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

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.

• 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
• Journal: European heart journal (Eur Heart J) Vol. 42 Issue 18 Pg. 1742-1756 (05 07 2021) ISSN: 1522-9645 [Electronic] England
• PMID: 33748830 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: [email protected].

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• NLRP3 protein, human

Topics

• Cardiovascular Diseases (mortality)
• Humans
• Inflammasomes (genetics)
• Inflammation (genetics)
• Leukocytes, Mononuclear
• NLR Family, Pyrin Domain-Containing 3 Protein (genetics)