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20 results on '"van den Berg, M. A."'

1. Female reproductive function after treatment of childhood acute lymphoblastic leukemia

Author

van Dulmen-den Broeder E, van den Berg M, van Dijk M, W.J.E. (Wim) Tissing, Dorine Bresters, van den Heuvel-Eibrink M, Catharina C. M. Beerendonk, Cécile M. Ronckers, L. C. M. Kremer, van der Pal, H.J.H., Gertjan J.L. Kaspers, A. Overbeek, van der Heiden-van der Loo M, Roshandel R, Jacqueline J. Loonen, van Leeuwen F, Birgitta Versluys, C.B. Lambalk, Obstetrics and gynaecology, Pediatric surgery, CCA - Cancer Treatment and quality of life, Amsterdam Reproduction & Development (AR&D), and Guided Treatment in Optimal Selected Cancer Patients (GUTS)

Subjects
Adult, Anti-Mullerian Hormone, Pediatrics, medicine.medical_specialty, childhood cancer survivors, pregnancy outcomes, acute lymphoblastic leukemia, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], 03 medical and health sciences, Ovarian function, 0302 clinical medicine, Cancer Survivors, Pregnancy, Medicine, Humans, reproductive function, Child, Childhood Acute Lymphoblastic Leukemia, Retrospective Studies, Menarche, fertility, business.industry, Obstetrics, Hematology, Odds ratio, Total body irradiation, Precursor Cell Lymphoblastic Leukemia-Lymphoma, medicine.disease, Antral follicle, Pediatric cancer, Women's cancers Radboud Institute for Health Sciences [Radboudumc 17], pediatric cancer, Reproductive Health, Oncology, 030220 oncology & carcinogenesis, Pediatrics, Perinatology and Child Health, Cohort, Female, Follicle Stimulating Hormone, business, After treatment, 030215 immunology
Abstract

Contains fulltext : 244604.pdf (Publisher’s version ) (Closed access) BACKGROUND: The aim was to evaluate self-reported reproductive characteristics and markers of ovarian function in a nationwide cohort of female survivors of childhood acute lymphoblastic leukemia (ALL), because prior investigations have produced conflicting data. PROCEDURE: Self-reported reproductive characteristics were assessed by questionnaire among 357 adult 5-year survivors, treated between 1964 and 2002, and 836 controls. Ovarian function was assessed by serum levels of anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), and inhibin B and by antral follicle count (AFC). Differences between controls and (subgroups of) survivors (total group, chemotherapy [CT]-only group, CT and radiotherapy [RT] group) were analyzed. RESULTS: Survivors treated with CT only do not differ from controls regarding timing of menarche, virginity status, desire for children, or pregnancy rates. Compared to controls, the CT+RT group was at significantly increased risk of a younger age at menarche (P

Published
2021

2. The Virtual River Game: Gaming using models to collaboratively explore river management complexity

Author

den Haan, R. J., van der Voort, M. C., Baart, F., Berends, K. D., van den Berg, M. C., Straatsma, M. W., Geenen, A. J.P., Hulscher, S. J.M.H., Leerstoel Leseman, Landdegradatie en aardobservatie, Landscape functioning, Geocomputation and Hydrology, Leerstoel Leseman, Landdegradatie en aardobservatie, Landscape functioning, Geocomputation and Hydrology, Design Engineering, Marine and Fluvial Systems, and Construction Management and Engineering

Subjects
Knowledge management, Environmental Engineering, 010504 meteorology & atmospheric sciences, Computer science, Interface (Java), Bidirectional coupling, UT-Hybrid-D, 010501 environmental sciences, 01 natural sciences, Domain (software engineering), Tangible interaction, Participatory decision-making, Stakeholder participation, River management, 0105 earth and related environmental sciences, business.industry, Social learning, Ecological Modeling, ComputingMilieux_PERSONALCOMPUTING, Stakeholder, Citizen journalism, Game board, Water management, Ecological Modelling, Serious gaming, business, Software
Abstract

Serious games are increasingly used as tools to facilitate stakeholder participation and stimulate social learning in environmental management. We present the Virtual River Game that aims to support stakeholders in collaboratively exploring the complexity of a changed river management paradigm in the Netherlands. The game uses a novel, hybrid interface design that features a bidirectional coupling of a physical game board to computer models. We ran five game sessions involving both domain experts and non-experts to assess the game’s value as a participatory tool. The results show that the game was effective in enabling participants to collaboratively experiment with various river interventions and in stimulating social learning. As a participatory tool, the game appears to be valuable to introduce non-expert stakeholders to Dutch river management. We further discuss how the hybrid interface combines qualities usually found in board and computer games that are beneficial in engaging stakeholders and stimulating learning.

Published
2020

3. Three patients with probable aerotoxic syndrome

Author

Hageman, G, Pal, T M, Nihom, J, MackenzieRoss, S J, van den Berg, M, Environmental Sciences, One Health Toxicologie, Environmental Sciences, and One Health Toxicologie

Subjects
Adult, Male, Aircraft, Central nervous system, Air Pollutants, Occupational, Toxicology, Bioinformatics, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Aerotoxic syndrome, organophosphates, Flight attendant, Occupational Exposure, medicine, Humans, cabin crew, 030212 general & internal medicine, contaminated cabin air, Butyrylcholinesterase, CNS/Psychological, biology, business.industry, Organophosphate, Paraoxonase, people.profession, 030208 emergency & critical care medicine, General Medicine, Middle Aged, Occupational Diseases, Pilots, medicine.anatomical_structure, chemistry, Air Pollution, Indoor, biology.protein, Aircrew, Female, Neurotoxicity Syndromes, medicine.symptom, people, business, aerotoxic syndrome, Balance problems
Abstract

INTRODUCTION: "Aerotoxic syndrome" is a debated entity. Regulatory authorities consider long-term health effects to be an unlikely consequence of exposure to contaminated air because several air quality monitoring studies report low concentrations of toxic chemicals in cabin air. We describe two pilots and one flight attendant, who developed ill health during their flying career which improved after cessation of flying. CASE DETAILS: The most frequently reported symptoms were headache, balance problems, fatigue, gastro-intestinal complaints and cognitive impairment. One of these patients had reduced levels of butyrylcholinesterase after a flight suggesting exposure to organophosphate compounds had occurred. All three were found to have elevated neuronal and glial auto-antibodies, biomarkers of central nervous system injury, and all three had genetic polymorphisms of paraoxonase (PON-1) and two of cytochrome P450, leading to a reduced ability to metabolize organophosphate compound (OPs). DISCUSSION: A similar constellation of symptoms has been described in other studies of aircrew, although objective evidence of exposure is lacking in most of these studies. Reduced levels of butyrylcholinesterases in one of our cases is suggestive of causation and elevated neuronal and glial autoantibodies provide objective evidence of damage to the central nervous system. We consider further research is warranted.

Published
2020

5. Carcinogenicity of some nitrobenzenes and other industrial chemicals

Author

Dunnick, J K, Schubauer-Berigan, M K, Grosse, Y, Straif, K, Jinot, J, Van den Berg, M, Perbellini, L, Nomiyama, T, Gohlke, J M, Bouvard, V, Sone, H, Paul, A, Matsumoto, M, Dorman, D C, Kopylev, L, Cherrie, J W, Benbrahim-Tallaa, L, Ogawa, K, El Ghissassi, F, Mattock, H, Käfferlein, H U, Hall, A, Guyton, K Z, Cattley, R, One Health Toxicologie, dIRAS RA-1, One Health Toxicologie, and dIRAS RA-1

Subjects
03 medical and health sciences, 0302 clinical medicine, Oncology, business.industry, 030220 oncology & carcinogenesis, Environmental chemistry, Medicine, Chemical industry, business, 030210 environmental & occupational health, Carcinogen
Published
2018

6. Imports and Productivity: The Impact of Geography and Factor Intensity

Author

van den Berg, M., van Marrewijk, J.G.M., Internationale macro-economie, UU LEG Research UUSE Multidisciplinary Economics, and UU LEG Research USE Tjalling C. Koopmans Institute

Subjects
factor intensity, SCI and SSCI Journals, 050208 finance, productivity, business.industry, 05 social sciences, Geography, Planning and Development, GEOGRAPHY, Aerospace Engineering, Monetary economics, International trade, International economics, Development, Negatively associated, firm heterogeneity, 0502 economics and business, Taverne, Economics, Portfolio, imports, 050207 economics, business, Productivity
Abstract

Usingmicro-data for Dutch firms, we argue that both the geographic component (what country is the import from) and the intensity component (what type of good is imported) is crucial for measuring and understanding productivity premia associated with importing. For example, our results indicate that the productivity premium associated with importing technology-intensive products from Taiwan differs from importing unskilled-labor-intensive products from Switzerland. We show that increasing distance and decreasing levels of development of the origin economy are negatively associated with the productivity premia of importing. Similarly, these premia are larger for technology- intensive goods and smaller for unskilled-labor-intensive goods. This implies that the geographic-intensity markets are unique and cannot be lumped together. In addition, a more dispersed import portfolio (the extensive dimension) is always positively associated with firm-level productivity.

Published
2017

7. Identification of vascular patients at very high risk for recurrent cardiovascular events : Validation of the current ACC/AHA very high risk criteria

Author

Van Den Berg, M. Johanneke, Bhatt, Deepak L., Kappelle, L. J., De Borst, Gert J., Cramer, Maarten J., Van Der Graaf, Yolanda, Steg, Ph Gabriel, Visseren, Frank L.J., Algra, A., Grobbee, D. E., and Rutten, G. E.H.M.

Subjects
Adult, Male, medicine.medical_specialty, Arterial disease, Disease, 030204 cardiovascular system & hematology, Risk Assessment, Cardiovascular events, 03 medical and health sciences, 0302 clinical medicine, Recurrence, Risk Factors, Internal medicine, Diabetes mellitus, Prevalence, Journal Article, Medicine, Humans, In patient, 030212 general & internal medicine, Prospective Studies, Registries, health care economics and organizations, Aged, Dyslipidemias, Netherlands, Secondary prevention, business.industry, Incidence (epidemiology), Incidence, Smoking, Middle Aged, medicine.disease, Atherosclerosis, Risk prediction, Very high risk, Early Diagnosis, Cardiovascular Diseases, Female, business, Cardiology and Cardiovascular Medicine, Mace, Diabetic Angiopathies, Glomerular Filtration Rate
Abstract

Aims: To validate and assess performance of the current ACC/AHA very high risk criteria in patients with clinically manifest arterial disease. Methods and results: Data were used from the SMART study (n = 7216) and REACH Registry (n = 48 322), two prospective cohorts of patients with manifest atherosclerotic arterial disease. Prevalence and incidence rates of recurrent major adverse cardiovascular events (MACE) were calculated, according to the ACC/AHA VHR criteria (cardiovascular disease combined with diabetes, smoking, dyslipidaemia, and/or recent recurrent coronary events). Performance of the ACC/AHA criteria was compared with single very high risk factors in terms of C-statistics and Net Reclassification Index. All patients were at VHR according to the ESC guidelines (incidence of recurrent MACE in SMART was 2.4/100PY, with 95% CI 2.3-2.5/100PY and in REACH 5.1/100PY with 95% CI 5.0-5.3/100PY). In SMART 57% of the patients were at VHR according to the ACC/AHA criteria (incidence of recurrent MACE 2.7/100PY, 95% CI 2.5-2.9/100PY) and in REACH this was 64% (5.9/100PY, 95% CI 5.7-6.1/100PY). The C-statistic for the ACC/AHA VHR criteria was 0.53 in REACH and 0.54 in SMART. Very high risk factors with comparable or slightly better performance were eGFR < 45, polyvascular disease and age >70 years. Around two third of the patients meeting the ACC/AHA VHR criteria had a predicted 10-year risk of recurrent MACE 70 years performs as well as the ACC/AHA VHR criteria.

Published
2017

8. Impact of remuneration on guideline adherence: Empirical evidence in general practice

Author

van Dijk, C.E., Verheij, R.A., Spreeuwenberg, P., van den Berg, M., Groenewegen, P.P., Braspenning, J.C., et al, [No Value], SGPL Stadsgeografie, Afd sociologie, Social Urban Transitions, Social Networks, Solidarity and Inequality, Tranzo, Scientific center for care and wellbeing, SGPL Stadsgeografie, Afd sociologie, Social Urban Transitions, and Social Networks, Solidarity and Inequality

Subjects
medicine.medical_specialty, Longitudinal study, Implementation Science [NCEBP 3], Empirical Research, Remuneration, Empirical research, quality of care, medicine, Humans, Longitudinal Studies, Medical prescription, Empirical evidence, guideline adherence, Netherlands, Quality of Health Care, general practice, Capitation, Guideline adherence, business.industry, Medical record, Public Health, Environmental and Occupational Health, The Netherlands, Family medicine, Original Article, Family Practice, business, remuneration system
Abstract

Background and objective. Changes in the Dutch GP remuneration system provided the opportunity to study the effects of changes in financial incentives on the quality of care. Separate remuneration systems for publicly insured patients (capitation) and privately insured patients (fee-for-service) were replaced by a combined system of capitation and fee-for-service for all in 2006. The effects of these changes on the quality of care in terms of guideline adherence were investigated. Design and setting. A longitudinal study from 2002 to 2009 using data from patient electronic medical records in general practice. A multilevel (patient and practice) approach was applied to study the effect of changes in the remuneration system on guideline adherence. Subjects. 21 421 to 39 828 patients from 32 to 52 general practices (dynamic panel of GPs). Main outcome measures. Sixteen guideline adherence indicators on prescriptions and referrals for acute and chronic conditions. Results. Guideline adherence increased between 2002 and 2008 by 7% for (formerly) publicly insured patients and 10% for (formerly) privately insured patients. In general, no significant differences in the trends for guideline adherence were found between privately and publicly insured patients, indicating the absence of an effect of the remuneration system on guideline adherence. Adherence to guidelines involving more time investment in terms of follow-up contacts was affected by changes in the remuneration system. For publicly insured patients, GPs showed a higher trend for guideline adherence for guidelines involving more time investment in terms of follow-up contacts compared with privately insured patients. Conclusion. The change in the remuneration system had a limited impact on guideline adherence.Keywords: General practice, guideline adherence, quality of care, remuneration system, The Netherlands

Published
2013

9. A mechanistic insight into 3,4-methylenedioxymethamphetamine ('ecstasy')-mediated hepatotoxicity

Author

Antolino-Lobo, I., Meulenbelt, J., van den Berg, M., van Duursen, M.B.M., Risk Assessment of Toxic and Immunomodulatory Agents, Dep IRAS, Risk Assessment of Toxic and Immunomodulatory Agents, and Dep IRAS

Subjects
Hallucinogen, Drug, medicine.medical_treatment, media_common.quotation_subject, Ecstasy, Poison control, Pharmacology, mental disorders, Animals, Humans, Medicine, Adverse effect, 3,4-Methylenedioxyamphetamine, media_common, Immunosuppression Therapy, Polymorphism, Genetic, General Veterinary, Illicit Drugs, business.industry, MDMA, Stimulant, Liver, Chemical and Drug Induced Liver Injury, business, Drug metabolism, psychological phenomena and processes, medicine.drug
Abstract

3,4-Methylenedioxymethamphetamine (MDMA, "ecstasy") is a popular drug of abuse among young people with stimulant and hallucinogenic properties. The drug is generally thought to be safe among consumers due to its low-mortality rates. However, MDMA-adverse effects can occur and the risks are not clearly associated to a specific pattern since the consumption quantity seems not to be correlated with the initiation and severity of the injury. MDMA-mediated adverse health effects have been widely studied and can be evoked by multiple factors such as hyperthermia, polydrug abuse (drug-drug interactions), the altered release of neurotransmitters, impairment of mitochondrial function and apoptosis, metabolism and immune responses. Another adverse effect often associated with MDMA is liver toxicity, yet the mechanism of MDMA-induced liver toxicity is not completely understood. A critical starting point appears to be the hepatic metabolism of MDMA by phase I and II enzymes, leading to reactive metabolites. Elucidating the mechanism of hepatic injury mediated by MDMA is of high toxicological and clinical relevance. In this review, an overview of the literature and the latest findings with respect to the mechanism of MDMA-mediated liver toxicity is described.

Published
2012

10. The impact of technology availability on the timing and costs of emission reductions for achieving long-term climate targets

Author

van Vliet, J., Hof, Andries, Mendoza Beltran, A., van den Berg, M.., Deetman, S., den Elzen, M.G.J., Lucas, P.L., van Vuuren, D.P., and Environmental Sciences

Subjects
Atmospheric Science, Global and Planetary Change, Emission Level, business.industry, Environmental resource management, Mitigation Cost, Climate change, Bio-energy with carbon capture and storage, Limited availability, Environmental economics, Carbon sequestration, Radiative forcing, Greenhouse gas, Abatement Cost, Taverne, Carbon capture and storage, Portfolio, Environmental science, business, Emission Reduction, Climate Policy
Abstract

While most long-term mitigation scenario studies build on a broad portfolio of mitigation technologies, there is quite some uncertainty about the availability and reduction potential of these technologies. This study explores the impacts of technology limitations on greenhouse gas emission reductions using the integrated model IMAGE. It shows that the required short-term emission reductions to achieve long-term radiative forcing targets strongly depend on assumptions on the availability and potential of mitigation technologies. Limited availability of mitigation technologies which are relatively important in the long run implies that lower short-term emission levels are required. For instance, limited bio-energy availability reduces the optimal 2020 emission level by more than 4 GtCO2eq in order to compensate the reduced availability of negative emissions from bioenergy and carbon capture and storage (BECCS) in the long run. On the other hand, reduced mitigation potential of options that are used in 2020 can also lead to a higher optimal level for 2020 emissions. The results also show the critical role of BECCS for achieving low radiative forcing targets in IMAGE. Without these technologies achieving these targets become much more expensive or even infeasible.

Published
2014

11. Expression of homeobox genes in the gastrointestinal tract

Author

van den Berg M, Rings E, and Pieter C. F. Stokkers

Subjects
Gastrointestinal tract, business.industry, Gastroenterology, Homeobox A1, Genes, Homeobox, Gene Expression, Pediatrics, Perinatology and Child Health, Cancer research, Medicine, Homeobox, Humans, business, CDX2, Digestive System
Published
1998

12. Question

Author

van den Berg M, A. J. Verboom, C. Meenken, and A. Bökenkamp

Subjects
medicine.medical_specialty, Kidney, Pathology, biology, business.industry, Acute kidney injury, medicine.disease, biology.organism_classification, Leptospirosis, medicine.anatomical_structure, Nephrology, Leptospira, Internal medicine, Pediatrics, Perinatology and Child Health, medicine, business, Uveitis
Published
2003

13. Genetic Basis of Alagille Syndrome Deciphered

Author

van den Berg M, Rings E, and Pieter C. F. Stokkers

Subjects
business.industry, Calcium-Binding Proteins, DNA Mutational Analysis, Gastroenterology, Membrane Proteins, Proteins, Bioinformatics, medicine.disease, Alagille Syndrome, Mutation, Pediatrics, Perinatology and Child Health, Alagille syndrome, Humans, Intercellular Signaling Peptides and Proteins, Medicine, Serrate-Jagged Proteins, business
Published
1998

14. Measles Vaccination and Inflammatory Bowel Disease

Author

Rings E, Pieter C. F. Stokkers, and van den Berg M

Subjects
business.industry, Measles Vaccine, Gastroenterology, Inflammatory Bowel Diseases, medicine.disease, Inflammatory bowel disease, Measles, Vaccination, Crohn Disease, Risk Factors, Pediatrics, Perinatology and Child Health, Immunology, medicine, Humans, Colitis, Ulcerative, business
Published
1998

15. ECMO for COVID-19 patients in Europe and Israel

Author

Lorusso, Roberto, Combes, Alain, Coco, Valeria Lo, De Piero, Maria Elena, Belohlavek, Jan, Delnoij, Thijs, van der Horst, Iwan, Miranda, Dinis Reis, van der Linden, Marcel, van der Heijden, JJ, Scholten, Erik, van Belle-van Haren, Nicole, Lagrand, Wim, de Jong, Sytse, Candura, Dario, Maas, Jacinta, van den Berg, MJ van Gijlswijk, Malfertheiner, Maximilian, Dreier, Esther, Mueller, Thomas, Boeken, Udo, Akhyari, Payam, Lichtenberg, Artur, Saeed, Diyar, Thiele, Holger, Baumgaertel, Matthias, Schmitto, Jan D, Mariani, Silvia, Thielmann, Matthias, Brenner, Thorsten, Benk, Cristoph, Czerny, Martin, Kalbhenn, Johannes, Maier, Sven, Schibilsky, David, Staudacher, Dawid L, Henn, Philipp, Iuliu, Torje, Muellenbach, Ralf, Reyher, Christian, Rolfes, Caroline, Zacharowski, Kai, Lotz, Gosta, Sonntagbauer, Michael, Kersten, Alexander, Karagiannidis, Christian, Schafer, Simone, Fichte, Julia, Hopf, Hans-Bernd, Samalavicius, Robertas, Lorini, Luca, Ghitti, Davide, Grazioli, Lorenzo, Loforte, Antonio, Baiocchi, Massimo, Checco, Erika Dal, Pacini, Davide, Meani, Paolo, Cappai, Antioco, Russo, Claudio Francesco, Bottiroli, Maurizio, Mondino, Michele, Ranucci, Marco, Fina, Dario, Ballotta, Andrea, Scandroglio, Anna Mara, Zangrillo, Alberto, Pieri, Marina, Nardelli, Pasquale, Fominskiy, Evgeny, Landoni, Giovanni, Fanelli, Vito, Brazzi, Luca, Montrucchio, Giorgia, Sales, Gabriele, Simonetti, Umberto, Urbino, Rosario, Livigni, Sergio, Degani, Antonella, Raffa, Giuseppe, Pilato, Michele, Martucci, Gennaro, Arcadipane, Antonio, Chiarini, Giovanni, Latronico, Nicola, Cattaneo, Sergio, Puglia, Carmine, Reina, Gianfranco, Sponga, Sandro, Livi, Ugolino, Foti, Giuseppe, Giani, Marco, Rona, Roberto, Avalli, Leonello, Bombino, Michela, Costa, Maria Cristina, Carozza, Roberto, Donati, Abele, Piciche, Marco, Favaro, Alessandro, Salvador, Loris, Danzi, Vinicio, Zanin, Anita, Condello, Ignazio, Fiore, Flavio, Moscarelli, Marco, Nasso, Giuseppe, Speziale, Giuseppe, Sandrelli, Luca, Montalto, Andrea, Musumeci, Francesco, Circelli, Alessandro, Gamberini, Emiliano, Russo, Emanuele, Benni, Marco, Agnoletti, Vanni, Rociola, Ruggero, Milano, Aldo D, Grasso, Salvatore, Civita, Antonio, Murgolo, Francesco, Pilato, Emanuele, Comentale, Giuseppe, Montisci, Andrea, Alessandri, Francesco, Tosi, Antonella, Pugliese, Francesco, Carelli, Simone, Grieco, Domenico Luca, Antonelli, Massimo, Ramoni, Enrico, Di Nardo, Matteo, Maisano, Francesco, Bettex, Dominique, Weber, Alberto, Grunenfelder, Jurg, Consiglio, Jolanda, Hansjoerg, Jenni, Haenggi, Matthias, Agus, Gianluca, Doeble, Thomas, Zenklusen, Urs, Bechtold, Xavier, Stockman, Bernard, De Backer, Daniel, Giglioli, Simone, Meyns, Bart, Vercaemst, Leen, Herman, Greet, Meersseman, Philippe, Vandenbriele, Christophe, Dauwe, Dieter, Vlasselaers, Dirk, Raes, Matthias, Debeuckelaere, Gerdy, Rodrigus, Inez, Biston, Patrick, Piagnerelli, Michael, Peperstraete, Harlinde, Germay, Olivier, Vandewiele, Korneel, Vandeweghe, Dimitri, Witters, Ine, Havrin, Sven, Bourgeois, Marc, Taccone, Fabio Silvio, Nobile, Leda, Lheureux, Olivier, Brasseur, Alexandre, Creteur, Jacques, Defraigne, Jean-Olivier, Misset, Benoit, Courcelle, Romain, Timmermans, Philippe, Lehaen, Jeroen, Frederik, Bonte, Riera, Jordi, Castro, Miguel angel, Gallart, Elisabet, Martinez-Martinez, Maria, Argudo, Eduard, Garcia-de-Acilu, Marina, de Pablo Sanchez, Raul, Ortiz, Aaron Blandino, Cabanes, Mari-Paz Fuset, Higa, Karina Osorio, Cassina, Albert Miralles, Berbel, Daniel Ortiz, Sanchez-Salado, Jose Carlos, Arnau, Blasco-Lucas, de Gopegui, Pablo Ruiz, Ricart, Pilar, Sandoval, Elena, Veganzones, Javier, Millan, Pablo, de la Sota, Perez, Santa Teresa, Patricia, Alcantara, Sara, Alvarez, Jorge Duerto, Gonzalez, Anxela Vidal, Lopez, Marta, Gordillo, Antonio, Naranjo-Izurieta, Jose, Costa, Ricardo Gimeno, Albacete Moreno, Carlos L, de Ayala, Jose angel, Blanco-Schweizer, Pablo, Andres, Nicolas Hidalgo, Boado, Victoria, Martinez, Jose Maria Nunez, Casal, Vanesa Gomez, Garcia, Esperanza Fernandez, Martin-Villen, Luis, Climent, Joaquin Colomina, Pinto, Luis F, Leprince, Pascal, Lebreton, Guillaume, Juvin, Charles, Schmidt, Matthieu, Pineton, Marc, Folliguet, Thierry, Saiydoun, Gabriel, Gaudard, Philippe, Colson, Pascal, Obadia, Jean-Francois, Pozzi, Matteo, Fellahi, Jean Luc, Yonis, Hodane, Richard, Jean Christophe, Parasido, Alessandro, Verhoye, Jean-Philippe, Flecher, Erwan, Ajrhourh, Lucrezia, Nesseler, Nicolas, Mansour, Alexandre, Guinot, Pierre-Gregoire, Zarka, Jonathan, Besserve, Patricia, Makhoul, Maged, Bolotin, Gil, Kassif, Yigal, Soufleris, Dimitros, Schellongowski, Peter, Bonaros, Nikolaos, Krapf, Christoph, Ebert, Kathrin, Mair, Peter, Kothleutner, Florian, Kowalewsky, Mariusz, Christensen, Steffen, Pedersen, Finn Moller, Balik, Martin, Blaha, Jan, Lips, Michal, Otahal, Michal, Camporota, Luigi, Daly, Kathleen, Agnew, Nicola, Barker, Julian, Head, Laura, Garcia, Miguel, Ledot, Stephane, Aquino, Verna, Lewis, Rebecca, Worthy, Jennifer, Noor, Hamza, Scott, Ian, O'Brien, Serena, Conrick-Martin, Ian, Carton, Edmund, Gillon, Stuart, Flemming, Lucy, Broman, Lars Mikael, Grins, Edgars, Ketskalo, Michail, Tsarenko, Sergey, Popugaev, Konstantin, Minin, Sergei, Kornilov, Igor, Skopets, Alexander, Kornelyuk, Roman, Turchaninov, Alexandr, Gorjup, Vojka, Shelukhin, Daniil, Dsouki, Youssef El, Sargin, Murat, Kaygin, Mehmet Ali, Liana, Shestakova, Puss, Severin, Soerensen, Gro, Magnus, Rosen, Kanetoft, Mikael, Watson, Pia, Redfors, Bengt, Krenner, Niklas, Velia Antonini, M, Barrett, Nicholas A, Belliato, Mirko, Davidson, Mark, Finney, Simon, Fowles, Jo-Anne, Halbe, Maximilian, Hennig, Felix, Jones, Tim, Pinto, Luis, Smith, Jonathan, Roeleveld, Peter, Swol, Justyna, Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Cardiovascular Research Institute Maastricht (CARIM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), First Faculty of Medicine Charles University [Prague], Intensive Care Medicine, AII - Inflammatory diseases, ANS - Neuroinfection & -inflammation, EuroECMO COVID-19 Working Group, Euro-ELSO Steering Committee, Lorusso, Roberto, Combes, Alain, Coco, Valeria Lo, De Piero, Maria Elena, Belohlavek, Jan (EuroECMO COVID-19, Workinggroup, Euro-ELSO Steering, Committee), Zangrillo, A, Landoni, G, CTC, MUMC+: MA Med Staf Spec CTC (9), RS: Carim - V04 Surgical intervention, MUMC+: MA Alg Ond Onderz CTC (9), Lorusso, R, Combes, A, Coco, V, De Piero, M, Belohlavek, J, Delnoij, T, van der Horst, I, Miranda, D, van der Linden, M, van der Heijden, J, Scholten, E, van Belle-van Haren, N, Lagrand, W, de Jong, S, Candura, D, Maas, J, van den Berg, M, Malfertheiner, M, Dreier, E, Mueller, T, Boeken, U, Akhyari, P, Lichtenberg, A, Saeed, D, Thiele, H, Baumgaertel, M, Schmitto, J, Mariani, S, Thielmann, M, Brenner, T, Benk, C, Czerny, M, Kalbhenn, J, Maier, S, Schibilsky, D, Staudacher, D, Henn, P, Iuliu, T, Muellenbach, R, Reyher, C, Rolfes, C, Zacharowski, K, Lotz, G, Sonntagbauer, M, Kersten, A, Karagiannidis, C, Schafer, S, Fichte, J, Hopf, H, Samalavicius, R, Lorini, L, Ghitti, D, Grazioli, L, Loforte, A, Baiocchi, M, Checco, E, Pacini, D, Meani, P, Cappai, A, Russo, C, Bottiroli, M, Mondino, M, Ranucci, M, Fina, D, Ballotta, A, Scandroglio, A, Pieri, M, Nardelli, P, Fominskiy, E, Fanelli, V, Brazzi, L, Montrucchio, G, Sales, G, Simonetti, U, Urbino, R, Livigni, S, Degani, A, Raffa, G, Pilato, M, Martucci, G, Arcadipane, A, Chiarini, G, Latronico, N, Cattaneo, S, Puglia, C, Reina, G, Sponga, S, Livi, U, Foti, G, Giani, M, Rona, R, Avalli, L, Bombino, M, Costa, M, Carozza, R, Donati, A, Piciche, M, Favaro, A, Salvador, L, Danzi, V, Zanin, A, Condello, I, Fiore, F, Moscarelli, M, Nasso, G, Speziale, G, Sandrelli, L, Montalto, A, Musumeci, F, Circelli, A, Gamberini, E, Russo, E, Benni, M, Agnoletti, V, Rociola, R, Milano, A, Grasso, S, Civita, A, Murgolo, F, Pilato, E, Comentale, G, Montisci, A, Alessandri, F, Tosi, A, Pugliese, F, Carelli, S, Grieco, D, Antonelli, M, Ramoni, E, Di Nardo, M, Maisano, F, Bettex, D, Weber, A, Grunenfelder, J, Consiglio, J, Hansjoerg, J, Haenggi, M, Agus, G, Doeble, T, Zenklusen, U, Bechtold, X, Stockman, B, De Backer, D, Giglioli, S, Meyns, B, Vercaemst, L, Herman, G, Meersseman, P, Vandenbriele, C, Dauwe, D, Vlasselaers, D, Raes, M, Debeuckelaere, G, Rodrigus, I, Biston, P, Piagnerelli, M, Peperstraete, H, Germay, O, Vandewiele, K, Vandeweghe, D, Witters, I, Havrin, S, Bourgeois, M, Taccone, F, Nobile, L, Lheureux, O, Brasseur, A, Creteur, J, Defraigne, J, Misset, B, Courcelle, R, Timmermans, P, Lehaen, J, Frederik, B, Riera, J, Castro, M, Gallart, E, Martinez-Martinez, M, Argudo, E, Garcia-de-Acilu, M, de Pablo Sanchez, R, Ortiz, A, Cabanes, M, Higa, K, Cassina, A, Berbel, D, Sanchez-Salado, J, Arnau, B, de Gopegui, P, Ricart, P, Sandoval, E, Veganzones, J, Millan, P, de la Sota, P, Santa Teresa, P, Alcantara, S, Alvarez, J, Gonzalez, A, Lopez, M, Gordillo, A, Naranjo-Izurieta, J, Costa, R, Albacete Moreno, C, de Ayala, J, Blanco-Schweizer, P, Andres, N, Boado, V, Martinez, J, Casal, V, Garcia, E, Martin-Villen, L, Climent, J, Pinto, L, Leprince, P, Lebreton, G, Juvin, C, Schmidt, M, Pineton, M, Folliguet, T, Saiydoun, G, Gaudard, P, Colson, P, Obadia, J, Pozzi, M, Fellahi, J, Yonis, H, Richard, J, Parasido, A, Verhoye, J, Flecher, E, Ajrhourh, L, Nesseler, N, Mansour, A, Guinot, P, Zarka, J, Besserve, P, Makhoul, M, Bolotin, G, Kassif, Y, Soufleris, D, Schellongowski, P, Bonaros, N, Krapf, C, Ebert, K, Mair, P, Kothleutner, F, Kowalewsky, M, Christensen, S, Pedersen, F, Balik, M, Blaha, J, Lips, M, Otahal, M, Camporota, L, Daly, K, Agnew, N, Barker, J, Head, L, Garcia, M, Ledot, S, Aquino, V, Lewis, R, Worthy, J, Noor, H, Scott, I, O'Brien, S, Conrick-Martin, I, Carton, E, Gillon, S, Flemming, L, Broman, L, Grins, E, Ketskalo, M, Tsarenko, S, Popugaev, K, Minin, S, Kornilov, I, Skopets, A, Kornelyuk, R, Turchaninov, A, Gorjup, V, Shelukhin, D, Dsouki, Y, Sargin, M, Kaygin, M, Liana, S, Puss, S, Soerensen, G, Magnus, R, Kanetoft, M, Watson, P, Redfors, B, Krenner, N, Velia Antonini, M, Barrett, N, Belliato, M, Davidson, M, Finney, S, Fowles, J, Halbe, M, Hennig, F, Jones, T, Smith, J, Roeleveld, P, Swol, J, Lorusso R., Combes A., Coco V.L., De Piero M.E., and Belohlavek J, EuroECMO COVID-19 WorkingGroup, and Euro-ELSO Steering Committee, Pacini D

Subjects
2019-20 coronavirus outbreak, medicine.medical_specialty, Letter, Coronavirus disease 2019 (COVID-19), Pain medicine, medicine.medical_treatment, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], MEDLINE, 610 Medicine & health, 030204 cardiovascular system & hematology, Critical Care and Intensive Care Medicine, 03 medical and health sciences, Extracorporeal Membrane Oxygenation, covid, ecmo, respiratory failure, 0302 clinical medicine, Critical Care Medicine, General & Internal Medicine, Anesthesiology, medicine, Extracorporeal membrane oxygenation, Humans, Israel, ComputingMilieux_MISCELLANEOUS, Science & Technology, business.industry, COVID-19, 030208 emergency & critical care medicine, 3. Good health, Europe, Emergency medicine, Human medicine, ECMO, business, Life Sciences & Biomedicine, Human
Abstract

ispartof: INTENSIVE CARE MEDICINE vol:47 issue:3 pages:344-348 ispartof: location:United States status: published

Published
2021

16. Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

Author

Paul M.L. Janssen, Jeff S. Healey, Nara Sobriera, Hugh Calkins, Samantha L. Simmons, Sharon L. Graw, Peter J. Mohler, Mona El-Refaey, Robert W. Davies, Brittney Murray, Danna A. Spears, Kirti Mittal, Duy T. Nguyen, Jason D. Roberts, Crystal Tichnell, Maarten P. van den Berg, J. Peter van Tintelen, Nathaniel P. Murphy, Sara N. Koenig, Daniel P. Judge, Philip C. Ursell, Meriam Åström Aneq, Mei Han, Crystal F. Kline, Robert A. Hegele, Anna Gréen, Luisa Mestroni, Andrew D. Krahn, Robert M. Hamilton, Amy C. Sturm, Arthur A.M. Wilde, Babak Nazer, Frank I. Marcus, Gianfranco Sinagra, Michael H. Gollob, Alberto Codima, David A. Chiasson, Chantal J. M. van Opbergen, Matthew R.G. Taylor, Shabana Aafaqi, Cynthia A. James, Edgar T. Hoorntje, Martin J. Gardner, Tamara T. Koopmann, Ellen R. Lubbers, Meena Fatah, Anthony Tang, Hassan Musa, Muhammad Rafiq, Loren E. Wold, Allan C. Skanes, Thomas J. Hund, John F. Robinson, Melvin M. Scheinman, Elisabeth M. Lodder, Toon A.B. van Veen, Roberts, J. D., Murphy, N. P., Hamilton, R. M., Lubbers, E. R., James, C. A., Kline, C. F., Gollob, M. H., Krahn, A. D., Sturm, A. C., Musa, H., El-Refaey, M., Koenig, S., Aneq, M. A., Hoorntje, E. T., Graw, S. L., Davies, R. W., Rafiq, M. A., Koopmann, T. T., Aafaqi, S., Fatah, M., Chiasson, D. A., Taylor, M. R. G., Simmons, S. L., Han, M., Van Opbergen, C. J. M., Wold, L. E., Sinagra, G., Mittal, K., Tichnell, C., Murray, B., Codima, A., Nazer, B., Nguyen, D. T., Marcus, F. I., Sobriera, N., Lodder, E. M., Van Den Berg, M. P., Spears, D. A., Robinson, J. F., Ursell, P. C., Green, A. K., Skanes, A. C., Tang, A. S., Gardner, M. J., Hegele, R. A., Van Veen, T. A. B., Wilde, A. A. M., Healey, J. S., Janssen, P. M. L., Mestroni, L., Van Tintelen, J. P., Calkins, H., Judge, D. P., Hund, T. J., Scheinman, M. M., Mohler, P. J., Cardiovascular Centre (CVC), Cardiology, Human Genetics, and ACS - Heart failure & arrhythmias

Subjects
Male, 0301 basic medicine, Indoles, Cardiac fibrosis, Cell- och molekylärbiologi, Cardiomyopathy, Arrhythmias, Cardiovascular, Medical and Health Sciences, Sudden cardiac death, Maleimides, Mice, 0302 clinical medicine, 2.1 Biological and endogenous factors, Aetiology, Wnt Signaling Pathway, Arrhythmogenic Right Ventricular Dysplasia, beta Catenin, Mice, Knockout, Ejection fraction, Cardiology, Cardiovascular disease, Cell Biology, Genetic diseases, Wnt signaling pathway, General Medicine, Phenotype, 3. Good health, Heart Disease, 030220 oncology & carcinogenesis, Female, Arrhythmia, Research Article, Ankyrins, Knockout, Immunology, 03 medical and health sciences, Rare Diseases, Clinical Research, ANK2, Journal Article, medicine, Animals, Humans, Loss function, Animal, business.industry, Myocardium, medicine.disease, Disease Models, Animal, 030104 developmental biology, Disease Models, Cancer research, business, Cell and Molecular Biology
Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project

Published
2019

17. Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls

Author

Charles Antzelevitch, Ahmad S. Amin, Bo Gregers Winkel, Dan M. Roden, Stefan Kääb, Jonathan R. Skinner, Seiko Ohno, Julien Barc, Birgit Stallmeyer, Carla Giustetto, Connie R. Bezzina, Francesco Mazzarotto, Tomas Robyns, Carlo Napolitano, Stellan Mörner, Doris Škorić-Milosavljević, Sven Dittmann, Kenichiro Yamagata, Sonia Van Dooren, Anniek Corveleyn, Carlo de Asmundis, Ramon Brugada, K Usuda, Yuji Tanaka, Sven Zumhagen, Tadashi Nakajima, Johan Saenen, Elijah R. Behr, Hector Barajas-Martinez, Stéphane Bézieau, Masao Yoshinaga, Georgia Sarquella-Brugada, Paul G.A. Volders, Juan R. Gimeno, Lia Crotti, Charlotte Glinge, Andrea Mazzanti, Ingrid P.C. Krapels, Nicola Whiffin, Sebastian Clauss, Yoshiaki Kaneko, James S. Ware, Minoru Horie, Keiko Shimamoto, Isabelle Denjoy, Pieter G. Postema, Christian Krijger, Takeshi Aiba, Masahiko Kurabayashi, Pyotr G. Platonov, Regina Sebastiano, Cristina Gil Ortuño, Annika Rydberg, Roddy Walsh, Michael J. Ackerman, Hideki Itoh, M. Benjamin Shoemaker, Can Hasdemir, Pascale Guicheney, J. Martijn Bos, Frederic Sacher, Takeru Makiyama, Julieta Lazarte, Maarten P. van den Berg, Dominique Babuty, David J. Tester, Silvia Castelletti, Jacques Mansourati, Antoine Leenhardt, Paul A. van der Zwaag, Sanjay Sharma, Elena Arbelo, Candan Celen, Pier D. Lambiase, Maria Christina Kotta, Johannes Steinfurt, Jean-Baptiste Gourraud, Pedro Brugada, Wataru Shimizu, Josep Brugada, Jørgen K. Kanters, Eline A. Nannenberg, Silvia G. Priori, Mary N. Sheppard, Richard Redon, Morten S. Olesen, Jeroen Breckpot, Britt M. Beckmann, Naomasa Makita, Martin Borggrefe, Rafik Tadros, Jean-Jacques Schott, Jacob Tfelt-Hansen, Steven A. Lubitz, Hatice Şahin, Najim Lahrouchi, Michael Papadakis, Daisuke Hazeki, Kenshi Hayashi, Oscar Campuzano, Katja E. Odening, Federica Dagradi, Eric Schulze-Bahr, Boris Rudic, Hiroki Kimoto, Vincent Probst, Jason D. Roberts, Raphaël P. Martins, Bart Loeys, Daniela F. Giachino, F. Kyndt, Kimie Ohkubo, Taisuke Ishikawa, Catarina Lundin, Lut Van Laer, Patrick T. Ellinor, Maria Sabater Molina, Peter J. Schwartz, Annika Winbo, Wellcome Trust, Rosetrees Trust, British Heart Foundation, Walsh, R, Lahrouchi, N, Tadros, R, Kyndt, F, Glinge, C, Postema, P, Amin, A, Nannenberg, E, Ware, J, Whiffin, N, Mazzarotto, F, Skoric-Milosavljevic, D, Krijger, C, Arbelo, E, Babuty, D, Barajas-Martinez, H, Beckmann, B, Bezieau, S, Bos, J, Breckpot, J, Campuzano, O, Castelletti, S, Celen, C, Clauss, S, Corveleyn, A, Crotti, L, Dagradi, F, de Asmundis, C, Denjoy, I, Dittmann, S, Ellinor, P, Ortuno, C, Giustetto, C, Gourraud, J, Hazeki, D, Horie, M, Ishikawa, T, Itoh, H, Kaneko, Y, Kanters, J, Kimoto, H, Kotta, M, Krapels, I, Kurabayashi, M, Lazarte, J, Leenhardt, A, Loeys, B, Lundin, C, Makiyama, T, Mansourati, J, Martins, R, Mazzanti, A, Morner, S, Napolitano, C, Ohkubo, K, Papadakis, M, Rudic, B, Molina, M, Sacher, F, Sahin, H, Sarquella-Brugada, G, Sebastiano, R, Sharma, S, Sheppard, M, Shimamoto, K, Shoemaker, M, Stallmeyer, B, Steinfurt, J, Tanaka, Y, Tester, D, Usuda, K, van der Zwaag, P, Van Dooren, S, Van Laer, L, Winbo, A, Winkel, B, Yamagata, K, Zumhagen, S, Volders, P, Lubitz, S, Antzelevitch, C, Platonov, P, Odening, K, Roden, D, Roberts, J, Skinner, J, Tfelt-Hansen, J, van den Berg, M, Olesen, M, Lambiase, P, Borggrefe, M, Hayashi, K, Rydberg, A, Nakajima, T, Yoshinaga, M, Saenen, J, Kaab, S, Brugada, P, Robyns, T, Giachino, D, Ackerman, M, Brugada, R, Brugada, J, Gimeno, J, Hasdemir, C, Guicheney, P, Priori, S, Schulze-Bahr, E, Makita, N, Schwartz, P, Shimizu, W, Aiba, T, Schott, J, Redon, R, Ohno, S, Probst, V, Arnaout, A, Amelot, M, Anselme, F, Billon, O, Defaye, P, Dupuis, J, Jesel, L, Laurent, G, Maury, P, Pasquie, J, Wiart, F, Behr, E, Barc, J, Bezzina, C, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Brest (CHRU Brest), CHU Pontchaillou [Rennes], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ege Üniversitesi, Cardiovascular Centre (CVC), Nantes Referral Ctr Inherited Car, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, Human Genetics, ACS - Amsterdam Cardiovascular Sciences, ACS - Atherosclerosis & ischemic syndromes, MUMC+: DA KG Polikliniek (9), RS: Carim - H02 Cardiomyopathy, Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), RS: Carim - H04 Arrhythmogenesis and cardiogenetics, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Clinical sciences, Heartrhythmmanagement, Medical Genetics, Reproduction and Genetics, and Cardio-vascular diseases

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], Nantes Referral Center for inherited cardiac arrhythmia, Disease, Arrhythmias, 030105 genetics & heredity, ACMG/AMP guidelines, Brugada, LQTS, variant interpretation, Medicine, Genetics (clinical), Brugada Syndrome, Brugada syndrome, Genetics, Genetics & Heredity, education.field_of_study, medicine.diagnostic_test, Molecular pathology, 3. Good health, Long QT Syndrome, Medical genetics, Population Control, Cardiology and Cardiovascular Medicine, Cardiac, Medical Genetics, Life Sciences & Biomedicine, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Long QT syndrome, Population, 610 Medicine & health, BIO/18 - GENETICA, Article, 03 medical and health sciences, Humans, Genetic Testing, cardiovascular diseases, education, Medicinsk genetik, Genetic testing, 0604 Genetics, Science & Technology, business.industry, Genetic heterogeneity, MUTATIONS, ACMG/AMP guideline, Arrhythmias, Cardiac, 1103 Clinical Sciences, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, medicine.disease, Mutation, 030104 developmental biology, Human medicine, business
Abstract

Purpose: Stringent variant interpretation guidelines can lead to high rates of variants of uncertain significance (VUS) for genetically heterogeneous disease like long QT syndrome (LQTS) and Brugada syndrome (BrS). Quantitative and disease-specific customization of American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines can address this false negative rate. Methods: We compared rare variant frequencies from 1847 LQTS (KCNQ1/KCNH2/SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data and developed disease-specific criteria for ACMG/AMP evidence classes-rarity (PM2/BS1 rules) and case enrichment of individual (PS4) and domain-specific (PM1) variants. Results: Rare SCN5A variant prevalence differed between European (20.8%) and Japanese (8.9%) BrS patients (p = 5.7 x 10(-18)) and diagnosis with spontaneous (28.7%) versus induced (15.8%) Brugada type 1 electrocardiogram (ECG) (p = 1.3 x 10(-13)). Ion channel transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterized by high enrichment of case variants and >95% probability of pathogenicity. Applying the customized rules, 17.4% of European BrS and 74.8% of European LQTS cases had (likely) pathogenic variants, compared with estimated diagnostic yields (case excess over gnomAD) of 19.2%/82.1%, reducing VUS prevalence to close to background rare variant frequency. Conclusion: Large case-control data sets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing., Amsterdam Cardiovascular Sciences fellowship; Dutch Heart Foundation (CVON Predict-2/Concor-genes); Netherlands Organization for Scientific ResearchNetherlands Organization for Scientific Research (NWO) [VICI 016.150.610]; Fondation LeducqLeducq Foundation, R.W. is supported by an Amsterdam Cardiovascular Sciences fellowship. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict-2/Concor-genes), Netherlands Organization for Scientific Research (VICI 016.150.610), and Fondation Leducq. See Supplement for all Acknowledgements.

Published
2020

18. Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome

Author

Yvonne M. Hoedemaekers, M. Ben Shoemaker, Pascale Guicheney, Antoine Leenhardt, Andrea Mazzanti, Minoru Horie, Jan H. Veldink, Isabelle Denjoy, Yu Kucho, Chiea Chuen Khor, Tomas Robyns, Carlo Napolitano, Peter Weeke, J. Martijn Bos, David J. Tester, Hanno L. Tan, Annika Rydberg, Patrick T. Ellinor, Pilar Galan, Taisuke Ishikawa, Seiko Ohno, Peter J. Schwartz, Masao Yoshinaga, Thomas Werge, Marta Ribasés, Bart Loeys, Jean-Jacques Schott, Jacob Tfelt-Hansen, Ulla-Britt Diamant, Marko Ernsting, Georgia Sarquella-Brugada, Yuka Mizusawa, Michael Christiansen, Pyotr G. Platonov, Annika Winbo, Thomas Meitinger, Keiko Shimamoto, Cristina Barlassina, Pieter G. Postema, Takeru Makiyama, Maarten P. van den Berg, Yanushi D. Wijeyeratne, Wataru Shimizu, Charles Antzelevitch, Christopher Newton-Cheh, Martina Müller-Nurasyid, Dan M. Roden, Vincent Probst, Takeshi Aiba, Lia Crotti, Daniele Cusi, Britt M. Beckmann, Johan Saenen, Peter Lichtner, Oscar Campuzano, Tin Aung, Nynke Hofman, Morten S. Olesen, Matteo Pedrazzini, Elijah R. Behr, Karen E. Morrison, Najim Lahrouchi, Katja E. Odening, Andrew D. Krahn, Kari L. Turkowski, J. Peter van Tintelen, Steven A. Lubitz, Federica Dagradi, Josep Brugada, Julien Barc, Birgit Stallmeyer, Stefan Kääb, Sven Zumhagen, Jonathan R. Skinner, Michael W.T. Tanck, Christopher Shaw, Brianna Davies, Eric Schulze-Bahr, Mineo Ozaki, Roddy Walsh, Antoine Andorin, Leonard H. van den Berg, Silvia G. Priori, Johannes Steinfurt, Jean-Baptiste Gourraud, Eline A. Nannenberg, Mark Lathrop, Rafik Tadros, Ramon Brugada, Leander Beekman, Peter M. Andersen, Ryan Pfeiffer, Boris Rudic, Reza Jabbari, Kanae Hasegawa, Jeroen Breckpot, Naomasa Makita, Michael J. Ackerman, Arthur A.M. Wilde, Hideki Itoh, Martin Borggrefe, Elena Arbelo, Connie R. Bezzina, Pamela J. Shaw, Ammar Al-Chalabi, Markus Munter, Cardiology, Graduate School, ACS - Heart failure & arrhythmias, ACS - Amsterdam Cardiovascular Sciences, Human Genetics, Epidemiology and Data Science, APH - Methodology, ACS - Atherosclerosis & ischemic syndromes, Heart Center, Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences. Amsterdam University Medical Center, University of Amsterdam, European Reference Network for Rare, Low Prevalence, and Complex Diseases of the Heart (ERN GUARD-Heart), Institut de Cardiologie de Montreal, Université de Montréal (UdeM), Istituto Auxologico Italiano, Shiga University of Medical Science, University of Fukui [Bunkyo], Equipe 3: EREN- Equipe de Recherche en Epidémiologie Nutritionnelle (CRESS - U1153), Université Sorbonne Paris Nord-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Conservatoire National des Arts et Métiers [CNAM] (CNAM)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), 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], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CIC - CHU Bichat, Institut National de la Santé et de la Recherche Médicale (INSERM), Lahrouchi, N, Tadros, R, Crotti, L, Mizusawa, Y, Postema, P, Beekman, L, Walsh, R, Hasegawa, K, Barc, J, Ernsting, M, Turkowski, K, Mazzanti, A, Beckmann, B, Shimamoto, K, Diamant, U, Wijeyeratne, Y, Kucho, Y, Robyns, T, Ishikawa, T, Arbelo, E, Christiansen, M, Winbo, A, Jabbari, R, Lubitz, S, Steinfurt, J, Rudic, B, Loeys, B, Shoemaker, M, Weeke, P, Pfeiffer, R, Davies, B, Andorin, A, Hofman, N, Dagradi, F, Pedrazzini, M, Tester, D, Bos, J, Sarquella-Brugada, G, Campuzano, Ó, Platonov, P, Stallmeyer, B, Zumhagen, S, Nannenberg, E, Veldink, J, van den Berg, L, Al-Chalabi, A, Shaw, C, Shaw, P, Morrison, K, Andersen, P, Müller-Nurasyid, M, Cusi, D, Barlassina, C, Galan, P, Lathrop, M, Munter, M, Werge, T, Ribasés, M, Aung, T, Khor, C, Ozaki, M, Lichtner, P, Meitinger, T, van Tintelen, J, Hoedemaekers, Y, Denjoy, I, Leenhardt, A, Napolitano, C, Shimizu, W, Schott, J, Gourraud, J, Makiyama, T, Ohno, S, Itoh, H, Krahn, A, Antzelevitch, C, Roden, D, Saenen, J, Borggrefe, M, Odening, K, Ellinor, P, Tfelt-Hansen, J, Skinner, J, van den Berg, M, Olesen, M, Brugada, J, Brugada, R, Makita, N, Breckpot, J, Yoshinaga, M, Behr, E, Rydberg, A, Aiba, T, Kääb, S, Priori, S, Guicheney, P, Tan, H, Newton-Cheh, C, Ackerman, M, Schwartz, P, Schulze-Bahr, E, Probst, V, Horie, M, Wilde, A, Tanck, M, Bezzina, C, and Cardiovascular Centre (CVC)

Subjects
Multifactorial Inheritance, [SDV]Life Sciences [q-bio], Genome-wide association study, 030204 cardiovascular system & hematology, Severity of Illness Index, Sudden cardiac death, Electrocardiography, 0302 clinical medicine, inheritance pattern, Medicine, Cardiac and Cardiovascular Systems, Age of Onset, Genetics, 0303 health sciences, Kardiologi, Genetic disorder, genome-wide association study, Prognosis, 3. Good health, Phenotype, Medical genetics, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Adolescent, Genotype, Long QT syndrome, 610 Medicine & health, BIO/18 - GENETICA, QT interval, Polymorphism, Single Nucleotide, 03 medical and health sciences, Young Adult, Physiology (medical), long QT syndrome, Humans, Genetic Predisposition to Disease, cardiovascular diseases, Alleles, Genetic Association Studies, MED/01 - STATISTICA MEDICA, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, inheritance patterns, MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Heritability, medicine.disease, Genetic architecture, Genome-wide Association Study, Inheritance Patterns, Long Qt Syndrome, Case-Control Studies, Human medicine, business
Abstract

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P P Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Published
2020

19. Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction

Author

Dennis O. Mook-Kanamori, Yalda Jamshidi, Peter K. Joshi, Seung Hoan Choi, Henry J. Lin, Rebecca D. Jackson, Alison D. Murray, May E. Montasser, Veikko Salomaa, Charles Kooperberg, Moritz F. Sinner, Gianfranco Sinagra, Luisa Foco, James G. Wilson, Johan Sundström, Kathleen A. Ryan, Eric A. Whitsel, Bruno H. Stricker, Sandosh Padmanabhan, Christopher Newton-Cheh, Ozren Polasek, Unnur Thorsteinsdottir, Niek Verweij, Pier D. Lambiase, Nathan R. Tucker, Stefan Kääb, Jun Ding, Stefan Weiss, Daniel F. Gudbjartsson, David Conen, Lars Lind, Ivana Kolcic, Lu-Chen Weng, J. Wouter Jukema, Kirill V. Tarasov, Xiuqing Guo, Stella Trompet, Patricia B. Munroe, Albert V. Smith, Elsayed Z. Soliman, Andrew Tinker, Antti Jula, J. Gustav Smith, Alexander P. Reiner, Sébastien Thériault, Kathryn L. Lunetta, Vilmundur Gudnason, Mika Kähönen, Massimo Mangino, Raymond Noordam, Joshua C. Bis, Alan R. Shuldiner, Tim D. Spector, Borbala Mifsud, Stefan van Duijvenboden, Jeffrey R. O'Connell, Emelia J. Benjamin, M. Benjamin Shoemaker, Stephan B. Felix, Peter W. Macfarlane, Lorenz Risch, Uwe Völker, Stephanie M. Gogarten, Maria Fernanda Lima-Costa, Julia Ramirez, Morten S. Olesen, Konstantin Strauch, Annette Peters, Aaron Isaacs, Steven A. Lubitz, Eric Boerwinkle, Carolina Roselli, James H. Cartwright, Nathalia M. Araujo, Ruth J. F. Loos, Diane Fatkin, Harry Campbell, Blair H. Smith, Thomas Meitinger, André G. Uitterlinden, Paul L. Huang, Tamara B. Harris, Kathleen F. Kerr, David J. Porteous, Martina Müller-Nurasyid, Francesco Cucca, Michiel Rienstra, Davíð O. Arnar, Amanda A. Seyerle, Caroline Hayward, M. Abdullah Said, Catriona L. K. Barnes, Kent D. Taylor, Nona Sotoodehnia, Nina Mononen, Dan M. Roden, Jonathan Marten, Terho Lehtimäki, Dan E. Arking, Anna F. Dominiczak, Jan A. Kors, Olli T. Raitakari, Igor Rudan, Yordi J. van de Vegte, Christopher P. Nelson, Erik Ingelsson, Ulrike Peters, Girish N. Nadkarni, Eduardo Tarazona-Santos, Edward G. Lakatta, Nina Hutri-Kähönen, Bruce M. Psaty, Patrick T. Ellinor, Christian Fuchsberger, Katharina Schramm, Amelia W. Hall, M. Yldau van der Ende, Alvaro Alonso, James F. Wilson, Sheila Ulivi, Rosa B. Thorolfsdottir, Stefanie Aeschbacher, Mary L. Biggs, Marten E. van den Berg, Nilesh J. Samani, Thibaud Boutin, Vilmantas Giedraitis, Honghuang Lin, Kjell Nikus, Helen R. Warren, Arie C. Maan, James J. Cranley, Adolfo Correa, Martin Gögele, Ian Ford, Katri Sääksjärvi, Georg Ehret, Michele Orini, Susan R. Heckbert, Cecilia M. Lindgren, Jie Yao, Maria Pina Concas, Pim van der Harst, Ioanna Ntalla, Jeffrey Haessler, Jerome I. Rotter, Pashupati P. Mishra, Michael J. Cutler, Erwin P. Bottinger, Cornelia M. van Duijn, Jennifer A. Brody, Paolo Gasparini, Lenore J. Launer, Andrew P. Morris, Renée de Mutsert, Aki S. Havulinna, James P. Cook, Hilma Holm, Patrick Sulem, Alessandro De Grandi, Cristian Pattaro, Gardar Sveinbjornsson, Antonio Luiz Pinho Ribeiro, Mark J. Caulfield, Gudmar Thorleifsson, Marcus Dörr, Muhammad B. Riaz, Peter P. Pramstaller, Yong Qian, Anubha Mahajan, Cathy C. Laurie, Kenneth Rice, Mark Chaffin, Kari Stefansson, Andrew A. Hicks, Solmaz Assa, Hao Mei, Leo-Pekka Lyytikäinen, Fabiola Del Greco M, Renan P. Souza, Michael Preuss, Adrienne M. Stilp, Barry London, Melanie Waldenberger, Christy L. Avery, Daniel Levy, Michael R. Barnes, Medical Informatics, Epidemiology, Internal Medicine, Weng, Lu-Chen [0000-0003-1475-4930], Hall, Amelia Weber [0000-0002-7915-0313], Tucker, Nathan R [0000-0002-5071-4218], Chaffin, Mark D [0000-0002-1234-5562], Roselli, Carolina [0000-0001-5267-6756], Barnes, Michael R [0000-0001-9097-7381], Mifsud, Borbala [0000-0003-3429-3094], Hayward, Caroline [0000-0002-9405-9550], Concas, Maria Pina [0000-0003-3598-2537], Boutin, Thibaud [0000-0003-4754-1675], Kolcic, Ivana [0000-0001-7918-6052], Rudan, Igor [0000-0001-6993-6884], Souza, Renan P [0000-0002-9479-4432], Giedraitis, Vilmantas [0000-0003-3423-2021], Ingelsson, Erik [0000-0003-2256-6972], Mahajan, Anubha [0000-0001-5585-3420], Morris, Andrew P [0000-0002-6805-6014], Hicks, Andrew A [0000-0001-6320-0411], Sundström, Johan [0000-0003-2247-8454], Nelson, Christopher P [0000-0001-8025-2897], Riaz, Muhammad B [0000-0002-5512-1745], Sinagra, Gianfranco [0000-0003-2700-8478], Mishra, Pashupati P [0000-0001-5177-3431], Caulfield, Mark J [0000-0001-9295-3594], Dominiczak, Anna [0000-0003-4913-3608], Risch, Lorenz [0000-0003-2692-6699], Joshi, Peter K [0000-0002-6361-5059], Wilson, James F [0000-0001-5751-9178], Isaacs, Aaron [0000-0001-5037-4834], van Duijn, Cornelia M [0000-0002-2374-9204], Gudnason, Vilmundur [0000-0001-5696-0084], Smith, Albert V [0000-0003-1942-5845], Loos, Ruth JF [0000-0002-8532-5087], Preuss, Michael H [0000-0001-5266-8465], Correa, Adolfo [0000-0002-9501-600X], Müller-Nurasyid, Martina [0000-0003-3793-5910], Waldenberger, Melanie [0000-0003-0583-5093], Mangino, Massimo [0000-0002-2167-7470], Rienstra, Michiel [0000-0002-2581-070X], van der Harst, Pim [0000-0002-2713-686X], Verweij, Niek [0000-0002-4303-7685], Fatkin, Diane [0000-0002-9010-9856], Brody, Jennifer A [0000-0001-8509-148X], Rice, Kenneth [0000-0002-3071-7278], Pattaro, Cristian [0000-0002-4119-0109], Wouter Jukema, J [0000-0002-3246-8359], Weiss, Stefan [0000-0002-3553-4315], Havulinna, Aki S [0000-0002-4787-8959], Sääksjärvi, Katri [0000-0002-5061-4911], Salomaa, Veikko [0000-0001-7563-5324], Rotter, Jerome I [0000-0001-7191-1723], Taylor, Kent D [0000-0002-2756-4370], Lakatta, Edward G [0000-0002-4772-0035], Lin, Honghuang [0000-0003-3043-3942], Lunetta, Kathryn L [0000-0002-9268-810X], Murray, Alison D [0000-0003-4915-4847], Porteous, David J [0000-0003-1249-6106], Smith, Blair H [0000-0002-5362-9430], Uitterlinden, André [0000-0002-7276-3387], Peters, Ulrike [0000-0001-5666-9318], Alonso, Alvaro [0000-0002-2225-8323], Ehret, Georg B [0000-0002-5730-0675], Soliman, Elsayed Z [0000-0001-5632-8150], Gogarten, Stephanie M [0000-0002-7231-9745], Kerr, Kathleen F [0000-0002-6438-9583], Abdullah Said, M [0000-0003-2920-7745], Orini, Michele [0000-0001-5773-0344], Ramirez, Julia [0000-0003-4130-5866], Van Duijvenboden, Stefan [0000-0001-8897-558X], Gudbjartsson, Daniel F [0000-0002-5222-9857], Sulem, Patrick [0000-0001-7123-6123], Thorolfsdottir, Rosa B [0000-0001-7475-0398], Benjamin, Emelia J [0000-0003-4076-2336], Stefansson, Kari [0000-0003-1676-864X], Ellinor, Patrick T [0000-0002-2067-0533], Jamshidi, Yalda [0000-0003-0151-6482], Lubitz, Steven A [0000-0002-9599-4866], Munroe, Patricia B [0000-0002-4176-2947], Apollo - University of Cambridge Repository, Medicum, Institute for Molecular Medicine Finland, Complex Disease Genetics, Helsinki Institute of Life Science HiLIFE, University of Helsinki, Cardiovascular Centre (CVC), Ntalla, I., Weng, L. -C., Cartwright, J. H., Hall, A. W., Sveinbjornsson, G., Tucker, N. R., Choi, S. H., Chaffin, M. D., Roselli, C., Barnes, M. R., Mifsud, B., Warren, H. R., Hayward, C., Marten, J., Cranley, J. J., Concas, M. P., Gasparini, P., Boutin, T., Kolcic, I., Polasek, O., Rudan, I., Araujo, N. M., Lima-Costa, M. F., Ribeiro, A. L. P., Souza, R. P., Tarazona-Santos, E., Giedraitis, V., Ingelsson, E., Mahajan, A., Morris, A. P., Del Greco M, F., Foco, L., Gogele, M., Hicks, A. A., Cook, J. P., Lind, L., Lindgren, C. M., Sundstrom, J., Nelson, C. P., Riaz, M. B., Samani, N. J., Sinagra, G., Ulivi, S., Kahonen, M., Mishra, P. P., Mononen, N., Nikus, K., Caulfield, M. J., Dominiczak, A., Padmanabhan, S., Montasser, M. E., O'Connell, J. R., Ryan, K., Shuldiner, A. R., Aeschbacher, S., Conen, D., Risch, L., Theriault, S., Hutri-Kahonen, N., Lehtimaki, T., Lyytikainen, L. -P., Raitakari, O. T., Barnes, C. L. K., Campbell, H., Joshi, P. K., Wilson, J. F., Isaacs, A., Kors, J. A., van Duijn, C. M., Huang, P. L., Gudnason, V., Harris, T. B., Launer, L. J., Smith, A. V., Bottinger, E. P., Loos, R. J. F., Nadkarni, G. N., Preuss, M. H., Correa, A., Mei, H., Wilson, J., Meitinger, T., Muller-Nurasyid, M., Peters, A., Waldenberger, M., Mangino, M., Spector, T. D., Rienstra, M., van de Vegte, Y. J., van der Harst, P., Verweij, N., Kaab, S., Schramm, K., Sinner, M. F., Strauch, K., Cutler, M. J., Fatkin, D., London, B., Olesen, M., Roden, D. M., Benjamin Shoemaker, M., Gustav Smith, J., Biggs, M. L., Bis, J. C., Brody, J. A., Psaty, B. M., Rice, K., Sotoodehnia, N., De Grandi, A., Fuchsberger, C., Pattaro, C., Pramstaller, P. P., Ford, I., Wouter Jukema, J., Macfarlane, P. W., Trompet, S., Dorr, M., Felix, S. B., Volker, U., Weiss, S., Havulinna, A. S., Jula, A., Saaksjarvi, K., Salomaa, V., Guo, X., Heckbert, S. R., Lin, H. J., Rotter, J. I., Taylor, K. D., Yao, J., de Mutsert, R., Maan, A. C., Mook-Kanamori, D. O., Noordam, R., Cucca, F., Ding, J., Lakatta, E. G., Qian, Y., Tarasov, K. V., Levy, D., Lin, H., Newton-Cheh, C. H., Lunetta, K. L., Murray, A. D., Porteous, D. J., Smith, B. H., Stricker, B. H., Uitterlinden, A., van den Berg, M. E., Haessler, J., Jackson, R. D., Kooperberg, C., Peters, U., Reiner, A. P., Whitsel, E. A., Alonso, A., Arking, D. E., Boerwinkle, E., Ehret, G. B., Soliman, E. Z., Avery, C. L., Gogarten, S. M., Kerr, K. F., Laurie, C. C., Seyerle, A. A., Stilp, A., Assa, S., Abdullah Said, M., Yldau van der Ende, M., Lambiase, P. D., Orini, M., Ramirez, J., Van Duijvenboden, S., Arnar, D. O., Gudbjartsson, D. F., Holm, H., Sulem, P., Thorleifsson, G., Thorolfsdottir, R. B., Thorsteinsdottir, U., Benjamin, E. J., Tinker, A., Stefansson, K., Ellinor, P. T., Jamshidi, Y., Lubitz, S. A., Munroe, P. B., Fysiologie, RS: FHML MaCSBio, RS: Carim - B01 Blood proteins & engineering, Læknadeild (HÍ), Faculty of Medicine (UI), Heilbrigðisvísindasvið (HÍ), School of Health Sciences (UI), Verkfræði- og náttúruvísindasvið (HÍ), School of Engineering and Natural Sciences (UI), Háskóli Íslands, and University of Iceland

Subjects
0301 basic medicine, Male, Multifactorial Inheritance, General Physics and Astronomy, Gene Expression, Genome-wide association study, 030204 cardiovascular system & hematology, Arrhythmias, Genome-wide association studies, CALCINEURIN, Electrocardiography, 0302 clinical medicine, Cardiovascular Disease, Multi-ancestry GWAS, ELEMENTS, Medicine, Cardiac and Cardiovascular Systems, Blóðrásarsjúkdómar, lcsh:Science, RISK, DECREASE, education.field_of_study, Multidisciplinary, Kardiologi, medicine.diagnostic_test, 1184 Genetics, developmental biology, physiology, Atrial fibrillation, 3142 Public health care science, environmental and occupational health, 3. Good health, Endophenotype, Arrhythmias, Cardiac, Cardiovascular Diseases, Endophenotypes, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Quantitative Trait Loci, cardiovascular system, Cardiology, medicine.symptom, Erfðarannsóknir, Cardiac, Medical Genetics, Human, Bradycardia, medicine.medical_specialty, Science, GENOME-WIDE ASSOCIATION, ATRIAL-FIBRILLATION, MUTATIONS, DURATION, CARDIOMYOPATHY, BRADYCARDIA, Population, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Internal medicine, Cardiac conduction, PR interval, education, Medicinsk genetik, business.industry, Cardiovascular genetics, General Chemistry, Arfgengi, medicine.disease, 030104 developmental biology, lcsh:Q, business
Abstract

Publisher's version (útgefin grein), The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N = 293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease., We provide all investigator and study-specific acknowledgements in Supplementary Note 1, and funding sources in Supplementary Note 2.

Published
2020

20. The Second Team Haemophilia Education Meeting, 2016, Frankfurt, Germany

Author

Marijke van den Berg, Yesim Dargaud, Roseline d'Oiron, Edward Laane, Sayma Raza, Pål Andre Holme, Susan Halimeh, Lorenzo G. Mantovani, Sébastien Lobet, Andrea S. Doria, Raquel Ciuvalschi Maia, Erik Berntorp, Thomas Sannié, Pia Petrini, Athina Dettoraki, Paul McLaughlin, Maria Elisa Mancuso, Radoslaw Kaczmarek, Anna Farrell, Jan Blatný, Debra Pollard, David Perry, Hervé Chambost, Daniel P. Hart, Lochana Nanayakkara, Stephanie Taylor, Berntorp, E, Dargaud, Y, Hart, D, Lobet, S, Mancuso, M, D'Oiron, R, Perry, D, Pollard, D, van den Berg, M, Blatny, J, Chambost, H, Doria, A, Holme, P, Kaczmarek, R, Mantovani, L, Mclaughlin, P, Nanayakkara, L, Petrini, P, Sannie, T, Laane, E, Maia, R, Dettoraki, A, Farrell, A, Halimeh, S, Raza, S, and Taylor, S

Subjects
medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, 030204 cardiovascular system & hematology, Haemophilia, Hemophilia A, Hemophilia B, Patient care, 03 medical and health sciences, 0302 clinical medicine, HDE HEM PED, Multidisciplinary approach, hemic and lymphatic diseases, Germany, Medicine, Humans, Disease management (health), Congresses, Clotting factor, Patient Care Team, Health professionals, business.industry, Disease Management, Hematology, General Medicine, Treatment team, medicine.disease, 3. Good health, clotting factor concentrates, genetics, haemophilia, laboratory assays, multidisciplinary, real-life data, Europe, Family medicine, Physical therapy, Patient representatives, Health Facilities, business, Delivery of Health Care, 030215 immunology
Abstract

The first Team Haemophilia Education (THE) Meeting was held on 7-8 May 2015 in Amsterdam, The Netherlands. It aimed to promote the optimal care of patients with haemophilia through education of the multidisciplinary treatment team. This was achieved by reviewing the latest developments in haemophilia management, considering how these can be implemented in the clinic to improve patient care and providing a platform for networking and debate for all haemophilia treatment team members. The second THE Meeting was held on 19-20 May in Frankfurt, Germany, and participants included doctors, nurses, physiotherapists, patient representatives and data management staff from 20 different countries. Topics covered the role of the multidisciplinary team in delivering the best haemophilia care, challenges in the management of haemophilia across Europe, available clotting factor treatments, future treatments and the use of genetics in advising carriers of haemophilia. This report is a summary of the key developments in haemophilia care presented by various investigators and healthcare professionals at THE Meeting 2016. info:eu-repo/semantics/publishedVersion

Published
2017

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