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

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.