Schunk, Stefan J. and Kleber, Marcus E. and Maerz, Winfried and Pang, Shichao and Zewinger, Stephen and Triem, Sarah and Ege, Philipp and Reichert, Matthias C. and Krawczyk, Marcin and Weber, Susanne N. and Jaumann, Isabella and Schmit, David and Sarakpi, Tamim and Wagenpfeil, Stefan and Kramann, Rafael and Boerwinkle, Eric and Ballantyne, Christie M. and Grove, Megan L. and Tragante, Vinicius and Pilbrow, Anna P. and Richards, A. Mark and Cameron, Vicky A. and Doughty, Robert N. and Dube, Marie-Pierre and Tardif, Jean-Claude and Feroz-Zada, Yassamin and Sun, Maxine and Liu, Chang and Ko, Yi-An and Quyyumi, Arshed A. and Hartiala, Jaana A. and Tang, W. H. Wilson and Hazen, Stanley L. and Allayee, Hooman and McDonough, Caitrin W. and Gong, Yan and Cooper-DeHoff, Rhonda M. and Johnson, Julie A. and Scholz, Markus and Teren, Andrej and Burkhardt, Ralph and Martinsson, Andreas and Smith, J. Gustav and Wallentin, Lars and James, Stefan K. and Eriksson, Niclas and White, Harvey and Held, Claes and Waterworth, Dawn and Trompet, Stella and Jukema, J. Wouter and Ford, Ian and Stott, David J. and Sattar, Naveed and Cresci, Sharon and Spertus, John A. and Campbell, Hannah and Tierling, Sascha and Walter, Joern and Ampofo, Emmanuel and Niemeyer, Barbara A. and Lipp, Peter and Schunkert, Heribert and Boehm, Michael and Koenig, Wolfgang and Fliser, Danilo and Laufs, Ulrich and Speer, Thimoteus (2021) Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality. EUROPEAN HEART JOURNAL, 42 (18). pp. 1742-1756. ISSN 0195-668X, 1522-9645
Full text not available from this repository. (Request a copy)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-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] .
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CORONARY-HEART-DISEASE; C-REACTIVE PROTEIN; BLOOD-PRESSURE; INTERLEUKIN-6 RECEPTOR; CLONAL HEMATOPOIESIS; ATHEROSCLEROSIS; RISK; AGE; HYPERTENSION; INHIBITOR; Cardiovascular diseases; Coronary artery disease; Inflammation; Inflammasome; NLRP3 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Klinische Chemie und Laboratoriumsmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 04 Oct 2022 12:24 |
| Last Modified: | 04 Oct 2022 12:24 |
| URI: | https://pred.uni-regensburg.de/id/eprint/48239 |
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