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7 results on '"Eline Slagboom P"'

1. DNA Methylation Signatures of Educational Attainment

Author

Jenny van Dongen, Marc Jan Bonder, Koen F. Dekkers, Michel G. Nivard, Maarten van Iterson, Gonneke Willemsen, Marian Beekman, Ashley van der Spek, Joyce B. J. van Meurs, Lude Franke, Bastiaan T. Heijmans, Cornelia M. van Duijn, P. Eline Slagboom, Dorret I. Boomsma, and BIOS Consortium

Abstract

Educational attainment is a key behavioural measure in studies of cognitive and physical health, and socioeconomic status. We measured DNA methylation at 410,746 CpGs (N = 4152) and identified 58 CpGs associated with educational attainment at loci characterized by pleiotropic functions shared with neuronal, immune and developmental processes. Associations overlapped with those for smoking behaviour, but remained after accounting for smoking at many CpGs: Effect sizes were on average 28% smaller and genome-wide significant at 11 CpGs after adjusting for smoking and were 62% smaller in never smokers. We examined sources and biological implications of education-related methylation differences, demonstrating correlations with maternal prenatal folate, smoking and air pollution signatures, and associations with gene expression in cis, dynamic methylation in foetal brain, and correlations between blood and brain. Our findings show that the methylome of lower-educated people resembles that of smokers beyond effects of their own smoking behaviour and shows traces of various other exposures.

Published
2018
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2. Genome of the Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels

Author

van Leeuwen, Elisabeth M, Karssen, Lennart C, Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, van Enckevort, David J, Huffman, Jennifer E, White, Charles C, Feitosa, Mary F, Bartz, Traci M, Manichaikul, Ani, Joshi, Peter K, Peloso, Gina M, Deelen, Patrick, van Dijk, Freerk, Willemsen, Gonneke, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Francioli, Laurent C, Menelaou, Androniki, Pulit, Sara L, Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A, Franco, Oscar H, Leach, Irene Mateo, Beekman, Marian, de Craen, Anton JM, Uh, Hae-Won, Trochet, Holly, Hocking, Lynne J, Porteous, David J, Sattar, Naveed, Packard, Chris J, Buckley, Brendan M, Brody, Jennifer A, Bis, Joshua C, Rotter, Jerome I, Mychaleckyj, Josyf C, Campbell, Harry, Duan, Qing, Lange, Leslie A, Wilson, James F, Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F, Rich, Stephen S, Psaty, Bruce M, Borecki, Ingrid B, Kearney, Patricia M, Stott, David J, Adrienne Cupples, L, Jukema, J Wouter, van der Harst, Pim, Sijbrands, Eric J, Hottenga, Jouke-Jan, Uitterlinden, Andre G, Swertz, Morris A, van Ommen, Gert-Jan B, de Bakker, Paul IW, Eline Slagboom, P, Boomsma, Dorret I, Wijmenga, Cisca, and van Duijn, Cornelia M

Subjects
Biological Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, ATP-Binding Cassette Transporters, Cholesterol, Gene Frequency, Genetic Association Studies, Humans, Mutation, Missense, Netherlands, Genome of The Netherlands Consortium
Abstract

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value

Published
2015

3. Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins

Author

Postmus, Iris, Trompet, Stella, Deshmukh, Harshal A, Barnes, Michael R, Li, Xiaohui, Warren, Helen R, Chasman, Daniel I, Zhou, Kaixin, Arsenault, Benoit J, Donnelly, Louise A, Wiggins, Kerri L, Avery, Christy L, Griffin, Paula, Feng, QiPing, Taylor, Kent D, Li, Guo, Evans, Daniel S, Smith, Albert V, de Keyser, Catherine E, Johnson, Andrew D, de Craen, Anton JM, Stott, David J, Buckley, Brendan M, Ford, Ian, Westendorp, Rudi GJ, Eline Slagboom, P, Sattar, Naveed, Munroe, Patricia B, Sever, Peter, Poulter, Neil, Stanton, Alice, Shields, Denis C, O’Brien, Eoin, Shaw-Hawkins, Sue, Ida Chen, Y-D, Nickerson, Deborah A, Smith, Joshua D, Pierre Dubé, Marie, Matthijs Boekholdt, S, Kees Hovingh, G, Kastelein, John JP, McKeigue, Paul M, Betteridge, John, Neil, Andrew, Durrington, Paul N, Doney, Alex, Carr, Fiona, Morris, Andrew, McCarthy, Mark I, Groop, Leif, Ahlqvist, Emma, Bis, Joshua C, Rice, Kenneth, Smith, Nicholas L, Lumley, Thomas, Whitsel, Eric A, Stürmer, Til, Boerwinkle, Eric, Ngwa, Julius S, O’Donnell, Christopher J, Vasan, Ramachandran S, Wei, Wei-Qi, Wilke, Russell A, Liu, Ching-Ti, Sun, Fangui, Guo, Xiuqing, Heckbert, Susan R, Post, Wendy, Sotoodehnia, Nona, Arnold, Alice M, Stafford, Jeanette M, Ding, Jingzhong, Herrington, David M, Kritchevsky, Stephen B, Eiriksdottir, Gudny, Launer, Leonore J, Harris, Tamara B, Chu, Audrey Y, Giulianini, Franco, MacFadyen, Jean G, Barratt, Bryan J, Nyberg, Fredrik, Stricker, Bruno H, Uitterlinden, André G, Hofman, Albert, Rivadeneira, Fernando, Emilsson, Valur, Franco, Oscar H, Ridker, Paul M, Gudnason, Vilmundur, Liu, Yongmei, Denny, Joshua C, Ballantyne, Christie M, Rotter, Jerome I, Adrienne Cupples, L, Psaty, Bruce M, Palmer, Colin NA, Tardif, Jean-Claude, Colhoun, Helen M, and Hitman, Graham

Subjects
Pharmacology and Pharmaceutical Sciences, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Cardiovascular, Cholesterol, LDL, Genome-Wide Association Study, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pharmacogenetics, Polymorphism, Single Nucleotide, Welcome Trust Case Control Consortium
Abstract

Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.

Published
2014

4. Significant locus and metabolic genetic correlations revealed in genome-wide association study of anorexia nervosa

Author

Duncan, Laramie, Yilmaz, Zeynep, Gaspar, Helena, Walters, Raymond, Goldstein, Jackie, Anttila, Verneri, Bulik-Sullivan, Brendan, Ripke, Stephan, Thornton, Laura, Hinney, Anke, Daly, Mark, Sullivan, Patrick F., Zeggini, Eleftheria, Breen, Gerome, Bulik, Cynthia M., Gaspar, Héléna, Adan, Roger, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole, Aschauer, Harald, Baker, Jessica, Barrett, Jeffrey, Bencko, Vladimir, Bergen, Andrew, Berrettini, Wade, Birgegård, Andreas, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Cesta, Carolyn, Cichon, Sven, Clementi, Maurizio, Cohen-Woods, Sarah, Coleman, Joni, Cone, Roger, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, Jim, Danner, Unna, Davis, Oliver, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, Desocio, Janiece, Danielle, Dick, Dikeos, Dimitris, Dina, Christian, Ding, Bo, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Egberts, Karin, Ehrlich, Stefan, Escaramís, Geòrgia, Esko, Tõnu, Espeseth, Thomas, Estivill, Xavier, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred, Finan, Chris, Fischer, Krista, Floyd, James, Föcker, Manuel, Foretova, Lenka, Forzan, Monica, Fox, Caroline, Franklin, Christopher, Gaborieau, Valerie, Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos, Monica, Guillaume, Sébastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine, Harrison, Rebecca, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske, Hendriks, Judith, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hilliard, Christopher, Huckins, Laura, Hudson, James, Huemer, Julia, Imgart, Hartmut, Inoko, Hidetoshi, Jall, Sigrid, Jamain, Stephane, Janout, Vladimir, Jiménez-Murcia, Susana, Johnson, Craig, Jordan, Jenny, Julià, Antonio, Juréus, Anders, Kalsi, Gursharan, Kaplan, Allan, Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien, Kaye, Walter, Kennedy, Martin, Kennedy, James, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klareskog, Lars, Klump, Kelly, Knudsen, Gun Peggy, Koeleman, Bobby, Koubek, Doris, La Via, Maria, Landén, Mikael, Le Hellard, Stephanie, Leboyer, Marion, Levitan, Robert, Dong, Li, Lichtenstein, Paul, Lilenfeld, Lisa, Lissowska, Jolanta, Lundervold, Astri, Magistretti, Pierre, Maj, Mario, Mannik, Katrin, Marsal, Sara, Kaminska, Debora, Martin, Nicholas, Mattingsdal, Morten, Mcdevitt, Sara, Mcguffin, Peter, Merl, Elisabeth, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, James, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Montgomery, Grant, Mortensen, Preben, Munn-Chernoff, Melissa, Müller, Timo, Nacmias, Benedetta, Navratilova, Marie, Nilsson, Ida, Norring, Claes, Ntalla, Ioanna, Ophoff, Roel, O’Toole, Julie, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Parker, Richard, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Rajewski, Andrzej, Ramoz, Nicolas, William Rayner, N., Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, André, Scherer, Stephen, Schmidt, Ulrike, Schork, Nicholas, Schosser, Alexandra, Scott, Laura, Seitz, Jochen, Slachtova, Lenka, Sladek, Robert, Eline Slagboom, P., Slof-Op ’t Landt, Margarita, Slopien, Agnieszka, Smith, Tosha, Soranzo, Nicole, Sorbi, Sandro, Southam, Lorraine, Steen, Vidar, Strengman, Eric, Strober, Michael, Szatkiewicz, Jin, Szeszenia-Dabrowska, Neonila, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tschöp, Matthias, Tsitsika, Artemis, Tziouvas, Konstantinos, van Elburg, Annemarie, van Furth, Eric, Wade, Tracey, Wagner, Gudrun, Walton, Esther, Watson, Hunna, Wichmann, H-Erich, Widen, Elisabeth, Woodside, Blake, Yanovski, Jack, Yao, Shuyang, Zerwas, Stephanie, Zipfel, Stephan, Duncan, Laramie, Yilmaz, Zeynep, Gaspar, Helena, Walters, Raymond, Goldstein, Jackie, Anttila, Verneri, Bulik-Sullivan, Brendan, Ripke, Stephan, Thornton, Laura, Hinney, Anke, Daly, Mark, Sullivan, Patrick F., Zeggini, Eleftheria, Breen, Gerome, Bulik, Cynthia M., Gaspar, Hã©lã©na, Adan, Roger, Alfredsson, Lar, Ando, Tetsuya, Andreassen, Ole, Aschauer, Harald, Baker, Jessica, Barrett, Jeffrey, Bencko, Vladimir, Bergen, Andrew, Berrettini, Wade, Birgegã¥rd, Andrea, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Cesta, Carolyn, Cichon, Sven, Clementi, Maurizio, Cohen-Woods, Sarah, Coleman, Joni, Cone, Roger, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, Jim, Danner, Unna, Davis, Oliver, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, Desocio, Janiece, Danielle, Dick, Dikeos, Dimitri, Dina, Christian, Ding, Bo, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Egberts, Karin, Ehrlich, Stefan, Escaramã­s, Geã²rgia, Esko, Tãµnu, Espeseth, Thoma, Estivill, Xavier, Favaro, Angela, Fernández-Aranda, Fernando, Fichter, Manfred, Finan, Chri, Fischer, Krista, Floyd, Jame, Fã¶cker, Manuel, Foretova, Lenka, Forzan, Monica, Fox, Caroline, Franklin, Christopher, Gaborieau, Valerie, Gallinger, Steven, Gambaro, Giovanni, Giegling, Ina, Gonidakis, Fragisko, Gorwood, Philip, Gratacos, Monica, Guillaume, Sã©bastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine, Harrison, Rebecca, Hatzikotoulas, Konstantino, Hauser, Joanna, Hebebrand, Johanne, Helder, Sietske, Hendriks, Judith, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hilliard, Christopher, Huckins, Laura, Hudson, Jame, Huemer, Julia, Imgart, Hartmut, Inoko, Hidetoshi, Jall, Sigrid, Jamain, Stephane, Janout, Vladimir, Jiménez-Murcia, Susana, Johnson, Craig, Jordan, Jenny, Juliã , Antonio, Jurã©us, Ander, Kalsi, Gursharan, Kaplan, Allan, Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andrea, Kas, Martien, Kaye, Walter, Kennedy, Martin, Kennedy, Jame, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klareskog, Lar, Klump, Kelly, Knudsen, Gun Peggy, Koeleman, Bobby, Koubek, Dori, La Via, Maria, Landã©n, Mikael, Le Hellard, Stephanie, Leboyer, Marion, Levitan, Robert, Li, Dong, Lichtenstein, Paul, Lilenfeld, Lisa, Lissowska, Jolanta, Lundervold, Astri, Magistretti, Pierre, Maj, Mario, Mannik, Katrin, Marsal, Sara, Kaminska, Debora, Martin, Nichola, Mattingsdal, Morten, Mcdevitt, Sara, Mcguffin, Peter, Merl, Elisabeth, Metspalu, Andre, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, Jame, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Montgomery, Grant, Mortensen, Preben, Munn-Chernoff, Melissa, Mã¼ller, Timo, Nacmias, Benedetta, Navratilova, Marie, Nilsson, Ida, Norring, Clae, Ntalla, Ioanna, Ophoff, Roel, Oâ toole, Julie, Palotie, Aarno, Pantel, Jacque, Papezova, Hana, Parker, Richard, Pinto, Dalila, Rabionet, Raquel, Raevuori, Anu, Rajewski, Andrzej, Ramoz, Nicola, William Rayner, N., Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rujescu, Dan, Rybakowski, Filip, Santonastaso, Paolo, Scherag, Andrã©, Scherer, Stephen, Schmidt, Ulrike, Schork, Nichola, Schosser, Alexandra, Scott, Laura, Seitz, Jochen, Slachtova, Lenka, Sladek, Robert, Eline Slagboom, P., Slof-Op â t Landt, Margarita, Slopien, Agnieszka, Smith, Tosha, Soranzo, Nicole, Sorbi, Sandro, Southam, Lorraine, Steen, Vidar, Strengman, Eric, Strober, Michael, Szatkiewicz, Jin, Szeszenia-Dabrowska, Neonila, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tschã¶p, Matthia, Tsitsika, Artemi, Tziouvas, Konstantino, van Elburg, Annemarie, van Furth, Eric, Wade, Tracey, Wagner, Gudrun, Walton, Esther, Watson, Hunna, Wichmann, H-Erich, Widen, Elisabeth, Woodside, Blake, Yanovski, Jack, Yao, Shuyang, Zerwas, Stephanie, Zipfel, Stephan, Universitat de Barcelona, and Kas lab

Subjects
0301 basic medicine, Linkage disequilibrium, Anorexia Nervosa, Eating Disorders, Medizin, Genome-wide association study, Diabete, Linkage Disequilibrium, Diabetes, GWAS, Genetics, Metabolism, Case-Control Studies, Genetic Predisposition to Disease, Humans, Phenotype, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Psychiatry and Mental Health, 0302 clinical medicine, Anorexia Nervosa/genetics, SCHIZOPHRENIA, Gwas, RISK, Genetic Predisposition to Disease/genetics, PSYCHIATRIC-DISORDERS, Anorèxia nerviosa, Eating Disorder, Single Nucleotide, Polymorphism, Single Nucleotide/genetics, Metabolisme, Psychiatry and Mental health, Psychology, Case-Control Studie, TRAITS, Human, Polymorphism, Single-nucleotide polymorphism, behavioral disciplines and activities, Article, Feeding and Eating Disorders, 03 medical and health sciences, Genetic, mental disorders, Journal Article, Linkage Disequilibrium/genetics, 1000 Genomes Project, Bulimia Nervosa, METAANALYSIS, Genetic association, EATING-DISORDERS, Settore MED/13 - ENDOCRINOLOGIA, Anorexia nervosa, Heritability, Minor allele frequency, 030104 developmental biology, UPDATE, 030217 neurology & neurosurgery, Imputation (genetics), Genètica, Meta-Analysis
Abstract

Objective: The authors conducted a genome-wide association study of anorexia nervosa and calculated genetic correlations with a series of psychiatric, educational, and metabolic phenotypes. Method: Following uniformquality control and imputation procedures using the 1000 Genomes Project (phase 3) in 12 case-control cohorts comprising 3, 495 anorexia nervosa cases and 10, 982 controls, the authors performed standard association analysis followed by a meta-analysis across cohorts. Linkage disequilibrium score regression was used to calculate genome-wide common variant heritability (single-nucleotide polymorphism [SNP]-based heritability [h2 SNP]), partitioned heritability, and genetic correlations (rg) between anorexia nervosa and 159 other phenotypes. Results: Results were obtained for 10, 641, 224 SNPs and insertion-deletion variants with minor allele frequencies.>1% and imputation quality scores >0.6. The h2 SNP of anorexia nervosa was 0.20 (SE=0.02), suggesting that a substantial fraction of the twin-based heritability arises from common genetic variation. The authors identified one genome-wide significant locus on chromosome 12 (rs4622308) in a region harboring a previously reported type 1 diabetes and autoimmune disorder locus. Significant positive genetic correlations were observed between anorexia nervosa and schizophrenia, neuroticism, educational attainment, and high-density lipoprotein cholesterol, and significant negative genetic correlations were observed between anorexia nervosa and body mass index, insulin, glucose, and lipid phenotypes. Conclusions: Anorexia nervosa is a complex heritable phenotype for which this study has uncovered the first genomewide significant locus. Anorexia nervosa also has large and significant genetic correlations with both psychiatric phenotypes and metabolic traits. The study results encourage a reconceptualization of this frequently lethal disorder as one with both psychiatric and metabolic etiology.

Published
2017
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5. A high-quality reference panel reveals the complexity and distribution of structural genome changes in a human population

Author

Jayne Y. Hehir-Kwa, van Ommen Gb, Dijkstra Lj, Guryev, Wigard P. Kloosterman, Andre G. Uitterlinden, Eric-Wubbo Lameijer, Patrick Deelen, de Bakker P, Kai Ye, Thung Dt, René Wardenaar, Alexander Schoenhuth, van Dijk F, Bradley P. Coe, Laurent C. Francioli, Jasmijn A. Baaijens, Ivo Renkens, de Ligt J, Eline Slagboom P, Evan E. Eichler, Fereydoun Hormozdiari, Cisca Wijmenga, Dorret I. Boomsma, Abdel Abdellaoui, Koval, Morris A. Swertz, and Tobias Marschall

Subjects
Genetics, 0303 health sciences, Linkage disequilibrium, education.field_of_study, Population, Computational biology, Biology, Genome, Structural variation, 03 medical and health sciences, 0302 clinical medicine, Human genome, Mobile genetic elements, education, 030217 neurology & neurosurgery, Imputation (genetics), 030304 developmental biology, Genetic association
Abstract

Structural variation (SV) represents a major source of differences between individual human genomes and has been linked to disease phenotypes. However, current studies on SVs have failed to provide a global view of the full spectrum of SVs and to integrate them into reference panels of genetic variation. Here, we analyzed 769 individuals from 250 Dutch families, whole genome sequenced at an average coverage of 14.5x, and provide a haplotype-resolved map of 1.9 million genome variants across 9 different variant classes, including novel forms of complex indels and retrotransposition-mediated insertions of mobile elements and processed RNAs. A large proportion of the structural variants (36%) were discovered in the size range of 21 to 100bp, a size range which remains under reported in many studies. Furthermore, we detected 4 megabases of novel sequence, extending the human pangenome with 11 new active transcripts. Finally, we show 191 known, trait-associated SNPs to be in strong linkage disequilibrium with a structural variant and demonstrate that our panel facilitates accurate imputation of SVs into unrelated individuals, which is essential for future genome-wide association studies.

Published
2016
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6. Leukocyte telomere length associates with prospective mortality independent of immune-related parameters and known genetic markers.

Author

Deelen, Joris, Beekman, Marian, Codd, Veryan, Trompet, Stella, Broer, Linda, Hägg, Sara, Fischer, Krista, Thijssen, Peter E, Suchiman, H Eka D, Postmus, Iris, Uitterlinden, André G, Hofman, Albert, de Craen, Anton J M, Metspalu, Andres, Pedersen, Nancy L, van Duijn, Cornelia M, Wouter Jukema, J, Houwing-Duistermaat, Jeanine J, Samani, Nilesh J, and Eline Slagboom, P

Subjects
LEUKOCYTES, TELOMERES, MORTALITY, GENETIC markers, SOMATOMEDIN C, C-reactive protein, INTERLEUKIN-6
Abstract

Background: Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans.Methods: We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS).Results: We found that shorter LTL is associated with increased prospective mortality in middle (30–80 years; hazard ratio (HR) = 0.75, P = 0.001) and highly advanced age (≥90 years; HR = 0.92, P = 0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (β = 0.006, P = 0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n = 8165).Conclusions: We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity. [ABSTRACT FROM PUBLISHER]

Published
2014
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7. Analysis of the machinery and intermediates of the 5hmC-mediated DNA demethylation pathway in aging on samples from the MARKAGE Study

Author

Valentini, Elisabetta, Zampieri, Michele, Malavolta, Marco, Bacalini, Maria Giulia, Calabrese, Roberta, Guastafierro, Tiziana, Reale, Anna, Franceschi, Claudio, Hervonen, Antti, Koller, Bernhard, Bernhardt, Jürgen, Slagboom, P. Eline, Toussaint, Olivier, Sikora, Ewa, Gonos, Efstathios S, Breusing, Nicolle, Grune, Tilman, Jansen, Eugène, Dollé, Martijn E.T., Moreno-Villanueva, María, Sindlinger, Thilo, Bürkle, Alexander, Ciccarone, Fabio, Caiafa, Paola, Valentini, Elisabetta, Zampieri, Michele, Malavolta, Marco, Bacalini, Maria Giulia, Calabrese, Roberta, Guastafierro, Tiziana, Reale, Anna, Franceschi, Claudio, Hervonen, Antti, Koller, Bernhard, Bernhardt, Jürgen, Eline Slagboom, P., Toussaint, Olivier, Sikora, Ewa, Gonos, Efstathios S., Breusing, Nicolle, Grune, Tilman, Jansen, Eugène, Dollé, Martijn E.T., Moreno-Villanueva, María, Sindlinger, Thilo, Bürkle, Alexander, Ciccarone, Fabio, and Caiafa, Paola

Subjects
0301 basic medicine, DNA Hydroxymethylation, Adult, Male, Aging, Gene Expression, TDG, Biology, Dioxygenases, Mixed Function Oxygenases, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, DNA hydroxymethylation, TET genes, Cell Biology, ddc:570, Proto-Oncogene Proteins, Humans, Epigenetics, Settore BIO/10, Aged, Genetics, Regulation of gene expression, DNA Repair Pathway, DNA Methylation, Middle Aged, 5-Methylcytosine, 030104 developmental biology, DNA demethylation, chemistry, Gene Expression Regulation, genesTET, aging, 030220 oncology & carcinogenesis, DNA methylation, Leukocytes, Mononuclear, TET gene, Female, Thymine-DNA glycosylase, Research Paper
Abstract

Gradual changes in the DNA methylation landscape occur throughout aging virtually in all human tissues. A widespread reduction of 5-methylcytosine (5mC), associated with highly reproducible site-specific hypermethylation, characterizes the genome in aging. Therefore, an equilibrium seems to exist between general and directional deregulating events concerning DNA methylation controllers, which may underpin the age-related epigenetic changes. In this context, 5mC-hydroxylases (TET enzymes) are new potential players. In fact, TETs catalyze the stepwise oxidation of 5mC to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC), driving the DNA demethylation process based on thymine DNA glycosylase (TDG)-mediated DNA repair pathway. The present paper reports the expression of DNA hydroxymethylation components, the levels of 5hmC and of its derivatives in peripheral blood mononuclear cells of age-stratified donors recruited in several European countries in the context of the EU Project 'MARK-AGE'. The results provide evidence for an age-related decline of TET1, TET3 and TDG gene expression along with a decrease of 5hmC and an accumulation of 5caC. These associations were independent of confounding variables, including recruitment center, gender and leukocyte composition. The observed impairment of 5hmC-mediated DNA demethylation pathway in blood cells may lead to aberrant transcriptional programs in the elderly. published

Published
2016

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