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Gustav Smith

Associate professor

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

Author

  • Stefan J. Schunk
  • J. Gustav Smith
  • Thimoteus Speer

Summary, in English

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. © The Author(s) 2021. For permissions, please email: journals [dot] permissions [at] oup [dot] com.

Department/s

  • Cardiology
  • EpiHealth: Epidemiology for Health
  • EXODIAB: Excellence of Diabetes Research in Sweden

Publishing year

2021-05-07

Language

English

Pages

1742-1756

Publication/Series

European Heart Journal

Volume

42

Issue

18

Document type

Journal article

Publisher

Oxford University Press

Topic

  • Cardiac and Cardiovascular Systems
  • Medical Genetics

Keywords

  • Cardiovascular diseases
  • Coronary artery disease
  • Inflammasome
  • Inflammation
  • NLRP3

Status

Published

ISBN/ISSN/Other

  • ISSN: 1522-9645