Stefan J Schunk1, Marcus E Kleber2,3, Winfried März2,4,5, Shichao Pang6, Stephen Zewinger1, Sarah Triem1, Philipp Ege1, Matthias C Reichert7, Marcin Krawczyk7,8, Susanne N Weber7, Isabella Jaumann1, David Schmit1, Tamim Sarakpi1, Stefan Wagenpfeil9, Rafael Kramann10,11, Eric Boerwinkle12,13, Christie M Ballantyne14,15, Megan L Grove12, Vinicius Tragante16, Anna P Pilbrow17, A Mark Richards17, Vicky A Cameron17, Robert N Doughty18, Marie-Pierre Dubé19,20, Jean-Claude Tardif19,20, Yassamin Feroz-Zada19, Maxine Sun20, Chang Liu21, Yi-An Ko22, Arshed A Quyyumi21, Jaana A Hartiala23, W H Wilson Tang24,25, Stanley L Hazen24,25, Hooman Allayee23, Caitrin W McDonough26, Yan Gong26, Rhonda M Cooper-DeHoff26,27, Julie A Johnson26,27, Markus Scholz28,29, Andrej Teren29,30, Ralph Burkhardt29,31, Andreas Martinsson32, J Gustav Smith33, Lars Wallentin34,35, Stefan K James34,35, Niclas Eriksson34,35, Harvey White36, Claes Held34,35, Dawn Waterworth37, Stella Trompet38, J Wouter Jukema39,40, Ian Ford41, David J Stott42, Naveed Sattar43, Sharon Cresci44,45, John A Spertus46, Hannah Campbell44,45, Sascha Tierling47, Jörn Walter47, Emmanuel Ampofo48, Barbara A Niemeyer49, Peter Lipp50, Heribert Schunkert6,51, Michael Böhm52, Wolfgang Koenig6,51,53, Danilo Fliser1, Ulrich Laufs54, Thimoteus Speer1,55. 1. Department of Internal Medicine IV, Nephrology and Hypertension, Saarland University Hospital, Kirrberger Strasse, Building 41, 66424 Homburg/Saar, Germany. 2. Vth Department of Medicine, University Heidelberg, Mannheim Medical Faculty, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany. 3. SYNLAB MVZ Humangenetik Mannheim, Harrlachweg 1, 68163 Mannheim, Germany. 4. Clinical Institute of Medical and Laboratory Diagnostics, Medical University Graz, Auenbruggerpl. 2, 8036 Graz, Austria. 5. Synlab Academy, Synlab Holding GmbH, Harrlachweg 1, 68163 Mannheim, Germany. 6. Kardiologie, Deutsches Herzzentrum München, Technische Universität München, Lazarettstraße 36, 80636 Munich, Germany. 7. Department of Medicine II, Saarland University Medical Center, Kirrberger Straße, 66424 Homburg, Germany. 8. Laboratory of Metabolic Liver Diseases, Centre for Preclinical Research, Department of General, Transplant and Liver Surgery, Medical University of Warsaw, ul. Banacha 1B, CePT, 02-097 Warsaw, Poland. 9. Institute of Medical Biometry, Epidemiology & Medical Informatics, Saarland University Campus Homburg/Saar, Kirrberger Straße, 66424 Homburg/Saar, Germany. 10. Division of Nephrology and Clinical Immunology, RWTH Aachen University, Pauwelsstrasse 30 52074 Aachen, Germany. 11. Institute of Experimental Medicine and Systems Biology, RWTH, Pauwelsstraße 30, 52074 Aachen, Germany. 12. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, 1200 Pressler Street, Houston, TX 77030, USA. 13. Human Genome Sequencing Center, Baylor College of Medicine, BCM226, Houston, TX 77030, USA. 14. Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. 15. Center of Cardiovascular Disease Prevention, Methodist DeBakey Heart and Vascular Center, 6565 Fannin St, Houston, TX 77030, USA. 16. Department of Cardiology, Heart and Lungs Division, UMC Utrecht, Heidelberglaan 100 3584 CX Utrecht, Netherlands. 17. The Christchurch Heart Institute, University of Otago Christchurch, 2 Riccarton Avenue, Christchurch Central City, Christchurch 8011, New Zealand. 18. Heart Health Research Group, University of Auckland, Level 2 / 22-30 Park Ave, Grafton, Auckland, New Zealand. 19. Montreal Heart Institute, 5000 Rue Bélanger, Montreal QC H1T 1C8, Canada. 20. Faculty of Medicine, Université der Montréal, Pavillon Roger-Gaudry, 2900 Edouard Montpetit Blvd, Montreal, Quebec H3T 1J4, Canada. 21. Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Emory University School of Medicine, 1462 Clifton Road NE, Atlanta, GA 30322, USA. 22. Department of Biostatistics and Bioinformatics, Rollins School of Public Healthy, Emory University, 1518 Clifton Road NE, Atlanta, GA 30322, USA. 23. Department of Preventive Medicine, University of Southern California, Keck School of Medicine, 2001 N. Soto St. Los Angeles, CA 90033, USA. 24. Department of Cardiovascular Medicine, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195, USA. 25. Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Ave, NB 21, Cleveland, OH 44195, USA. 26. Department of Pharmacotherapy and Translational Research, University of Florida, College of Pharmacy, 1225 Center Drive, HPNP Building, Gainesville, FL 32610-0486, USA. 27. Division of Cardiovascular Medicine, Department of Medicine, University of Florida, 1600 SW Archer Rd, Gainesville, FL 32610, USA. 28. Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany. 29. LIFE Research Center for Civilization Diseases, University of Leipzig, Härtelstraße 16-18, 04107 Leipzig, Germany. 30. Heart Center Leipzig, Strümpellstraße 39, 04289 Leipzig, Germany. 31. Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Franz-Josef-Strauß-Allee 11, 93053 Regensburg,Germany. 32. Department of Cardiology, Sahlgrenska University Hospital, Blå stråket 5, 413 45 Göteborg, Sweden. 33. Department of Cardiology, Clinical Sciences, Lund University and Skane University Hospital, BMC F12, 221 84 Lund, Sweden. 34. Department of Medical Sciences, Cardiology, Uppsala University, Akademiska sjukhuset Entrance 40, 751 85 Uppsala, Sweden. 35. Uppsala Clinical Research Center, Uppsala University, Dag Hammarskjölds Väg 38, 751 85 Uppsala, Sweden. 36. Green Lane Cardiovascular Service, Auckland City Hospital, 2 Park Road, Grafton, Auckland 1023, New Zealand. 37. Genetics, GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, USA. 38. Department of Internal Medicine, Section of Gerontology and Geriatrics, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. 39. Department of Cardiology, Leiden University Medical Cernter, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. 40. Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, The Netherlands. 41. Robertson Centre for Biostatistics, University of Glasgow, Boyd Orr Building University Avenue, Glasgow G12 8QQ, UK. 42. Institute of Cardiovascular and Medical Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA, UK. 43. BHF Glasgow Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, 126 University Place, Glasgow G12 8TA UK. 44. Washington University School of Medicine, 2300 I St NW, Washington, DC 20052, USA. 45. Department of Medicine & Genetics, Campus Box 8232, 4515 McKinley Ave., St. Louis, MO 63110, USA. 46. Saint Luke's Mid America Heart Institute and University of Missouri-Kansas City, 4401 Wornall Rd, Kansas City, MO 64111, USA. 47. Faculty of Natural Sciences and Technology, Department of Genetics/Epigenetics, Saarland University, Postfach 151150, 66041 Saarbrücken, Germany. 48. Institute of Clinical & Experimental Surgery, Saarland University, Kirrberger Straße, 66424 Homburg/Saar, Germany. 49. Molecular Biophysics, CIPMM, Saarland University, Kirrberger Straße, 66424 Homburg/Saar, Germany. 50. Center for Molecular Signaling (PZMS), Institute for Molecular Cell Biology, Research Center for Molecular Imaging and Screening, Medical Faculty, Saarland University, Kirrberger Straße, 66424 Homburg, Germany. 51. Partner Site Munich Heart Alliance, German Centre of Cardiovascular Research (DZHK), Ismaninger Straße 22, 81675 Munich, Germany. 52. Department of Internal Medicine III, Cardiology, Angiology, and Intensive Care Medicine, Saarland University Hospital, Kirrberger Strasse, Building 41, 66424 Homburg/Saar, Germany. 53. Institute of Epidemiology and Medical Biometry, University of Ulm, Helmholtzstr. 22, 89081 Ulm, Germany. 54. Department of Cardiology, University Medical Center Leipzig, Liebigstraße 20, Leipzig, Germany. 55. Translational Cardio-Renal Medicine, Saarland University, Kirrberger Straße, 66424 Homburg/Saar, Germany.
Abstract
AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. METHODS AND RESULTS: We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. CONCLUSION: The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Alexander G Bick; James P Pirruccello; Gabriel K Griffin; Namrata Gupta; Stacey Gabriel; Danish Saleheen; Peter Libby; Sekar Kathiresan; Pradeep Natarajan Journal: Circulation Date: 2019-11-11 Impact factor: 29.690
Authors: Paul M Ridker; Brendan M Everett; Tom Thuren; Jean G MacFadyen; William H Chang; Christie Ballantyne; Francisco Fonseca; Jose Nicolau; Wolfgang Koenig; Stefan D Anker; John J P Kastelein; Jan H Cornel; Prem Pais; Daniel Pella; Jacques Genest; Renata Cifkova; Alberto Lorenzatti; Tamas Forster; Zhanna Kobalava; Luminita Vida-Simiti; Marcus Flather; Hiroaki Shimokawa; Hisao Ogawa; Mikael Dellborg; Paulo R F Rossi; Roland P T Troquay; Peter Libby; Robert J Glynn Journal: N Engl J Med Date: 2017-08-27 Impact factor: 91.245
Authors: Jean-Claude Tardif; Simon Kouz; David D Waters; Olivier F Bertrand; Rafael Diaz; Aldo P Maggioni; Fausto J Pinto; Reda Ibrahim; Habib Gamra; Ghassan S Kiwan; Colin Berry; José López-Sendón; Petr Ostadal; Wolfgang Koenig; Denis Angoulvant; Jean C Grégoire; Marc-André Lavoie; Marie-Pierre Dubé; David Rhainds; Mylène Provencher; Lucie Blondeau; Andreas Orfanos; Philippe L L'Allier; Marie-Claude Guertin; François Roubille Journal: N Engl J Med Date: 2019-11-16 Impact factor: 91.245
Authors: Thimoteus Speer; Paul M Ridker; Arnold von Eckardstein; Stefan J Schunk; Danilo Fliser Journal: Eur Heart J Date: 2021-06-07 Impact factor: 29.983
Authors: Jeannette Simino; Gang Shi; Joshua C Bis; Daniel I Chasman; Georg B Ehret; Xiangjun Gu; Xiuqing Guo; Shih-Jen Hwang; Eric Sijbrands; Albert V Smith; Germaine C Verwoert; Jennifer L Bragg-Gresham; Gemma Cadby; Peng Chen; Ching-Yu Cheng; Tanguy Corre; Rudolf A de Boer; Anuj Goel; Toby Johnson; Chiea-Chuen Khor; Carla Lluís-Ganella; Jian'an Luan; Leo-Pekka Lyytikäinen; Ilja M Nolte; Xueling Sim; Siim Sõber; Peter J van der Most; Niek Verweij; Jing Hua Zhao; Najaf Amin; Eric Boerwinkle; Claude Bouchard; Abbas Dehghan; Gudny Eiriksdottir; Roberto Elosua; Oscar H Franco; Christian Gieger; Tamara B Harris; Serge Hercberg; Albert Hofman; Alan L James; Andrew D Johnson; Mika Kähönen; Kay-Tee Khaw; Zoltan Kutalik; Martin G Larson; Lenore J Launer; Guo Li; Jianjun Liu; Kiang Liu; Alanna C Morrison; Gerjan Navis; Rick Twee-Hee Ong; George J Papanicolau; Brenda W Penninx; Bruce M Psaty; Leslie J Raffel; Olli T Raitakari; Kenneth Rice; Fernando Rivadeneira; Lynda M Rose; Serena Sanna; Robert A Scott; David S Siscovick; Ronald P Stolk; Andre G Uitterlinden; Dhananjay Vaidya; Melanie M van der Klauw; Ramachandran S Vasan; Eranga Nishanthie Vithana; Uwe Völker; Henry Völzke; Hugh Watkins; Terri L Young; Tin Aung; Murielle Bochud; Martin Farrall; Catharina A Hartman; Maris Laan; Edward G Lakatta; Terho Lehtimäki; Ruth J F Loos; Gavin Lucas; Pierre Meneton; Lyle J Palmer; Rainer Rettig; Harold Snieder; E Shyong Tai; Yik-Ying Teo; Pim van der Harst; Nicholas J Wareham; Cisca Wijmenga; Tien Yin Wong; Myriam Fornage; Vilmundur Gudnason; Daniel Levy; Walter Palmas; Paul M Ridker; Jerome I Rotter; Cornelia M van Duijn; Jacqueline C M Witteman; Aravinda Chakravarti; Dabeeru C Rao Journal: Am J Hum Genet Date: 2014-06-19 Impact factor: 11.025
Authors: Gonzalo Villapalos-García; Pablo Zubiaur; Rebeca Rivas-Durán; Pilar Campos-Norte; Cristina Arévalo-Román; Marta Fernández-Rico; Lucio García-Fraile Fraile; Paula Fernández-Campos; Paula Soria-Chacartegui; Sara Fernández de Córdoba-Oñate; Pablo Delgado-Wicke; Elena Fernández-Ruiz; Isidoro González-Álvaro; Jesús Sanz; Francisco Abad-Santos; Ignacio de Los Santos Journal: Life Sci Alliance Date: 2022-05-30
Authors: Stefan J Schunk; Juliane Hermann; Tamim Sarakpi; Sarah Triem; Michaela Lellig; Eunsil Hahm; Stephen Zewinger; David Schmit; Ellen Becker; Julia Möllmann; Michael Lehrke; Rafael Kramann; Peter Boor; Peter Lipp; Ulrich Laufs; Winfried März; Jochen Reiser; Joachim Jankowski; Danilo Fliser; Thimoteus Speer; Vera Jankowski Journal: J Am Soc Nephrol Date: 2021-09-29 Impact factor: 10.121
Authors: Katarina Andelova; Barbara Szeiffova Bacova; Matus Sykora; Peter Hlivak; Miroslav Barancik; Narcis Tribulova Journal: Int J Mol Sci Date: 2022-01-26 Impact factor: 5.923