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

Schunk, S. J. et al. (2021) Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. European Heart Journal, 42(18), pp. 1742-1756. (doi: 10.1093/eurheartj/ehab107) (PMID:33748830)

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.

• Item Type: Articles
• Additional Information: This work was supported by grants of Deutsche Forschungsgemeinschaft (DFG, SFB TRR 219, Project-ID 322900939) for Stephen Zewinger, Stefan Wagenpfeil, Michael Böhm, Rafael Kramann, Barbara Niemeyer, Danilo Fliser, and Thimoteus Speer, CORONA Stiftung (Ulrich Laufs), Universität Leipzig (Ulrich Laufs), as well as European Uremic Toxin (EUTox) Work Group of the ERA-EDTA (Danilo Fliser, Thimoteus Speer). Support for genotyping in the LURIC cohort was provided by the seventh framework program of the European commission (AtheroRemo, grant 201668). The measurement of DNA methylation in LURIC was supported by the seventh framework program of the European commission (RiskyCAD, grant 305739) and the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), which is funded by the German Federal Ministry of Education and Research (grant 01EA1801A). The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, and HHSN268201700005I), R01HL087641, R01HL59367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C. Infrastructure was partly supported by Grant Number UL1RR025005, a component of the National Institutes of Health and NIH Roadmap for Medical Research. GeneBank was supported, in part, by grants P01HL076491, R01HL103931, R01HL113452, R01HL103866, R01DK106000, R01HL126827, R01HL133169, and R01HL148110 from the National Institutes for Health (NIH). INVEST was supported by the University of Florida and grants from BASF Pharma and Abbott Laboratories and was supported by NIH grants R01HL074730 and U01GM074492. The INVEST GWAS genotyping was supported by RIKEN. Additional support for this project comes from NIH grant KL2 TR001429 (C.W.M.). LIFE-Heart was funded by the Leipzig Research Center for Civilization Diseases (LIFE). LIFE is an organizational unit affiliated to the Medical Faculty of the University of Leipzig. LIFE is funded by means of the European Union, by the European Regional Development Fund and by funds of the Free State of Saxony within the framework of the excellence initiative. The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. J.W.J. is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework programme of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). S.C.’s effort is supported, in part, by the National Institutes of Health (R01 NR013396). The Coronary Disease Cohort Study was funded by the New Zealand Health Research Council and the Heart Foundation of New Zealand, with funding for genotyping from the Christchurch Heart Institute Trust. TRIUMPH was sponsored by the National Institutes of Health: Washington University School of Medicine SCCOR Grant P50 HL077113. The PLATO trial was supported by Uppsala Clinical Research Center, AstraZeneca, and the Swedish Heart-Lung Foundation.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Stott J, Professor David and Ford, Professor Ian and Sattar, Professor Naveed
• Authors: Schunk, S. J., Kleber, M. E., März, W., Pang, S., Zewinger, S., Triem, S., Ege, P., Reichert, M. C., Krawczyk, M., Weber, S. N., Jaumann, I., Schmit, D., Sarakpi, T., Wagenpfeil, S., Kramann, R., Boerwinkle, E., Ballantyne, C. M., Grove, M. L., Tragante, V., Pilbrow, A. P., Richards, A. M., Cameron, V. A., Doughty, R. N., Dubé, M.-P., Tardif, J.-C., Feroz-Zada, Y., Sun, M., Liu, C., Ko, Y.-A., Quyyumi, A. A., Hartiala, J. A., Tang, W. H. W., Hazen, S. L., Allayee, H., McDonough, C. W., Gong, Y., Cooper-DeHoff, R. M., Johnson, J. A., Scholz, M., Teren, A., Burkhardt, R., Martinsson, A., Smith, J. G., Wallentin, L., James, S. K., Eriksson, N., White, H., Held, C., Waterworth, D., Trompet, S., Jukema, J. W., Ford, I., Stott, D. J., Sattar, N., Cresci, S., Spertus, J. A., Campbell, H., Tierling, S., Walter, J., Ampofo, E., Niemeyer, B. A., Lipp, P., Schunkert, H., Böhm, M., Koenig, W., Fliser, D., Laufs, U., and Speer, T.
• Subjects: R Medicine > R Medicine (General)
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health; College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Robertson Centre
• Journal Name: European Heart Journal
• Publisher: Oxford University Press
• ISSN: 0195-668X
• ISSN (Online): 1522-9645
• Published Online: 22 March 2021
• Copyright Holders: Copyright © The Author(s) 2021
• First Published: First published in European Heart Journal 42(18):1742-1756
• Publisher Policy: Reproduced in accordance with the publisher copyright policy