Gustav Smith
Associate professor
Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality
Author
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
Links
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