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Your search keyword '"Meurs, J.B.J. van"' showing total 27 results
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27 results on '"Meurs, J.B.J. van"'

1. Higher testosterone is associated with open-angle glaucoma in women: a genetic predisposition?

Author

Vergroesen, J.E., Kaynak, A., Aribas, E., Kavousi, M., Meurs, J.B.J. van, Klaver, C.C.W., Ramdas, W.D., Vergroesen, J.E., Kaynak, A., Aribas, E., Kavousi, M., Meurs, J.B.J. van, Klaver, C.C.W., and Ramdas, W.D.

Abstract

Contains fulltext : 292748.pdf (Publisher’s version ) (Open Access), BACKGROUND: Testosterone may be a possible modifiable risk factor for open-angle glaucoma (OAG) and intraocular pressure (IOP), but evidence has been scarce and conflicting. In this study we evaluated the association of testosterone and its genetic predisposition with incident (i) OAG, IOP, retinal nerve fiber layer (RNFL), and ganglion cell-inner plexiform layer (GCL +). METHODS: Participants aged 45-100 years were derived from the prospective, population-based Rotterdam Study. Ophthalmic examinations and serum testosterone measurements (including bioavailable and free testosterone) were performed from 1991 onwards. Follow-up took place every 4-5 years. A total of 187 out of 7898 participants were diagnosed with incident (i) OAG during follow-up. Genotyping was performed in 165 glaucoma cases and 6708 controls. We calculated sex-specific weighted genetic risk scores (GRS) for total and bioavailable testosterone. Associations with iOAG were analyzed using multivariable logistic regression. Associations with IOP, RNFL, and GCL + were analyzed with multivariable linear regression. Analyses were stratified on sex and adjusted for at least age, body mass index, and follow-up duration. RESULTS: In men, testosterone was not associated with iOAG. However, the GRS for higher total testosterone was associated with an increased iOAG risk (odds ratio [OR] with 95% confidence interval [95% CI]: 2.48 [1.18; 5.22], per unit). In women, higher values of bioavailable testosterone (2.05 [1.00; 4.18] per nmol/L) and free testosterone (1.79 [1.00; 3.20] per ng/dL) were significantly associated with increased risk of iOAG. Moreover, the GRS for higher bioavailable testosterone was associated with an increased iOAG risk (2.48 [1.09; 5.65], per unit). Higher bioavailable and free testosterone were adversely associated with IOP (0.58 [0.05; 1.10] per nmol/L and 0.47 [0.04; 0.90] per ng/dL). Higher total testosterone was inversely associated with peripapillary RNFL and GCL + (Beta [95% CI]

Published
2023

2. The prevalence, incidence, and progression of radiographic thumb base osteoarthritis in a population-based cohort: the Rotterdam Study

Author

Teunissen, J.S., Wouters, R.M., Bierma-Zeintra, S.M.A., Meurs, J.B.J. van, Schreuders, T.A., Zuidam, J.M., Selles, R.W., Teunissen, J.S., Wouters, R.M., Bierma-Zeintra, S.M.A., Meurs, J.B.J. van, Schreuders, T.A., Zuidam, J.M., and Selles, R.W.

Abstract

Item does not contain fulltext, OBJECTIVE: To describe the prevalence, incidence, and progression of radiographic thumb carpometacarpal (CMC-1) and trapezioscaphoid (TS) radiographic osteoarthritis (ROA) in the general Dutch population aged ≥55y. DESIGN: Data were from the first and second cohort of the Rotterdam Study (1990-2005, 4-12 years follow-up, age 55+). Participants underwent bilateral radiographs at baseline (N = 7792) and follow-up (N = 3804), read for Kellgren-Lawrence (K-L) grade. ROA was defined on the joint level as K-L grade ≥2. The prevalence was assessed at baseline, incidence at follow-up in those free of ROA at baseline, and progression in those with ROA. Differences based on sex and age were evaluated using logistic regression models. RESULTS: At baseline, 1977 (25.3%) had CMC-1 ROA and 1133 (14.5%) TS ROA. The prevalence was higher in females for CMC-1 (aOR = 1.98 95%CI [1.77-2.21]) and TS ROA (aOR = 2.00 [1.74-2.29]) and increased for every year of age (CMC-1 ROA 1.08 [1.07-1.08]) (TS ROA 1.06 [1.05-1.07]). Most (437/512; 85.4%) incident cases of CMC-1 ROA (2994 at risk) were mild (K-L = 2), whereas most (145/167; 86,8%) incident cases of TS ROA (3311 at risk) were moderate to severe (K-L = 3/4). CMC-1 ROA progression was mostly (88/100; 88.0%) seen in the K-L 2 group at baseline, whereas that was (4/17; 23.5%) for TS ROA. CONCLUSION: CMC-1 ROA and TS ROA are prevalent in the general Dutch population. While incident CMC-1 ROA was primarily mild, incident TS ROA was more often moderate to severe. CMC-1 ROA was a strong predictor for incident TS ROA.

Published
2022

3. Validated inference of smoking habits from blood with a finite DNA methylation marker set

Author

Maas, S.C.E., Vidaki, A., Wilson, R., Teumer, A., Liu, F., Meurs, J.B.J. van, Uitterlinden, A.G., Boomsma, D.I., Geus, E.J.C. de, Willemsen, G., Dongen, J. van, Kallen, C.J.H. van der, Slagboom, P.E., Beekman, M., Heemst, D. van, Berg, L.H. van den, Duijts, L., Jaddoe, V.W.V., Ladwig, K.H., Kunze, S., Peters, A., Ikram, M.A., Grabe, H.J., Felix, J.F., Waldenberger, M., Franco, O.H., Ghanbari, M., Kayser, M., and BIOS Consortium

Subjects
DNA methylation, Epidemiology, Epigenetics, Smoking inference, Forensics
Abstract

Inferring a person's smoking habit and history from blood is relevant for complementing or replacing self-reports in epidemiological and public health research, and for forensic applications. However, a finite DNA methylation marker set and a validated statistical model based on a large dataset are not yet available. Employing 14 epigenome-wide association studies for marker discovery, and using data from six population-based cohorts (N = 3764) for model building, we identified 13 CpGs most suitable for inferring smoking versus non-smoking status from blood with a cumulative Area Under the Curve (AUC) of 0.901. Internal fivefold cross-validation yielded an average AUC of 0.897 +/- 0.137, while external model validation in an independent population-based cohort (N = 1608) achieved an AUC of 0.911. These 13 CpGs also provided accurate inference of current (average AUC(crossvalidation) 0.925 +/- 0.021, AUC(externalvalidation)0.914), former (0.766 +/- 0.023, 0.699) and never smoking (0.830 +/- 0.019, 0.781) status, allowed inferring pack-years in current smokers (10 pack-years 0.800 +/- 0.068, 0.796; 15 pack-years 0.767 +/- 0.102, 0.752) and inferring smoking cessation time in former smokers (5 years 0.774 +/- 0.024, 0.760; 10 years 0.766 +/- 0.033, 0.764; 15 years 0.767 +/- 0.020, 0.754). Model application to children revealed highly accurate inference of the true non- smoking status (6 years of age: accuracy 0.994, N = 355; 10 years: 0.994, N = 309), suggesting prenatal and passive smoking exposure having no impact on model applications in adults. The finite set of DNA methylation markers allow accurate inference of smoking habit, with comparable accuracy as plasma cotinine use, and smoking history from blood, which we envision becoming useful in epidemiology and public health research, and in medical and forensic applications.

Published
2019

4. Insulin-like growth factor I gene promoter polymorphism, collagen type II alpha 1 (COL2A1) gene, and the prevalence of radiographic osteoarthritis: the Rotterdam study

Author

Zhai, G., Rivadeneira, F., Houwing-Duistermaat, J.J., Meulenbelt, I., Bijkerk, C., Hofman, A., Meurs, J.B.J. van, Uitterlinden, A. G., Pols, H.A.P., Slagboom, P.E., and Duijn, C.M. van

Subjects
Insulin-like growth factor 1 -- Evaluation, Osteoarthritis -- Care and treatment, Health
Abstract

The main aim of this study is to identify the role of insulin-like growth factor I in the prevalence of radiographic osteoarthritis. Insulin-like growth factor I is a polypeptide mediator with a potent anabolic impact on cartilage homeostasis.

Published
2004

5. Homocysteine levels associate with subtle changes in leukocyte DNA methylation: an epigenome-wide analysis

Author

Mandaviya, P.R., Aissi, D., Dekkers, K.F., Joehanes, R., Kasela, S., Truong, V., Stolk, L., Heemst, D. van, Ikram, M.A., Lindemans, J., Slagboom, P.E., Tregouet, D.A., Uitterlinden, A.G., Wei, C., Wells, P., Gagnon, F., Greevenbroek, M.M.J. van, Heijmans, B.T., Milani, L., Morange, P.E., Meurs, J.B.J. van, Heil, S.G., BIOS Consortium, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), University of Toronto, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Leiden University Medical Center (LUMC), Universiteit Leiden, Ottawa Hospital Research Institute, The Estonian Genome Center, University of Tartu, Fibrinolyse et Pathologie Vasculaire, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition, obésité et risque thrombotique (NORT), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), ALESSI, Marie-Christine, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Interne Geneeskunde, RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Clinical Chemistry, Internal Medicine, and Epidemiology

Subjects
0301 basic medicine, Male, Cancer Research, Homocysteine, SMOOTH-MUSCLE-CELLS, FOLIC-ACID, 030204 cardiovascular system & hematology, Epigenesis, Genetic, chemistry.chemical_compound, 0302 clinical medicine, Leukocytes, Large-Conductance Calcium-Activated Potassium Channel alpha Subunits, [SDV.MHEP.EM] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, DNA methylation, S-ADENOSYLHOMOCYSTEINE, VASCULAR-DISEASE, Tenascin, Methylation, RANDOMIZED CONTROLLED-TRIAL, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, LIM Domain Proteins, Fatty Acid Transport Proteins, Basic-Leucine Zipper Transcription Factors, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Female, ESTROGEN-RECEPTOR-ALPHA, Biology, 03 medical and health sciences, 450 k array, Chromosome 19, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Genetics, Humans, Epigenetics, DMP, DMR, GENOME-WIDE, association, Chromosome, Epigenome, homocysteine, Molecular biology, LIM PROTEIN, Activating Transcription Factor 6, meta-analysis, 030104 developmental biology, chemistry, MYOCARDIAL-INFARCTION, PLASMA HOMOCYSTEINE, epigenome-wide analysis, DNA hypomethylation, Genome-Wide Association Study
Abstract

International audience; Aim: Homocysteine (Hcy) is a sensitive marker of one-carbon metabolism. Higher Hcy levels have been associated with global DNA hypomethylation. We investigated the association between plasma Hcy and epigenome-wide DNA methylation in leukocytes.Methods: Methylation was measured using Illumina 450 k arrays in 2035 individuals from six cohorts. Hcy-associated differentially methylated positions and regions were identified using meta-analysis.Results: Three differentially methylated positions cg21607669 (SLC27A1), cg26382848 (AJUBA) and cg10701000 (KCNMA1) at chromosome 19, 14 and 10, respectively, were significantly associated with Hcy. In addition, we identified 68 Hcy-associated differentially methy-lated regions, the most significant of which was a 1.8-kb spanning domain (TNXB/ATF6B) at chromosome 6.Conclusion: We identified novel epigenetic loci associated with Hcy levels, of which specific role needs to be further validated.

Published
2017
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6. A systematic analysis highlights multiple long non-coding RNAs associated with cardiometabolic disorders

Author

Ghanbari, M., Peters, M.J., Vries, P.S. de, Boer, C.G., Rooij, J.G.M. van, Lee, Y.C., Kumar, V., Uitterlinden, A.G., Ikram, M.Arfan, Wijmenga, C., Ordovas, J.M., Smith, C.E., Meurs, J.B.J. van, Erkeland, S.J., Franco, O.H., Dehghan, A., Ghanbari, M., Peters, M.J., Vries, P.S. de, Boer, C.G., Rooij, J.G.M. van, Lee, Y.C., Kumar, V., Uitterlinden, A.G., Ikram, M.Arfan, Wijmenga, C., Ordovas, J.M., Smith, C.E., Meurs, J.B.J. van, Erkeland, S.J., Franco, O.H., and Dehghan, A.

Abstract

Item does not contain fulltext, Genome-wide association studies (GWAS) have identified many susceptibility loci for cardiometabolic disorders. Most of the associated variants reside in non-coding regions of the genome including long non-coding RNAs (lncRNAs), which are thought to play critical roles in diverse biological processes. Here, we leveraged data from the available GWAS meta-analyses on lipid and obesity-related traits, blood pressure, type 2 diabetes, and coronary artery disease and identified 179 associated single-nucleotide polymorphisms (SNPs) in 102 lncRNAs (p-value < 2.3 x 10(-7)). Of these, 55 SNPs, either the lead SNP or in strong linkage disequilibrium with the lead SNP in the related loci, were selected for further investigations. Our in silico predictions and functional annotations of the SNPs as well as expression and DNA methylation analysis of their lncRNAs demonstrated several lncRNAs that fulfilled predefined criteria for being potential functional targets. In particular, we found evidence suggesting that LOC157273 (at 8p23.1) is involved in regulating serum lipid-cholesterol. Our results showed that rs4841132 in the second exon and cg17371580 in the promoter region of LOC157273 are associated with lipids; the lncRNA is expressed in liver and associates with the expression of its nearby coding gene, PPP1R3B. Collectively, we highlight a number of loci associated with cardiometabolic disorders for which the association may act through lncRNAs.

Published
2018

8. Genome-wide association study meta-analysis of chronic widespread pain: evidence for involvement of the 5p15.2 region

Author

Peters, M.J., Broer, L., Willemen, H.L.D.M., Eiriksdottir, G., Hocking, L.J., Holliday, K.L., Horan, M.A., Meulenbelt, I., Neogi, T., Popham, M., Schmidt, C.O., Soni, A., Valdes, A.M., Amin, N., Dennison, E.M., Eijkelkamp, N., Harris, T.B., Hart, D.J., Hofman, A., Huygen, F.J.P.M., Jameson, K.A., Jones, G.T., Launer, L.J., Kerkhof, H.J.M., Kruijf, M. de, McBeth, J., Kloppenburg, M., Ollier, W.E., Oostra, B., Payton, A., Rivadeneira, F., Smith, B.H., Smith, A.V., Stolk, L., Teumer, A., Thomson, W., Uitterlinden, A.G., Wang, K., Wingerden, S.H. van, Arden, N.K., Cooper, C., Felson, D., Gudnason, V., Macfarlane, G.J., Pendleton, N., Slagboom, P.E., Spector, T.D., Volzke, H., Kavelaars, A., Duijn, C.M. van, Williams, F.M.K., and Meurs, J.B.J. van

Published
2013

9. Identification of new susceptibility loci for osteoarthritis (arcOGEN): a genome-wide association study

Author

Zeggini, E., Panoutsopoulou, K., Southam, L., Rayner, N.W., Day-Williams, A.G., Lopes, M.C., Boraska, V., Esko, T., Evangelou, E., Hofman, A., Houwing-Duistermaat, J.J., Ingvarsson, T., Jonsdottir, I., Jonsson, H., Kerkhof, H.J.M., Kloppenburg, M., Bos, S.D., Mangino, M., Metrustry, S., Slagboom, P.E., Thorleifsson, G., Raine, E.V.A., Ratnayake, M., Ricketts, M., Beazley, C., Blackburn, H., Bumpstead, S., Elliott, K.S., Hunt, S.E., Potter, S.C., Shin, S.Y., Yadav, V.K., Zhai, G.J., Sherburn, K., Dixon, K., Arden, E., Aslam, N., Battley, P.K., Carluke, I., Doherty, S., Gordon, A., Joseph, J., Keen, R., Koller, N.C., Mitchell, S., O'Neill, F., Paling, E., Reed, M.R., Rivadeneira, F., Swift, D., Walker, K., Watkins, B., Wheeler, M., Birrell, F., Ioannidis, J.P.A., Meulenbelt, I., Metspalu, A., Rai, A., Salter, D., Stefansson, K., Styrkarsdottir, U., Uitterlinden, A.G., Meurs, J.B.J. van, Chapman, K., Deloukas, P., Ollier, W.E.R., Wallis, G.A., Arden, N., Carr, A., Doherty, M., McCaskie, A., Wilkinson, J.M., Ralston, S.H., Valdes, A.M., Spector, T.D., Loughlin, J., and arcOGEN Consortium & arcOGEN Colla

Published
2012

11. Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes

Author

Strawbridge, R.J. Dupuis, J. Prokopenko, I. Barker, A. Ahlqvist, E. Rybin, D. Petrie, J.R. Travers, M.E. Bouatia-Naji, N. Dimas, A.S. Nica, A.C. Wheeler, E. Chen, H. Voight, B.F. Taneera, J. Kanoni, S. Peden, J.F. Turrini, F. Gustafsson, S. Zabena, C. Almgren, P. Barker, D.J.P. Barnes, D. Dennison, E.M. Eriksson, J.G. Eriksson, P. Eury, E. Folkersen, L. Fox, C.S. Frayling, T.M. Goel, A. Gu, H.F. Horikoshi, M. Isomaa, B. Jackson, A.U. Jameson, K.A. Kajantie, E. Kerr-Conte, J. Kuulasmaa, T. Kuusisto, J. Loos, R.J.F. Luan, J. Makrilakis, K. Manning, A.K. Martínez-Larrad, M.T. Narisu, N. Mannila, M.N. Öhrvik, J. Osmond, C. Pascoe, L. Payne, F. Sayer, A.A. Sennblad, B. Silveira, A. Stančcáková, A. Stirrups, K. Swift, A.J. Syvänen, A.-C. Tuomi, T. Van't Hooft, F.M. Walker, M. Weedon, M.N. Xie, W. Zethelius, B. Scott, L.J. Steinthorsdottir, V. Morris, A.P. Dina, C. Welch, R.P. Zeggini, E. Huth, C. Aulchenko, Y.S. Thorleifsson, G. Mcculloch, L.J. Ferreira, T. Grallert, H. Amin, N. Wu, G. Willer, C.J. Raychaudhuri, S. McCarroll, S.A. Hofmann, O.M. Qi, L. Segre, A.V. Van Hoek, M. Navarro, P. Ardlie, K. Balkau, B. Benediktsson, R. Bennett, A.J. Blagieva, R. Boerwinkle, E. Bonnycastle, L.L. Bostrom, K.B. Bravenboer, B. Bumpstead, S. Burtt, N.P. Charpentier, G. Chines, P.S. Cornelis, M. Couper, D.J. Crawford, G. Doney, A.S.F. Elliott, K.S. Elliott, A.L. Erdos, M.R. Franklin, C.S. Ganser, M. Gieger, C. Grarup, N. Green, T. Griffin, S. Groves, C.J. Guiducci, C. Hadjadj, S. Hassanali, N. Herder, C. Johnson, P.R.V. Jorgensen, T. Kao, W.H.L. Klopp, N. Kong, A. Kraft, P. Lauritzen, T. Li, M. Lieverse, A. Lindgren, C.M. Lyssenko, V. Marre, M. Meitinger, T. Midthjell, K. Morken, M.A. Nilsson, P. Owen, K.R. Perry, J.R.B. Petersen, A.-K. Platou, C. Proenca, C. Rathmann, W. Rayner, N.W. Robertson, N.R. Rocheleau, G. Roden, M. Sampson, M.J. Saxena, R. Shields, B.M. Shrader, P. Sigurdsson, G. Sparso, T. Strassburger, K. Stringham, H.M. Sun, Q. Thorand, B. Tichet, J. Van Dam, R.M. Van Haeften, T.W. Van Herpt, T. Van Vliet-Ostaptchouk, J.V. Walters, G.B. Wijmenga, C. Witteman, J.C.M. Bergman, R.N. Cauchi, S. Collins, F.S. Gloyn, A.L. Gyllensten, U. Hansen, T. Hide, W.A. Hitman, G.A. Hofman, A. Hunter, D.J. Hveem, K. Laakso, M. Mohlke, K.L. Morris, A.D. Palmer, C.N.A. Pramstaller, P.P. Rudan, I. Sijbrands, E. Stein, L.D. Tuomilehto, J. Uitterlinden, A.G. Wareham, N.J. Watanabe, R.M. Abecasis, G.R. Boehm, B.O. Campbell, H. Daly, M.J. Hattersley, A.T. Hu, F.B. Meigs, J.B. Pankow, J.S. Pedersen, O. Wichmann, H.-E. Barroso, I. Groop, L. Sladek, R. Thorsteinsdottir, U. Wilson, J.F. Illig, T. Froguel, P. Van Duijn, C.M. Stefansson, K. Altshuler, D. Boehnke, M. McCarthy, M.I. Speliotes, E.K. Berndt, S.I. Monda, K.L. Allen, H.L. Magi, R. Randall, J.C. Vedantam, S. Winkler, T.W. Workalemahu, T. Heid, I.M. Wood, A.R. Weyant, R.J. Estrada, K. Liang, L. Nemesh, J. Park, J.-H. Kilpelainen, T.O. Yang, J. Esko, T. Feitosa, M.F. Kutalik, Z. Mangino, M. Scherag, A. Smith, A.V. Zhao, J.H. Aben, K.K. Absher, D.M. Dixon, A.L. Fisher, E. Glazer, N.L. Goddard, M.E. Heard-Costa, N.L. Hoesel, V. Hottenga, J.-J. Johansson, A. Johnson, T. Ketkar, S. Lamina, C. Li, S. Moffatt, M.F. Myers, R.H. Peters, M.J. Preuss, M. Ripatti, S. Rivadeneira, F. Sandholt, C. Timpson, N.J. Tyrer, J.P. Van Wingerden, S. White, C.C. Wiklund, F. Barlassina, C. Chasman, D.I. Cooper, M.N. Jansson, J.-O. Lawrence, R.W. Pellikka, N. Shi, J. Thiering, E. Alavere, H. Alibrandi, M.T.S. Arnold, A.M. Aspelund, T. Atwood, L.D. Balmforth, A.J. Ben-Shlomo, Y. Bergmann, S. Biebermann, H. Blakemore, A.I.F. Boes, T. Bornstein, S.R. Brown, M.J. Buchanan, T.A. Busonero, F. Cappuccio, F.P. Cavalcanti-Proenca, C. Chen, Y.-D.I. Chen, C.-M. Clarke, R. Coin, L. Connell, J. Day, I.N.M. Den Heijer, M. Duan, J. Ebrahim, S. Elliott, P. Elosua, R. Eiriksdottir, G. Facheris, M.F. Felix, S.B. Fischer-Posovszky, P. Folsom, A.R. Friedrich, N. Freimer, N.B. Fu, M. Gaget, S. Gejman, P.V. Geus, E.J.C. Gjesing, A.P. Goyette, P. Grasler, J. Greenawalt, D.M. Gudnason, V. Hartikainen, A.-L. Hall, A.S. Havulinna, A.S. Hayward, C. Heath, A.C. Hengstenberg, C. Hicks, A.A. Hinney, A. Homuth, G. Hui, J. Igl, W. Iribarren, C. Jacobs, K.B. Jarick, I. Jewell, E. John, U. Jousilahti, P. Jula, A. Kaakinen, M. Kaplan, L.M. Kathiresan, S. Kettunen, J. Kinnunen, L. Knowles, J.W. Kolcic, I. König, I.R. Koskinen, S. Kovacs, P. Kvaloy, K. Laitinen, J. Lantieri, O. Lanzani, C. Launer, L.J. Lecoeur, C. Lehtimaki, T. Lettre, G. Liu, J. Lokki, M.-L. Lorentzon, M. Luben, R.N. Ludwig, B. Manunta, P. Marek, D. Martin, N.G. McArdle, W.L. McCarthy, A. McKnight, B. Melander, O. Meyre, D. Montgomery, G.W. Mulic, R. Ngwa, J.S. Nelis, M. Neville, M.J. Nyholt, D.R. O'Donnell, C.J. O'Rahilly, S. Ong, K.K. Oostra, B. Pare, G. Parker, A.N. Perola, M. Pichler, I. Pietilainen, K.H. Platou, C.G.P. Polasek, O. Pouta, A. Rafelt, S. Raitakari, O. Rayner, N.W. Ridderstrale, M. Rief, W. Ruokonen, A. Rzehak, P. Salomaa, V. Sanders, A.R. Sandhu, M.S. Sanna, S. Saramies, J. Savolainen, M.J. Scherag, S. Schipf, S. Schreiber, S. Schunkert, H. Silander, K. Sinisalo, J. Siscovick, D.S. Smit, J.H. Soranzo, N. Sovio, U. Stephens, J. Surakka, I. Tammesoo, M.-L. Tardif, J.-C. Teder-Laving, M. Teslovich, T.M. Thompson, J.R. Thomson, B. Tonjes, A. Van Meurs, J.B.J. Van Ommen, G.-J. Vatin, V. Viikari, J. Visvikis-Siest, S. Vitart, V. Vogel, C.I.G. Waite, L.L. Wallaschofski, H. Widen, E. Wiegand, S. Wild, S.H. Willemsen, G. Witte, D.R. Xu, J. Zhang, Q. Zgaga, L. Ziegler, A. Zitting, P. Beilby, J.P. Farooqi, I.S. Hebebrand, J. Huikuri, H.V. James, A.L. Kahonen, M. Levinson, D.F. Macciardi, F. Nieminen, M.S. Ohlsson, C. Palmer, L.J. Ridker, P.M. Stumvoll, M. Beckmann, J.S. Boeing, H. Boomsma, D.I. Caulfield, M.J. Chanock, S.J. Cupples, L.A. Smith, G.D. Erdmann, J. Gronberg, H. Hall, P. Harris, T.B. Hayes, R.B. Heinrich, J. Jarvelin, M.-R. Kaprio, J. Karpe, F. Khaw, K.-T. Kiemeney, L.A. Krude, H. Lawlor, D.A. Metspalu, A. Munroe, P.B. Ouwehand, W.H. Penninx, B.W. Peters, A. Quertermous, T. Reinehr, T. Rissanen, A. Samani, N.J. Schwarz, P.E.H. Shuldiner, A.R. Spector, T.D. Uda, M. Valle, T.T. Wabitsch, M. Waeber, G. Watkins, H. Wright, A.F. Zillikens, M.C. Chatterjee, N. Purcell, S. Schadt, E.E. Visscher, P.M. Assimes, T.L. Borecki, I.B. Deloukas, P. Haritunians, T. Kaplan, R.C. O'Connell, J.R. Peltonen, L. Schlessinger, D. Strachan, D.P. North, K.E. Hirschhorn, J.N. Ingelsson, E. Parts, L. Glass, D. Nisbet, J. Barrett, A. Sekowska, M. Potter, S. Grundberg, E. Small, K. Hedman, A.K. Bataille, V. Bell, J.T. Surdulescu, G. Ingle, C. Nestle, F.O. Di Meglio, P. Min, J.L. Wilk, A. Hammond, C.J. Yang, T.-P. Montgomery, S.B. Zondervan, K.T. Durbin, R. Ahmadi, K. Dermitzakis, E.T. Reilly, M.P. Holm, H. Stewart, A.F.R. Barbalic, M. Aherrahrou, Z. Allayee, H. Anand, S.S. Andersen, K. Anderson, J.L. Ardissino, D. Ball, S.G. Barnes, T.A. Becker, D.M. Becker, L.C. Berger, K. Bis, J.C. Boekholdt, S.M. Braund, P.S. Burnett, M.S. Buysschaert, I. Carlquist, J.F. Chen, L. Codd, V. Davies, R.W. Cichon, S. Dedoussis, G.V. Demissie, S. Dehghan, A. Devaney, J.M. Diemert, P. Do, R. Doering, A. Eifert, S. El Mokhtari, N.E. Ellis, S.G. Engert, J.C. Epstein, S.E. De Faire, U. Fischer, M. Freyer, J. Gigante, B. Girelli, D. Gretarsdottir, S. Gulcher, J.R. Halperin, E. Hammond, N. Hazen, S.L. Horne, B.D. Jones, G.T. Jukema, J.W. Kaiser, M.A. Kastelein, J.J.P. Kolovou, G. Laaksonen, R. Lambrechts, D. Leander, K. Li, M. Lieb, W. Loley, C. Lotery, A.J. Mannucci, P.M. Maouche, S. Martinelli, N. McKeown, P.P. Meisinger, C. Merlini, P.A. Mooser, V. Morgan, T. Mühleisen, T.W. Muhlestein, J.B. Münzel, T. Musunuru, K. Nahrstaedt, J. Nelson, C.P. Nöthen, M.M. Olivieri, O. Patel, R.S. Patterson, C.C. Peyvandi, F. Qu, L. Quyyumi, A.A. Rader, D.J. Rallidis, L.S. Rice, C. Rosendaal, F.R. Rubin, D. Sampietro, M.L. Sandhu, M.S. Schadt, E. Schäfer, A. Schillert, A. Schrezenmeir, J. Schwartz, S.M. Sivananthan, M. Sivapalaratnam, S. Smith, T.B. Snoep, J.D. Spertus, J.A. Stark, K. Stoll, M. Wilson Tang, W.H. Tennstedt, S. Thorgeirsson, G. Tomaszewski, M. Van Rij, A.M. Wells, G.A. Wild, P.S. Willenborg, C. Wright, B.J. Ye, S. Zeller, T. Cambien, F. Goodall, A.H. Marz, W. Blankenberg, S. Roberts, R. McPherson, R. Hopewell, J.C. Parish, S. Offer, A. Bowman, L. Sleight, P. Armitage, J. Peto, R. Collins, R. Chambers, J.C. Ahmed, N. Donnelly, P. Kooner, A.S. Scott, J. Sehmi, J. Zhang, W. Kooner, J. Sabater-Lleal, M. Mälarstig, A. Hellénius, M.-L. Olsson, G. Rust, S. Assmann, G. Seedorf, U. Barlera, S. Tognoni, G. Franzosi, M.G. Linksted, P. Ongen, H. Kyriakou, T. Green, F. Farrall, M. Saleheen, D. Rasheed, A. Zaidi, M. Shah, N. Samuel, M. Mallick, N. Azhar, M. Zaman, K. Samad, A. Ishaq, M. Gardezi, A. Memon, F.-U.-R. Frossard, P. Danesh, J. Östenson, C.-G. Lind, L. Cooper, C.C. Serrano-Ríos, M. Ferrannini, E. Forsen, T.J. Pattou, F. Langenberg, C. Hamsten, A. Florez, J.C.

Subjects
endocrine system, endocrine system diseases, nutritional and metabolic diseases
Abstract

OBJECTIVE - Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired b-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS - We have conducted a meta-analysis of genome-wide association tests of ;2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS - Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10-8). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/ C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 3 10-4), improved b-cell function (P = 1.1 × 10-5), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10-6). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS - We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis. © 2011 by the American Diabetes Association.

Published
2011

12. A Genome-Wide Association Study Identifies an Osteoarthritis Susceptibility Locus on Chromosome 7q22

Author

Kerkhof, H.J.M., Lories, R.J., Meulenbelt, I., Jonsdottir, I., Valdes, A.M., Arp, P., Ingvarsson, T., Jhamai, M., Jonsson, H., Stolk, L., Thorleifsson, G., Zhai, G.J., Zhang, F., Zhu, Y.Y., Breggen, R. van der, Carr, A., Doherty, M., Doherty, S., Felson, D.T., Gonzalez, A., Halldorsson, B.V., Hart, D.J., Hauksson, V.B., Hofman, A., Ioannidis, J.P.A., Kloppenburg, M., Lane, N.E., Loughlin, J., Luyten, F.P., Nevitt, M.C., Parimi, N., Pols, H.A.P., Rivadeneira, F., Slagboom, E.P., Styrkarsdottir, U., Tsezou, A., Putte, T. van de, Zmuda, J., Spector, T.D., Stefansson, K., Uitterlinden, A.G., and Meurs, J.B.J. van

Subjects
Cartilage, Articular, Male, Osteoarthritis, Knee/ethnology/*genetics, Papain/pharmacology, Synovial Membrane/drug effects/pathology/physiology, Polymorphism, Single Nucleotide, Osteoarthritis, Hip, White People, Article, Receptors, G-Protein-Coupled, Cell Line, Mice, Risk Factors, Papain, Prevalence, Animals, Chromosomes, Human, Pair 7, Humans, Genetic Predisposition to Disease, Lymphocytes, Genome-Wide Association Study, Osteoarthritis, Hip/ethnology/*genetics, protein-kinase-a rii-beta-subunit knee osteoarthritis osteoporotic fractures general-population hand osteoarthritis risk gdf5 hip expression, Netherlands, Synovial Membrane, Serum Albumin, Bovine, Serum Albumin, Bovine/pharmacology, Lymphocytes/cytology/physiology, Osteoarthritis, Knee, European Continental Ancestry Group/*genetics/statistics & numerical data, Phenotype, Cartilage, Articular/drug effects/pathology/physiology, Female, Receptors, G-Protein-Coupled/genetics
Abstract

OBJECTIVE: To identify novel genes involved in osteoarthritis (OA), by means of a genome-wide association study. METHODS: We tested 500,510 single-nucleotide polymorphisms (SNPs) in 1,341 Dutch Caucasian OA cases and 3,496 Dutch Caucasian controls. SNPs associated with at least 2 OA phenotypes were analyzed in 14,938 OA cases and approximately 39,000 controls. Meta-analyses were performed using the program Comprehensive Meta-analysis, with P values

Published
2010

13. Common genetic loci influencing plasma homocysteine concentrations and their effect on risk of coronary artery disease

Author

Meurs, J.B.J. van, Pare, G., Schwartz, S.M., Hazra, A., Tanaka, T., Vermeulen, S., Cotlarciuc, I., Yuan, X., Malarstig, A., Bandinelli, S., Bis, J.C., Blom, H., Brown, M.J., Chen, C., Chen, Y.D., Clarke, R.J., Dehghan, A., Erdmann, J., Ferrucci, L., Hamsten, A., Hofman, A., Hunter, D.J., Goel, A., Johnson, A.D., Kathiresan, S., Kampman, E., Kiel, D.P., Kiemeney, L.A.L.M., Chambers, J.C., Kraft, P., Lindemans, J., McKnight, B., Nelson, C.P., O'Donnell, C.J., Psaty, B.M., Ridker, P.M., Rivadeneira, F., Rose, L.M., Seedorf, U., Siscovick, D.S., Schunkert, H., Selhub, J., Ueland, P.M., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Witteman, J.C., Heijer, M. den, Jacques, P., Uitterlinden, A.G., Kooner, J.S., Rader, D.J., Reilly, M.P., Mooser, V., Chasman, D.I., Samani, N.J., Ahmadi, K.R., Meurs, J.B.J. van, Pare, G., Schwartz, S.M., Hazra, A., Tanaka, T., Vermeulen, S., Cotlarciuc, I., Yuan, X., Malarstig, A., Bandinelli, S., Bis, J.C., Blom, H., Brown, M.J., Chen, C., Chen, Y.D., Clarke, R.J., Dehghan, A., Erdmann, J., Ferrucci, L., Hamsten, A., Hofman, A., Hunter, D.J., Goel, A., Johnson, A.D., Kathiresan, S., Kampman, E., Kiel, D.P., Kiemeney, L.A.L.M., Chambers, J.C., Kraft, P., Lindemans, J., McKnight, B., Nelson, C.P., O'Donnell, C.J., Psaty, B.M., Ridker, P.M., Rivadeneira, F., Rose, L.M., Seedorf, U., Siscovick, D.S., Schunkert, H., Selhub, J., Ueland, P.M., Vollenweider, P., Waeber, G., Waterworth, D.M., Watkins, H., Witteman, J.C., Heijer, M. den, Jacques, P., Uitterlinden, A.G., Kooner, J.S., Rader, D.J., Reilly, M.P., Mooser, V., Chasman, D.I., Samani, N.J., and Ahmadi, K.R.

Abstract

Item does not contain fulltext, BACKGROUND: The strong observational association between total homocysteine (tHcy) concentrations and risk of coronary artery disease (CAD) and the null associations in the homocysteine-lowering trials have prompted the need to identify genetic variants associated with homocysteine concentrations and risk of CAD. OBJECTIVE: We tested whether common genetic polymorphisms associated with variation in tHcy are also associated with CAD. DESIGN: We conducted a meta-analysis of genome-wide association studies (GWAS) on tHcy concentrations in 44,147 individuals of European descent. Polymorphisms associated with tHcy (P < 10(-8)) were tested for association with CAD in 31,400 cases and 92,927 controls. RESULTS: Common variants at 13 loci, explaining 5.9% of the variation in tHcy, were associated with tHcy concentrations, including 6 novel loci in or near MMACHC (2.1 x 10(-9)), SLC17A3 (1.0 x 10(-8)), GTPB10 (1.7 x 10(-8)), CUBN (7.5 x 10(-10)), HNF1A (1.2 x 10(-12)), and FUT2 (6.6 x 10(-9)), and variants previously reported at or near the MTHFR, MTR, CPS1, MUT, NOX4, DPEP1, and CBS genes. Individuals within the highest 10% of the genotype risk score (GRS) had 3-mumol/L higher mean tHcy concentrations than did those within the lowest 10% of the GRS (P = 1 x 10(-36)). The GRS was not associated with risk of CAD (OR: 1.01; 95% CI: 0.98, 1.04; P = 0.49). CONCLUSIONS: We identified several novel loci that influence plasma tHcy concentrations. Overall, common genetic variants that influence plasma tHcy concentrations are not associated with risk of CAD in white populations, which further refutes the causal relevance of moderately elevated tHcy concentrations and tHcy-related pathways for CAD.

Published
2013

15. Cleavage of aggrecan at ASN341-PHE342 site coincides with the initiation of collagen damage in murine antigen induced arthritis. A pivotal role for stromelysin-1 in MMP-cativity

Author

Meurs, J.B.J. van, Lent, P.L.E.M. van, Stoop, R., Holthuysen, A.E.M., Singer, I.I., Bayne, E.K., Mudgett, J.S., Poole, A.R., Billinghurst, R.C., Kraan, P.M. van der, Buma, P., and Berg, W.B. van den

Subjects
The importance of collagen destruction in irreversible cartilage damage in arthritis and arthrosis, Het belang van collageenafbraak bij irreversibele kraakbeendestructie in arthritis en osteoarthrose, Kraakbeenafbraak en chondrocytschade bij gewrichtsontstekingen, Cartilage degradation and chondrocyte damage in inflammatory processes
Abstract

Item does not contain fulltext

Published
1999

16. Adenoviral vector-mediated overexpression of IL-4 in the knee joint of mice with collagen-induced arthritis prevents cartilage destruction

Author

Lubberts, G.J.H., Joosten, L.A.B., Bersselaar, L.A.M. van den, Helsen, M.M.A., Bakker, A.C., Meurs, J.B.J. van, Graham, F.L., Richards, C.D., and Berg, W.B. van den

Subjects
Rol van IL-4, IL-10 en T6Fbeta [Modulatie van exacerbaties van chronische arthritis], Role of IL-4, IL-10 and T6Fbeta [Modulation of flares of chronic arthritis]
Abstract

Item does not contain fulltext 11 p.

Published
1999

18. The role of Matrix Metalloproteinases in cartilage destruction during murine arthritis

Author

Meurs, J.B.J. van, Berg, W.B. van den, Lent, P.L.E.M. van, and Radboud University Nijmegen

Subjects
Pathogenese en behandeling [Chronische arthritis], Pathogenesis and treatment [Chronic arthritis]
Abstract

Item does not contain fulltext University Hospital Nijmegen, 07 december 1998 Promotor : Berg, W.B. van den Co-promotor : Lent, P.L.E.M. van 171 p.

Published
1998

19. Estrogen Receptor Gene Polymorphisms Associated with Incident Aging Macula Disorder

Author

Boekhoorn, S.S., Vingerling, J.R., Uitterlinden, A.G., Meurs, J.B.J. van, Duijn, C.M. van, Pols, H.A.P., Hofman, A., de Jong, P.T.V.M., Boekhoorn, S.S., Vingerling, J.R., Uitterlinden, A.G., Meurs, J.B.J. van, Duijn, C.M. van, Pols, H.A.P., Hofman, A., and de Jong, P.T.V.M.

Abstract

PURPOSE. It has been suggested that early menopause increases the risk of aging-macula disorder (AMD), the major cause of incurable blindness with a dry and wet late subtype, and that exposure to endogenous or postmenopausal exogenous estrogens reduces this risk. This study was undertaken to investigate whether genetic variations in the estrogen receptor a(ESR1) gene are associated with incident AMD. METHODS. In the Rotterdam Study, a prospective population-based cohort study of participants aged 55 years and older, associations between ESR1 PvuII-XbaI haplotypes and incident early or late AMD were studied in 4571 participants after a mean follow-up time of 7.7 years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), with adjustment for the most common confounders. RESULTS. ESR1 PvuII-XbaI haplotype 1 was a risk factor for late AMD. Persons with two copies of haplotype 1 were at 3.20 (95% CI, 1.47¿6.99) times higher risk for late AMD than noncarriers of haplotype 1, after adjustment for age and sex. This increase was more pronounced for wet AMD (hazard ratio [HR] 4.29; 95% CI, 1.47¿12.49) after adjustment for age, sex, smoking, and complement factor H genotype. Correction for additional confounders, including age at menopause, use of hormone replacement therapy, blood pressure, and body mass index did not essentially alter the findings. CONCLUSIONS. Persons with one or two copies of ESR1 PvuII-XbaI haplotype 1 have an increased risk of late AMD, especially of the wet form., PURPOSE. It has been suggested that early menopause increases the risk of aging-macula disorder (AMD), the major cause of incurable blindness with a dry and wet late subtype, and that exposure to endogenous or postmenopausal exogenous estrogens reduces this risk. This study was undertaken to investigate whether genetic variations in the estrogen receptor a(ESR1) gene are associated with incident AMD. METHODS. In the Rotterdam Study, a prospective population-based cohort study of participants aged 55 years and older, associations between ESR1 PvuII-XbaI haplotypes and incident early or late AMD were studied in 4571 participants after a mean follow-up time of 7.7 years. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs), with adjustment for the most common confounders. RESULTS. ESR1 PvuII-XbaI haplotype 1 was a risk factor for late AMD. Persons with two copies of haplotype 1 were at 3.20 (95% CI, 1.47¿6.99) times higher risk for late AMD than noncarriers of haplotype 1, after adjustment for age and sex. This increase was more pronounced for wet AMD (hazard ratio [HR] 4.29; 95% CI, 1.47¿12.49) after adjustment for age, sex, smoking, and complement factor H genotype. Correction for additional confounders, including age at menopause, use of hormone replacement therapy, blood pressure, and body mass index did not essentially alter the findings. CONCLUSIONS. Persons with one or two copies of ESR1 PvuII-XbaI haplotype 1 have an increased risk of late AMD, especially of the wet form.

Published
2007

24. [Untitled]

Author

Willems van Dijk, J.A.P., Verschuren, W.M.M., Dollé, M.E.T., Heijmans, B.T., Rensen, P.C.N., Houtkooper, R.H.L., Meurs, J.B.J. van, and Leiden University

Subjects
Mendelian Randomization, Single nucleotide polymorphism (SNP), Life course epidemiology, Genetics, Environmental factors, Personalized Medicine, Body mass index (BMI), Obesity, Cardiovascular disease, Lipid Metabolism
Abstract

In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity.

Published
2023

25. Genetics and life course epidemiology of cardiometabolic disease: towards personalized medicine

Author

Ibi, D., Willems van Dijk, J.A.P., Verschuren, W.M.M., Dollé, M.E.T., Heijmans, B.T., Rensen, P.C.N., Houtkooper, R.H.L., Meurs, J.B.J. van, and Leiden University

Subjects
Mendelian Randomization, Single nucleotide polymorphism (SNP), Life course epidemiology, Genetics, Environmental factors, Personalized Medicine, Body mass index (BMI), Obesity, Cardiovascular disease, Lipid Metabolism
Abstract

In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity.

Published
2023

26. Aged human osteochondral explants as biomimetic osteoarthritis model

Author

Houtman, E., Meulenbelt, I., Nelissen, R.G.H.H., Ramos, Y.F.M., Slagboom, P.E., Lories, R.J., Kloppenburg, G., Meurs, J.B.J. van, and Leiden University

Subjects
Thyroid hormone, Cartilage, Vitamin K, Osteochondral explants, Mechanical stress, DIO2, Osteoarthritis, MGP, Functional genomics, Iopanoic acid
Abstract

This thesis aims to increase the understanding of human osteoarthritis pathophysiology by developing reliable biomimetic ex vivo human osteochondral explant models and focussing on the role of osteoarthritis-relevant triggers (mechanical stress) and interacting genetic factors for developing treatment targets. Human aged joint tissues were collected in the Research in Articular Osteoarthritis Cartilage (RAAK) biobank. To add knowledge of the osteoarthritis pathophysiological processes, aged human ex vivo osteochondral explants were subject to three osteoarthritis-relevant triggers, being inflammation, hypertrophy and injurious mechanical stress. Next, knowledge on early initiating processes occurring in mechano-pathology was investigated by applying RNA-sequencing to cartilage of aged human osteochondral explants subjected to mechanical stress. In addition, to show that the human osteochondral explant model could also be used for genetic interaction studies, we investigated expression of the osteoarthritis risk gene MGP in relation to rs1800801 genotypes. By combining information from RNA-sequencing datasets of cartilage and bone with osteoarthritis-relevant triggers in cartilage and bone explants we investigated the role of MGP and vitamin K in osteoarthritis. Lastly, the injurious mechanical explant model was exploited to determine the effectivity of inhibiting the osteoarthritis risk gene DIO2 by iopanoic acid treatment either by burst or prolonged release from PLGA-PEG nanoparticles.

Published
2022

27. Pro-resolving fatty acids and oxylipids in osteoarthritis and rheumatoid arthritis

Author

Brouwers, H., Toes, R.E.M., Kloppenburg, G., Ioan-Facsinay, A., Huizinga, T.W.J., Meulenbelt, I., Meurs, J.B.J. van, Mastbergen, S.C., and Leiden University

Subjects
Specialized pro-resolving lipid mediators, Osteoarthritis, Lipidomics, Synovial fluid, Rheumatoid arthritis, Fatty acids
Abstract

The studies described in this thesis provides the field with valuable data on the potential therapeutic effects of fatty acids and specialized pro-resolving lipid mediators in rheumatoid arthritis and osteoarthritis. The omega-6 fatty acid AdA shows potent pro-resolving effects on the production of pro-inflammatory chemoattractantLTB4 with great promise to limit RA disease progression. In contrast to the promising potential therapeutic effects of AdA in RA, the evidence for pro-resolving effects in OA is still scarce. The results of the studies from this thesis show that neither LXA4, LXB4, RvE2 or Mar-1 were able to reduce OA disease activity in the experimental set-up we used. Finally, the studies described in this thesis show the utmost critical importance of the right sample preparation and storage for the intended subsequent analysis.

Published
2022

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