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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; [...]

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

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  • Medientyp: E-Artikel
  • Titel: Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality
  • Beteiligte: 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; [...]
  • Erschienen: Oxford University Press (OUP), 2021
  • Erschienen in: European Heart Journal
  • Sprache: Englisch
  • DOI: 10.1093/eurheartj/ehab107
  • ISSN: 0195-668X; 1522-9645
  • Schlagwörter: Cardiology and Cardiovascular Medicine
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>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.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang