%0 Journal Article %1 Schunk2021-hv %A Schunk, Stefan J %A Kleber, Marcus E %A März, Winfried %A Pang, Shichao %A Zewinger, Stephen %A Triem, Sarah %A Ege, Philipp %A Reichert, Matthias C %A Krawczyk, Marcin %A Weber, Susanne N %A Jaumann, Isabella %A Schmit, David %A Sarakpi, Tamim %A Wagenpfeil, Stefan %A Kramann, Rafael %A Boerwinkle, Eric %A Ballantyne, Christie M %A Grove, Megan L %A Tragante, Vinicius %A Pilbrow, Anna P %A Richards, A Mark %A Cameron, Vicky A %A Doughty, Robert N %A Dubé, Marie-Pierre %A Tardif, Jean-Claude %A Feroz-Zada, Yassamin %A Sun, Maxine %A Liu, Chang %A Ko, Yi-An %A Quyyumi, Arshed A %A Hartiala, Jaana A %A Tang, W H Wilson %A Hazen, Stanley L %A Allayee, Hooman %A McDonough, Caitrin W %A Gong, Yan %A Cooper-DeHoff, Rhonda M %A Johnson, Julie A %A Scholz, Markus %A Teren, Andrej %A Burkhardt, Ralph %A Martinsson, Andreas %A Smith, J Gustav %A Wallentin, Lars %A James, Stefan K %A Eriksson, Niclas %A White, Harvey %A Held, Claes %A Waterworth, Dawn %A Trompet, Stella %A Jukema, J Wouter %A Ford, Ian %A Stott, David J %A Sattar, Naveed %A Cresci, Sharon %A Spertus, John A %A Campbell, Hannah %A Tierling, Sascha %A Walter, Jörn %A Ampofo, Emmanuel %A Niemeyer, Barbara A %A Lipp, Peter %A Schunkert, Heribert %A Böhm, Michael %A Koenig, Wolfgang %A Fliser, Danilo %A Laufs, Ulrich %A Speer, Thimoteus %A eQTLGen consortium, %A BIOS consortium, %D 2021 %I Oxford University Press (OUP) %J Eur. Heart J. %K Cardiovascular Coronary Inflammasome; Inflammation; NLRP3 artery disease; diseases; %N 18 %P 1742--1756 %T Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality %V 42 %X 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 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.

@article{Schunk2021-hv, 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 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.}, added-at = {2024-09-10T11:54:51.000+0200}, author = {Schunk, Stefan J and Kleber, Marcus E and M{\"a}rz, 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 Dub{\'e}, 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, J{\"o}rn and Ampofo, Emmanuel and Niemeyer, Barbara A and Lipp, Peter and Schunkert, Heribert and B{\"o}hm, Michael and Koenig, Wolfgang and Fliser, Danilo and Laufs, Ulrich and Speer, Thimoteus and {eQTLGen consortium} and {BIOS consortium}}, biburl = {https://puma.scadsai.uni-leipzig.de/bibtex/289af00c48242d37f3683df9edaf17797/scadsfct}, copyright = {https://academic.oup.com/journals/pages/open\_access/funder\_policies/chorus/standard\_publication\_model}, interhash = {66cb4bacc844aaa02e86ffe5bd90717f}, intrahash = {89af00c48242d37f3683df9edaf17797}, journal = {Eur. Heart J.}, keywords = {Cardiovascular Coronary Inflammasome; Inflammation; NLRP3 artery disease; diseases;}, language = {en}, month = may, number = 18, pages = {1742--1756}, publisher = {Oxford University Press (OUP)}, timestamp = {2024-09-10T11:54:51.000+0200}, title = {Genetically determined {NLRP3} inflammasome activation associates with systemic inflammation and cardiovascular mortality}, volume = 42, year = 2021 }