Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality
(2021) In European Heart Journal 42(18). p.1742-1756- 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... (More)
- 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.permissions@oup.com. (Less)
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https://lup.lub.lu.se/record/62a33c65-b1a0-4cef-a193-463b0e13dd9d
- author
- Schunk, Stefan J. ; Smith, J. Gustav LU and Speer, Thimoteus
- author collaboration
- organization
- publishing date
- 2021-05-07
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- Cardiovascular diseases, Coronary artery disease, Inflammasome, Inflammation, NLRP3
- in
- European Heart Journal
- volume
- 42
- issue
- 18
- pages
- 15 pages
- publisher
- Oxford University Press
- external identifiers
-
- scopus:85106539003
- pmid:33748830
- ISSN
- 1522-9645
- DOI
- 10.1093/eurheartj/ehab107
- language
- English
- LU publication?
- yes
- id
- 62a33c65-b1a0-4cef-a193-463b0e13dd9d
- alternative location
- https://www.scopus.com/inward/record.uri?eid=2-s2.0-85106539003&doi=10.1093%2feurheartj%2fehab107&partnerID=40&md5=62dd2fde089cce4a5c8b922dab9933b3
- date added to LUP
- 2021-06-08 14:15:08
- date last changed
- 2022-04-27 02:19:59
@article{62a33c65-b1a0-4cef-a193-463b0e13dd9d,
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. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.}},
author = {{Schunk, Stefan J. and Smith, J. Gustav and Speer, Thimoteus}},
issn = {{1522-9645}},
keywords = {{Cardiovascular diseases; Coronary artery disease; Inflammasome; Inflammation; NLRP3}},
language = {{eng}},
month = {{05}},
number = {{18}},
pages = {{1742--1756}},
publisher = {{Oxford University Press}},
series = {{European Heart Journal}},
title = {{Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality}},
url = {{http://dx.doi.org/10.1093/eurheartj/ehab107}},
doi = {{10.1093/eurheartj/ehab107}},
volume = {{42}},
year = {{2021}},
}