Journal
EUROPEAN HEART JOURNAL
Volume 42, Issue 18, Pages 1742-1756Publisher
OXFORD UNIV PRESS
DOI: 10.1093/eurheartj/ehab107
Keywords
Cardiovascular diseases; Coronary artery disease; Inflammation; Inflammasome; NLRP3
Categories
Funding
- Deutsche Forschungsgemeinschaft (DFG) [SFB TRR 219, 322900939]
- CORONA Stiftung
- Universitat Leipzig
- European Uremic Toxin (EUTox) Work Group of the ERA-EDTA
- European commission [201668, 305739, 223004]
- Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD) - German Federal Ministry of Education and Research [01EA1801A]
- National Heart, Lung, and Blood Institute
- National Institutes of Health, Department of Health and Human Services [HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I, R01HL087641, R01HL59367, R01HL086694]
- National Human Genome Research Institute [U01HG004402]
- National Institutes of Health (NIH) [HHSN26 8200625226C, UL1RR025005, P01HL076491, R01HL103931, R01HL113452, R01HL103866, R01DK106000, R01HL126827, R01HL133169, R01HL148110, R01HL074730, U01G M074492, KL2 TR001429, R01 NR013396, P50 HL077113]
- NIH Roadmap for Medical Research
- BASF Pharma
- Abbott Laboratories
- RIKEN
- Leipzig Research Center for Civilization Diseases (LIFE)
- European Union
- European Regional Development Fund
- Free State of Saxony
- Bristol-Myers Squibb
- Netherlands Heart Foundation [2001 D 032]
- Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging) [050-060-810]
- New Zealand Health Research Council
- Heart Foundation of New Zealand
- Christchurch Heart Institute Trust
- Uppsala Clinical Research Center
- AstraZeneca
- Swedish Heart-Lung Foundation
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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.
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-1 beta 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 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. [GRAPHICS] .
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