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188 Publications visible to you, out of a total of 188
Catalyzing Transcriptomics Research in Cardiovascular Disease: The CardioRNA COST Action CA17129
Genetical Statistics and Systems Biology

Abstract (Expand)

Cardiovascular disease (CVD) remains the leading cause of death worldwide and, despite continuous advances, better diagnostic and prognostic tools, as well as therapy, are needed. The human transcriptome, … which is the set of all RNA produced in a cell, is much more complex than previously thought and the lack of dialogue between researchers and industrials and consensus on guidelines to generate data make it harder to compare and reproduce results. This European Cooperation in Science and Technology (COST) Action aims to accelerate the understanding of transcriptomics in CVD and further the translation of experimental data into usable applications to improve personalized medicine in this field by creating an interdisciplinary network. It aims to provide opportunities for collaboration between stakeholders from complementary backgrounds, allowing the functions of different RNAs and their interactions to be more rapidly deciphered in the cardiovascular context for translation into the clinic, thus fostering personalized medicine and meeting a current public health challenge. Thus, this Action will advance studies on cardiovascular transcriptomics, generate innovative projects, and consolidate the leadership of European research groups in the field.COST (European Cooperation in Science and Technology) is a funding organization for research and innovation networks (www.cost.eu).

Authors: Clarissa Pedrosa da C. Gomes, Bence Ágg, Andrejaana Andova, Serdal Arslan, Andrew Baker, Monika Barteková, Dimitris Beis, Fay Betsou, Stephanie Bezzina Wettinger, Branko Bugarski, Gianluigi Condorelli, Gustavo José Justo da Silva, Sabrina Danilin, David de Gonzalo-Calvo, Alfonso Buil, Maria Carmo-Fonseca, Francisco J. Enguita, Kyriacos Felekkis, Peter Ferdinandy, Mariann Gyöngyösi, Matthias Hackl, Kanita Karaduzovic-Hadziabdic, Jan Hellemans, Stephane Heymans, Markéta Hlavackova, Morten Andre Hoydal, Aleksandra Jankovic, Amela Jusic, Dimitris Kardassis, Risto Kerkelä, Gabriela M. Kuster, Päivi Lakkisto, Przemyslaw Leszek, Mitja Lustrek, Lars Maegdefessel, Fabio Martelli, Susana Novella, Timothy O’Brien, Christos Papaneophytou, Thierry Pedrazzini, Florence Pinet, Octavian Popescu, Ines Potočnjak, Emma Robinson, Shlomo Sasson, Markus Scholz, Maya Simionescu, Monika Stoll, Zoltan V. Varga, Manlio Vinciguerra, Angela Xuereb, Mehmet Birhan Yilmaz, Costanza Emanueli, Yvan Devaux, behalf of the EU-CardioRNA COST Action on

Date Published: 1st Jun 2019

Publication Type: Journal article

A catalog of genetic loci associated with kidney function from analyses of a million individuals
Genetical Statistics and Systems Biology

Abstract (Expand)

Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through trans-ancestry meta-analysis of genome-wide association studies of estimated glomerular … filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these, 147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.

Authors: Matthias Wuttke, Yong Li, Man Li, Karsten B. Sieber, Mary F. Feitosa, Mathias Gorski, Adrienne Tin, Lihua Wang, Audrey Y. Chu, Anselm Hoppmann, Holger Kirsten, Ayush Giri, Jin-Fang Chai, Gardar Sveinbjornsson, Bamidele O. Tayo, Teresa Nutile, Christian Fuchsberger, Jonathan Marten, Massimiliano Cocca, Sahar Ghasemi, Yizhe Xu, Katrin Horn, Damia Noce, Peter J. van der Most, Sanaz Sedaghat, Zhi Yu, Masato Akiyama, Saima Afaq, Tarunveer S. Ahluwalia, Peter Almgren, Najaf Amin, Johan Ärnlöv, Stephan J. L. Bakker, Nisha Bansal, Daniela Baptista, Sven Bergmann, Mary L. Biggs, Ginevra Biino, Michael Boehnke, Eric Boerwinkle, Mathilde Boissel, Erwin P. Bottinger, Thibaud S. Boutin, Hermann Brenner, Marco Brumat, Ralph Burkhardt, Adam S. Butterworth, Eric Campana, Archie Campbell, Harry Campbell, Mickaël Canouil, Robert J. Carroll, Eulalia Catamo, John C. Chambers, Miao-Ling Chee, Miao-Li Chee, Xu Chen, Ching-Yu Cheng, Yurong Cheng, Kaare Christensen, Renata Cifkova, Marina Ciullo, Maria Pina Concas, James P. Cook, Josef Coresh, Tanguy Corre, Cinzia Felicita Sala, Daniele Cusi, John Danesh, E. Warwick Daw, Martin H. de Borst, Alessandro de Grandi, Renée de Mutsert, Aiko P. J. de Vries, Frauke Degenhardt, Graciela Delgado, Ayse Demirkan, Emanuele Di Angelantonio, Katalin Dittrich, Jasmin Divers, Rajkumar Dorajoo, Kai-Uwe Eckardt, Georg Ehret, Paul Elliott, Karlhans Endlich, Michele K. Evans, Janine F. Felix, Valencia Hui Xian Foo, Oscar H. Franco, Andre Franke, Barry I. Freedman, Sandra Freitag-Wolf, Yechiel Friedlander, Philippe Froguel, Ron T. Gansevoort, He Gao, Paolo Gasparini, J. Michael Gaziano, Vilmantas Giedraitis, Christian Gieger, Giorgia Girotto, Franco Giulianini, Martin Gögele, Scott D. Gordon, Daniel F. Gudbjartsson, Vilmundur Gudnason, Toomas Haller, Pavel Hamet, Tamara B. Harris, Catharina A. Hartman, Caroline Hayward, Jacklyn N. Hellwege, Chew-Kiat Heng, Andrew A. Hicks, Edith Hofer, Wei Huang, Nina Hutri-Kähönen, Shih-Jen Hwang, M. Arfan Ikram, Olafur S. Indridason, Erik Ingelsson, Marcus Ising, Vincent W. V. Jaddoe, Johanna Jakobsdottir, Jost B. Jonas, Peter K. Joshi, Navya Shilpa Josyula, Bettina Jung, Mika Kähönen, Yoichiro Kamatani, Candace M. Kammerer, Masahiro Kanai, Mika Kastarinen, Shona M. Kerr, Chiea-Chuen Khor, Wieland Kiess, Marcus E. Kleber, Wolfgang Koenig, Jaspal S. Kooner, Antje Körner, Peter Kovacs, Aldi T. Kraja, Alena Krajcoviechova, Holly Kramer, Bernhard K. Krämer, Florian Kronenberg, Michiaki Kubo, Brigitte Kühnel, Mikko Kuokkanen, Johanna Kuusisto, Martina La Bianca, Markku Laakso, Leslie A. Lange, Carl D. Langefeld, Jeannette Jen-Mai Lee, Benjamin Lehne, Terho Lehtimäki, Wolfgang Lieb, Su-Chi Lim, Lars Lind, Cecilia M. Lindgren, Jun Liu, Jianjun Liu, Markus Loeffler, Ruth J. F. Loos, Susanne Lucae, Mary Ann Lukas, Leo-Pekka Lyytikäinen, Reedik Mägi, Patrik K. E. Magnusson, Anubha Mahajan, Nicholas G. Martin, Jade Martins, Winfried März, Deborah Mascalzoni, Koichi Matsuda, Christa Meisinger, Thomas Meitinger, Olle Melander, Andres Metspalu, Evgenia K. Mikaelsdottir, Yuri Milaneschi, Kozeta Miliku, Pashupati P. Mishra, Karen L. Mohlke, Nina Mononen, Grant W. Montgomery, Dennis O. Mook-Kanamori, Josyf C. Mychaleckyj, Girish N. Nadkarni, Mike A. Nalls, Matthias Nauck, Kjell Nikus, Boting Ning, Ilja M. Nolte, Raymond Noordam, Jeffrey O’Connell, Michelle L. O’Donoghue, Isleifur Olafsson, Albertine J. Oldehinkel, Marju Orho-Melander, Willem H. Ouwehand, Sandosh Padmanabhan, Nicholette D. Palmer, Runolfur Palsson, Brenda W. J. H. Penninx, Thomas Perls, Markus Perola, Mario Pirastu, Nicola Pirastu, Giorgio Pistis, Anna I. Podgornaia, Ozren Polasek, Belen Ponte, David J. Porteous, Tanja Poulain, Peter P. Pramstaller, Michael H. Preuss, Bram P. Prins, Michael A. Province, Ton J. Rabelink, Laura M. Raffield, Olli T. Raitakari, Dermot F. Reilly, Rainer Rettig, Myriam Rheinberger, Kenneth M. Rice, Paul M. Ridker, Fernando Rivadeneira, Federica Rizzi, David J. Roberts, Antonietta Robino, Peter Rossing, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Kathleen A. Ryan, Yasaman Saba, Charumathi Sabanayagam, Veikko Salomaa, Erika Salvi, Kai-Uwe Saum, Helena Schmidt, Reinhold Schmidt, Ben Schöttker, Christina-Alexandra Schulz, Nicole Schupf, Christian M. Shaffer, Yuan Shi, Albert V. Smith, Blair H. Smith, Nicole Soranzo, Cassandra N. Spracklen, Konstantin Strauch, Heather M. Stringham, Michael Stumvoll, Per O. Svensson, Silke Szymczak, E-Shyong Tai, Salman M. Tajuddin, Nicholas Y. Q. Tan, Kent D. Taylor, Andrej Teren, Yih-Chung Tham, Joachim Thiery, Chris H. L. Thio, Hauke Thomsen, Gudmar Thorleifsson, Daniela Toniolo, Anke Tönjes, Johanne Tremblay, Ioanna Tzoulaki, André G. Uitterlinden, Simona Vaccargiu, Rob M. van Dam, Pim van der Harst, Cornelia M. van Duijn, Digna R. Velez Edward, Niek Verweij, Suzanne Vogelezang, Uwe Völker, Peter Vollenweider, Gerard Waeber, Melanie Waldenberger, Lars Wallentin, Ya Xing Wang, Chaolong Wang, Dawn M. Waterworth, Wen Bin Wei, Harvey White, John B. Whitfield, Sarah H. Wild, James F. Wilson, Mary K. Wojczynski, Charlene Wong, Tien-Yin Wong, Liang Xu, Qiong Yang, Masayuki Yasuda, Laura M. Yerges-Armstrong, Weihua Zhang, Alan B. Zonderman, Jerome I. Rotter, Murielle Bochud, Bruce M. Psaty, Veronique Vitart, James G. Wilson, Abbas Dehghan, Afshin Parsa, Daniel I. Chasman, Kevin Ho, Andrew P. Morris, Olivier Devuyst, Shreeram Akilesh, Sarah A. Pendergrass, Xueling Sim, Carsten A. Böger, Yukinori Okada, Todd L. Edwards, Harold Snieder, Kari Stefansson, Adriana M. Hung, Iris M. Heid, Markus Scholz, Alexander Teumer, Anna Köttgen, Cristian Pattaro

Date Published: 1st Jun 2019

Publication Type: Journal article

Sequential organ failure assessment score is an excellent operationalization of disease severity of adult patients with hospitalized community acquired pneumonia - results from the prospective observational PROGRESS study.
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND: CAP (Community acquired pneumonia) is frequent, with a high mortality rate and a high burden on health care systems. Development of predictive biomarkers, new therapeutic concepts, and … epidemiologic research require a valid, reproducible, and quantitative measure describing CAP severity. METHODS: Using time series data of 1532 patients enrolled in the PROGRESS study, we compared putative measures of CAP severity for their utility as an operationalization. Comparison was based on ability to correctly identify patients with an objectively severe state of disease (death or need for intensive care with at least one of the following: substantial respiratory support, treatment with catecholamines, or dialysis). We considered IDSA/ATS minor criteria, CRB-65, CURB-65, Halm criteria, qSOFA, PSI, SCAP, SIRS-Score, SMART-COP, and SOFA. RESULTS: SOFA significantly outperformed other scores in correctly identifying a severe state of disease at the day of enrollment (AUC = 0.948), mainly caused by higher discriminative power at higher score values. Runners-up were the sum of IDSA/ATS minor criteria (AUC = 0.916) and SCAP (AUC = 0.868). SOFA performed similarly well on subsequent study days (all AUC > 0.9) and across age groups. In univariate and multivariate analysis, age, sex, and pack-years significantly contributed to higher SOFA values whereas antibiosis before hospitalization predicted lower SOFA. CONCLUSIONS: SOFA score can serve as an excellent operationalization of CAP severity and is proposed as endpoint for biomarker and therapeutic studies. TRIAL REGISTRATION: clinicaltrials.gov NCT02782013 , May 25, 2016, retrospectively registered.

Authors: P. Ahnert, P. Creutz, K. Horn, F. Schwarzenberger, M. Kiehntopf, H. Hossain, M. Bauer, F. M. Brunkhorst, K. Reinhart, U. Volker, T. Chakraborty, M. Witzenrath, M. Loffler, N. Suttorp, M. Scholz

Date Published: 4th Apr 2019

Publication Type: Journal article

Human Diseases: pneumonia

Association of Chromosome 9p21 with Subsequent Coronary Heart Disease Events: A GENIUS-CHD Study of Individual Participant Data
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND Genetic variation at chromosome 9p21 is a recognized risk factor for coronary heart disease (CHD). However, its effect on disease progression and subsequent events is unclear, raising questions …s about its value for stratification of residual risk. METHODS A variant at chromosome 9p21 (rs1333049) was tested for association with subsequent events during follow-up in 103,357 Europeans with established CHD at baseline from the GENIUS-CHD Consortium (73.1% male, mean age 62.9 years). The primary outcome, subsequent CHD death or myocardial infarction (CHD death/MI), occurred in 13,040 of the 93,115 participants with available outcome data. Effect estimates were compared to case/control risk obtained from CARDIoGRAMPlusC4D including 47,222 CHD cases and 122,264 controls free of CHD. RESULTS Meta-analyses revealed no significant association between chromosome 9p21 and the primary outcome of CHD death/MI among those with established CHD at baseline (GENIUS-CHD OR 1.02; 95% CI 0.99-1.05). This contrasted with a strong association in CARDIoGRAMPlusC4D OR 1.20; 95% CI 1.18-1.22; p for interaction Conclusions: In contrast to studies comparing individuals with CHD to disease free controls, we found no clear association between genetic variation at chromosome 9p21 and risk of subsequent acute CHD events when all individuals had CHD at baseline. However, the association with subsequent revascularization may support the postulated mechanism of chromosome 9p21 for promoting atheroma development.

Authors: Riyaz S. Patel, Amand F. Schmidt, Vinicius Tragante, Raymond O. McCubrey, Michael V. Holmes, Laurence J. Howe, Kenan Direk, Axel Åkerblom, Karin Leander, Salim S. Virani, Karol A. Kaminski, Jochen D. Muehlschlegel, Marie-Pierre Dubé, Hooman Allayee, Peter Almgren, Maris Alver, Ekaterina V. Baranova, Hassan Behlouli, Bram Boeckx, Peter S. Braund, Lutz P. Breitling, Graciela Delgado, Nubia E. Duarte, Line Dufresne, Niclas Eriksson, Luisa Foco, Crystel M. Gijsberts, Yan Gong, Jaana Hartiala, Mahyar Heydarpour, Jaroslav A. Hubacek, Marcus Kleber, Daniel Kofink, Pekka Kuukasjärvi, Vei-Vei Lee, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Nicola Martinelli, Ute Mons, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, Rafal Ploski, Yan V. Sun, Michael W. T. Tanck, W. H. Wilson Tang, Stella Trompet, Sander W. van der Laan, Jessica van Setten, Ragnar O. Vilmundarson, Chiara Viviani Anselmi, Efthymia Vlachopoulou, Eric Boerwinkle, Carlo Briguori, John F. Carlquist, Kathryn F. Carruthers, Gavino Casu, John Deanfield, Panos Deloukas, Frank Dudbridge, Natalie Fitzpatrick, Bruna Gigante, Stefan James, Marja-Liisa Lokki, Paulo A. Lotufo, Nicola Marziliano, Ify R. Mordi, Joseph B. Muhlestein, Christopher Newton-Cheh, Jan Pitha, Christoph H. Saely, Ayman Samman-Tahhan, Pratik B. Sandesara, Andrej Teren, Adam Timmis, Frans van de Werf, Els Wauters, Arthur A. M. Wilde, Ian Ford, David J. Stott, Ale Algra, Maria G. Andreassi, Diego Ardissino, Benoit J. Arsenault, Christie M. Ballantyne, Thomas O. Bergmeijer, Connie R. Bezzina, Simon C. Body, Peter Bogaty, Gert J. de Borst, Hermann Brenner, Ralph Burkhardt, Clara Carpeggiani, Gianluigi Condorelli, Rhonda M. Cooper-DeHoff, Sharon Cresci, Ulf de Faire, Robert N. Doughty, Heinz Drexel, James C. Engert, Keith A. A. Fox, Domenico Girelli, Emil Hagström, Stanley L. Hazen, Claes Held, Harry Hemingway, Imo E. Hoefer, G. Kees Hovingh, Julie A. Johnson, Pim A. de Jong, J. Wouter Jukema, Marcin P. Kaczor, Mika Kähönen, Jiri Kettner, Marek Kiliszek, Olaf H. Klungel, Bo Lagerqvist, Diether Lambrechts, Jari O. Laurikka, Terho Lehtimäki, Daniel Lindholm, B. K. Mahmoodi, Anke H. Maitland-van der Zee, Ruth McPherson, Olle Melander, Andres Metspalu, Witold Pepinski, Oliviero Olivieri, Grzegorz Opolski, Colin N. Palmer, Gerard Pasterkamp, Carl J. Pepine, Alexandre C. Pereira, Louise Pilote, Arshed A. Quyyumi, A. Mark Richards, Marek Sanak, Markus Scholz, Agneta Siegbahn, Juha Sinisalo, J. Gustav Smith, John A. Spertus, Alexandre F. R. Stewart, Wojciech Szczeklik, Anna Szpakowicz, Jurriën M. ten Berg, George Thanassoulis, Joachim Thiery, Yolanda van der Graaf, Frank L. J. Visseren, Johannes Waltenberger, Pim van der Harst, Jean-Claude Tardif, Naveed Sattar, Chim C. Lang, Guillaume Paré, James M. Brophy, Jeffrey L. Anderson, Winfried März, Lars Wallentin, Vicky A. Cameron, Benjamin D. Horne, Nilesh J. Samani, Aroon D. Hingorani, Folkert W. Asselbergs

Date Published: 1st Apr 2019

Publication Type: Journal article

Subsequent Event Risk in Individuals with Established Coronary Heart Disease: Design and Rationale of the GENIUS-CHD Consortium
Genetical Statistics and Systems Biology

Abstract (Expand)

BACKGROUND The \textquotedblGENetIcs of sUbSequent Coronary Heart Disease\textquotedbl (GENIUS-CHD) consortium was established to facilitate discovery and validation of genetic variants and biomarkers …s for risk of subsequent CHD events, in individuals with established CHD. METHODS The consortium currently includes 57 studies from 18 countries, recruiting 185,614 participants with either acute coronary syndrome, stable CHD or a mixture of both at baseline. All studies collected biological samples and followed-up study participants prospectively for subsequent events. RESULTS Enrollment into the individual studies took place between 1985 to present day with duration of follow up ranging from 9 months to 15 years. Within each study, participants with CHD are predominantly of self-reported European descent (38%-100%), mostly male (44%-91%) with mean ages at recruitment ranging from 40 to 75 years. Initial feasibility analyses, using a federated analysis approach, yielded expected associations between age (HR 1.15 95% CI 1.14-1.16) per 5-year increase, male sex (HR 1.17, 95% CI 1.13-1.21) and smoking (HR 1.43, 95% CI 1.35-1.51) with risk of subsequent CHD death or myocardial infarction, and differing associations with other individual and composite cardiovascular endpoints. CONCLUSIONS GENIUS-CHD is a global collaboration seeking to elucidate genetic and non-genetic determinants of subsequent event risk in individuals with established CHD, in order to improve residual risk prediction and identify novel drug targets for secondary prevention. Initial analyses demonstrate the feasibility and reliability of a federated analysis approach. The consortium now plans to initiate and test novel hypotheses as well as supporting replication and validation analyses for other investigators.

Authors: Riyaz Patel, Vinicius Tragante, Amand F. Schmidt, Raymond O. McCubrey, Michael V. Holmes, Laurence J. Howe, Kenan Direk, Axel Åkerblom, Karin Leander, Salim S. Virani, Karol A. Kaminski, Jochen D. Muehlschlegel, Hooman Allayee, Peter Almgren, Maris Alver, Ekaterina V. Baranova, Hassan Behlouli, Bram Boeckx, Peter S. Braund, Lutz P. Breitling, Graciela Delgado, Nubia E. Duarte, Marie-Pierre Dubé, Line Dufresne, Niclas Eriksson, Luisa Foco, Markus Scholz, Crystel M. Gijsberts, Charlotte Glinge, Yan Gong, Jaana Hartiala, Mahyar Heydarpour, Jaroslav A. Hubacek, Marcus Kleber, Daniel Kofink, Salma Kotti, Pekka Kuukasjärvi, Vei-Vei Lee, Andreas Leiherer, Petra A. Lenzini, Daniel Levin, Leo-Pekka Lyytikäinen, Nicola Martinelli, Ute Mons, Christopher P. Nelson, Kjell Nikus, Anna P. Pilbrow, Rafal Ploski, Yan V. Sun, Michael W. T. Tanck, W. H. Wilson Tang, Stella Trompet, Sander W. van der Laan, Jessica van Setten, Ragnar O. Vilmundarson, Chiara Viviani Anselmi, Efthymia Vlachopoulou, Lawien Al Ali, Eric Boerwinkle, Carlo Briguori, John F. Carlquist, Kathryn F. Carruthers, Gavino Casu, John Deanfield, Panos Deloukas, Frank Dudbridge, Thomas Engström, Natalie Fitzpatrick, Kim Fox, Bruna Gigante, Stefan James, Marja-Liisa Lokki, Paulo A. Lotufo, Nicola Marziliano, Ify R. Mordi, Joseph B. Muhlestein, Christopher Newton-Cheh, Jan Pitha, Christoph H. Saely, Ayman Samman-Tahhan, Pratik B. Sandesara, Andrej Teren, Adam Timmis, Frans van de Werf, Els Wauters, Arthur A. M. Wilde, Ian Ford, David J. Stott, Ale Algra, Maria G. Andreassi, Diego Ardissino, Benoit J. Arsenault, Christie M. Ballantyne, Thomas O. Bergmeijer, Connie R. Bezzina, Simon C. Body, Eric H. Boersma, Peter Bogaty, Michiel Bots, Hermann Brenner, Jasper J. Brugts, Ralph Burkhardt, Clara Carpeggiani, Gianluigi Condorelli, Rhonda M. Cooper-DeHoff, Sharon Cresci, Nicolas Danchin, Ulf de Faire, Robert N. Doughty, Heinz Drexel, James C. Engert, Keith A. A. Fox, Domenico Girelli, Diederick E. Grobbee, Emil Hagström, Stanley L. Hazen, Claes Held, Harry Hemingway, Imo E. Hoefer, G. Kees Hovingh, Reza Jabbari, Julie A. Johnson, J. Wouter Jukema, Marcin P. Kaczor, Mika Kähönen, Jiri Kettner, Marek Kiliszek, Olaf H. Klungel, Bo Lagerqvist, Diether Lambrechts, Jari O. Laurikka, Terho Lehtimäki, Daniel Lindholm, B. K. Mahmoodi, Anke H. Maitland-van der Zee, Ruth McPherson, Olle Melander, Andres Metspalu, Anna Niemcunowicz-Janica, Oliviero Olivieri, Grzegorz Opolski, Colin N. Palmer, Gerard Pasterkamp, Carl J. Pepine, Alexandre C. Pereira, Louise Pilote, Arshed A. Quyyumi, A. Mark Richards, Marek Sanak, Agneta Siegbahn, Tabassome Simon, Juha Sinisalo, J. Gustav Smith, John A. Spertus, Steen Stender, Alexandre F. R. Stewart, Wojciech Szczeklik, Anna Szpakowicz, Jean-Claude Tardif, Jurriën M. ten Berg, Jacob Tfelt-Hansen, George Thanassoulis, Joachim Thiery, Christian Torp-Pedersen, Yolanda van der Graaf, Frank L. J. Visseren, Johannes Waltenberger, Peter E. Weeke, Pim van der Harst, Chim C. Lang, Naveed Sattar, Vicky A. Cameron, Jeffrey L. Anderson, James M. Brophy, Guillaume Paré, Benjamin D. Horne, Winfried März, Lars Wallentin, Nilesh J. Samani, Aroon D. Hingorani, Folkert W. Asselbergs

Date Published: 1st Apr 2019

Publication Type: Journal article

Circulating Adipokine VASPIN Is Associated with Serum Lipid Profiles in Humans
Genetical Statistics and Systems Biology

Abstract (Expand)

VASPIN, visceral adipose tissue-derived serpin, is an adipokine ameliorating insulin resistance in obesity. Here, we investigated the role of VASPIN and its genetic variants in lipid metabolism. We … measured serum VASPIN concentrations by ELISA in 823 metabolically well-characterized Caucasian subjects (Sorbs from Germany). Furthermore, we genotyped 30 representative single nucleotide polymorphisms (SNP) in two independent cohorts with metabolic phenotyping, the Sorbs (N = 823) and Leipzig (N = 919), and conducted genotype-phenotype association analyses. Circulating VASPIN strongly correlated with triacylglycerol levels (TAG; p = 1.079 \times 10-11 ), and moderately with apolipoprotein A1 and low-density lipoprotein cholesterol (p = 0.026). Genetic variants in VASPIN were nominally associated with cholesterol, high-density and low-density lipoprotein (HDL-chol, LDL-chol), lipoprotein A, and apolipoprotein B as well as with TAG and free fatty acids (all p \textless 0.05 adjusted for age, sex, and body mass index [BMI]). Mendelian randomization analysis using VASPIN SNP as an instrumental variable showed borderline influence of VASPIN on LDL-chol levels (p = 0.05). Associations of VASPIN and its genetic variation with metabolic traits suggest a role of VASPIN in human lipid metabolism.

Authors: Jana Breitfeld, Norman Wiele, Beate Gutsmann, Michael Stumvoll, Matthias Blüher, Markus Scholz, Peter Kovacs, Anke Tönjes

Date Published: 18th Mar 2019

Publication Type: Journal article

Modeling individual time courses of thrombopoiesis during multi-cyclic chemotherapy.
Genetical Statistics and Systems Biology, HaematoOpt - Individualized model-based managing of the next-cycle thrombopenia of CHOEP/CHOP treated patients based on platelets dynamics during the previous cycles

Abstract (Expand)

BACKGROUND: Thrombocytopenia is a major side-effect of cytotoxic cancer therapies. The aim of precision medicine is to develop therapy modifications accounting for the individual's risk. … METHODOLOGY/PRINCIPLE FINDINGS: To solve this task, we develop an individualized bio-mechanistic model of the dynamics of bone marrow thrombopoiesis, circulating platelets and therapy effects thereon. Comprehensive biological knowledge regarding cell differentiation, amplification, apoptosis rates, transition times and corresponding regulations are translated into ordinary differential equations. A model of osteoblast/osteoclast interactions was incorporated to mechanistically describe bone marrow support of quiescent cell stages. Thrombopoietin (TPO) as a major regulator is explicitly modelled including pharmacokinetics and-dynamics of TPO injections. Effects of cytotoxic drugs are modelled by transient depletions of proliferating cells. To calibrate the model, we used population data from the literature and close-meshed individual data of N = 135 high-grade non-Hodgkin's lymphoma patients treated with CHOP-like chemotherapies. To limit the number of free parameters, several parsimony assumptions were derived from biological data and tested via Likelihood methods. Heterogeneity of patients was explained by a few model parameters. The over-fitting issue of individual parameter estimation was successfully dealt with a virtual participation of each patient in population-based experiments. The model qualitatively and quantitatively explains a number of biological observations such as the role of osteoblasts in explaining long-term toxic effects, megakaryocyte-mediated feedback on stem cells, bi-phasic stimulation of thrombopoiesis by TPO, dynamics of megakaryocyte ploidies and non-exponential platelet degradation. Almost all individual time series could be described with high precision. We demonstrated how the model can be used to provide predictions regarding individual therapy adaptations. CONCLUSIONS: We propose a mechanistic thrombopoiesis model of unprecedented comprehensiveness in both, biological mechanisms considered and experimental data sets explained. Our innovative method of parameter estimation allows robust determinations of individual parameter settings facilitating the development of individual treatment adaptations during chemotherapy.

Authors: Y. Kheifetz, M. Scholz

Date Published: 7th Mar 2019

Publication Type: Not specified

Human Diseases: blood platelet disease

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