Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.

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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.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.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.

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Authors: Stefan J Schunk, Marcus E Kleber, Winfried März, Shichao Pang, Stephen Zewinger, Sarah Triem, Philipp Ege, Matthias C Reichert, Marcin Krawczyk, Susanne N Weber, Isabella Jaumann, David Schmit, Tamim Sarakpi, Stefan Wagenpfeil, Rafael Kramann, Eric Boerwinkle, Christie M Ballantyne, Megan L Grove, Vinicius Tragante, Anna P Pilbrow, A Mark Richards, Vicky A Cameron, Robert N Doughty, Marie-Pierre Dubé, Jean-Claude Tardif, Yassamin Feroz-Zada, Maxine Sun, Chang Liu, Yi-An Ko, Arshed A Quyyumi, Jaana A Hartiala, W H Wilson Tang, Stanley L Hazen, Hooman Allayee, Caitrin W McDonough, Yan Gong, Rhonda M Cooper-DeHoff, Julie A Johnson, Markus Scholz, Andrej Teren, Ralph Burkhardt, Andreas Martinsson, J Gustav Smith, Lars Wallentin, Stefan K James, Niclas Eriksson, Harvey White, Claes Held, Dawn Waterworth, Stella Trompet, J Wouter Jukema, Ian Ford, David J Stott, Naveed Sattar, Sharon Cresci, John A Spertus, Hannah Campbell, Sascha Tierling, Jörn Walter, Emmanuel Ampofo, Barbara A Niemeyer, Peter Lipp, Heribert Schunkert, Michael Böhm, Wolfgang Koenig, Danilo Fliser, Ulrich Laufs, Thimoteus Speer, eQTLGen consortium‡; BIOS consortium‡