Akeila, additional

Published
2024
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41. Moderate-Intensity and High-Intensity Interval Exercise Training Offer Equal Cardioprotection, with Different Mechanisms, during the Development of Type 2 Diabetes in Rats

Author

D’Haese, Sarah, primary, Claes, Lisa, additional, de Laat, Iris, additional, Van Campenhout, Sven, additional, Deluyker, Dorien, additional, Heeren, Ellen, additional, Haesen, Sibren, additional, Lambrichts, Ivo, additional, Wouters, Kristiaan, additional, Schalkwijk, Casper G., additional, Hansen, Dominique, additional, Eijnde, BO, additional, and Bito, Virginie, additional

Published
2024
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42. Microvascular Dysfunction and Whole‐Brain White Matter Connectivity: The Maastricht Study

Author

Beran, Magdalena, primary, van Gennip, April C.E., additional, Stehouwer, Coen D.A., additional, Jansen, Jacobus F.A., additional, Gupta, Monideepa D., additional, Houben, Alfons J.H.M., additional, Berendschot, Tos T.J.M., additional, Webers, Carroll A.B., additional, Wesselius, Anke, additional, Schalkwijk, Casper G., additional, Backes, Walter H., additional, de Jong, Joost J.A., additional, van der Kallen, Carla J.H., additional, van Greevenbroek, Marleen M.J., additional, Köhler, Sebastian, additional, Vonk, Jet M.J., additional, Geerlings, Mirjam I., additional, Schram, Miranda T., additional, and van Sloten, Thomas T., additional

Published
2024
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47. The association of hyperglycaemia and insulin resistance with incident depressive symptoms over 4 years of follow-up: The Maastricht Study

Author

Geraets, Anouk F. J., Köhler, Sebastian, Muzambi, Rutendo, Schalkwijk, Casper G., Oenema, Anke, Eussen, Simone J. P. M., Dagnelie, Pieter C., Stehouwer, Coen D. A., Schaper, Nicolaas C., Henry, Ronald M. A., van der Kallen, Carla J. H., Wesselius, Anke, Koster, Annemarie, Verhey, Frans R. J., and Schram, Miranda T.

Published
2020
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