Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. (22nd March 2021)

• Record Type: Journal Article
• Authors: Schunk, Stefan J; Kleber, Marcus E; März, Winfried; Pang, Shichao; Zewinger, Stephen; Triem, Sarah; Ege, Philipp; Reichert, Matthias C; Krawczyk, Marcin; Weber, Susanne N; Jaumann, Isabella; Schmit, David; Sarakpi, Tamim; Wagenpfeil, Stefan; Kramann, Rafael; Boerwinkle, Eric; Ballantyne, Christie M; Grove, Megan L; Tragante, Vinicius; Pilbrow, Anna P; Richards, A Mark; Cameron, Vicky A; Doughty, Robert N; Dubé, Marie-Pierre; Tardif, Jean-Claude; Feroz-Zada, Yassamin; Sun, Maxine; Liu, Chang; Ko, Yi-An; Quyyumi, Arshed A; Hartiala, Jaana A; Tang, W H Wilson; Hazen, Stanley L; Allayee, Hooman; McDonough, Caitrin W; Gong, Yan; Cooper-DeHoff, Rhonda M; Johnson, Julie A; Scholz, Markus; Teren, Andrej; Burkhardt, Ralph; Martinsson, Andreas; Smith, J Gustav; Wallentin, Lars; James, Stefan K; Eriksson, Niclas; White, Harvey; Held, Claes; Waterworth, Dawn; Trompet, Stella; Jukema, J Wouter; Ford, Ian; Stott, David J; Sattar, Naveed; Cresci, Sharon; Spertus, John A; Campbell, Hannah; Tierling, Sascha; Walter, Jörn; Ampofo, Emmanuel; Niemeyer, Barbara A; Lipp, Peter; Schunkert, Heribert; Böhm, Michael; Koenig, Wolfgang; Fliser, Danilo; Laufs, Ulrich; Speer, Thimoteus;
• Is Part Of: European heart journal. Volume 42:Number 18(2021)
• Page Start: 1742
• Page End: 1756
• Publication Date: 2021-03-22
• Subjects: Cardiovascular diseases -- Coronary artery disease -- Inflammation -- Inflammasome -- NLRP3; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehab107
• Languages: English
• ISSNs: 0195-668X

Abstract

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. Graphical Abstract: