|Title||Genetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.|
|Publication Type||Journal Article|
|Year of Publication||2021|
|Authors||Schunk, SJ, Kleber, ME, Marz, W, Pang, S, Zewinger, S, Triem, S, Ege, P, Reichert, MC, Krawczyk, M, Weber, SN, Jaumann, I, Schmit, D, Sarakpi, T, Wagenpfeil, S, Kramann, R, Boerwinkle, E, Ballantyne, CM, Grove, ML, Tragante, V, Pilbrow, AP, A Richards, M, Cameron, VA, Doughty, RN, Dube, M-P, Tardif, J-C, Feroz-Zada, Y, Sun, M, Liu, C, Ko, Y-A, Quyyumi, AA, Hartiala, JA, Tang, WHWilson, Hazen, SL, Allayee, H, McDonough, CW, Gong, Y, Cooper-Dehoff, RM, Johnson, JA, Scholz, M, Teren, A, Burkhardt, R, Martinsson, A, J Smith, G, Wallentin, L, James, SK, Eriksson, N, White, H, Held, C, Waterworth, D, Trompet, S, J Jukema, W, Ford, I, Stott, DJ, Sattar, N, Cresci, S, Spertus, JA, Campbell, H, Tierling, S, Walter, J, Ampofo, E, Niemeyer, BA, Lipp, P, Schunkert, H, Böhm, M, Koenig, W, Fliser, D, Laufs, U, Speer, T|
|Corporate Authors||eQTLGen consortium, BIOS Consortium|
|Journal||Eur Heart J|
|Date Published||2021 05 07|
|Keywords||Cardiovascular Diseases, Humans, Inflammasomes, Inflammation, Leukocytes, Mononuclear, NLR Family, Pyrin Domain-Containing 3 Protein|
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.
|Alternate Journal||Eur Heart J|
|PubMed Central ID||PMC8244638|
|Grant List||R01 HL113252 / HL / NHLBI NIH HHS / United States |
R01 DK106000 / DK / NIDDK NIH HHS / United States
R01 HL103866 / HL / NHLBI NIH HHS / United States
R01 HL126827 / HL / NHLBI NIH HHS / United States
P20 HL113452 / HL / NHLBI NIH HHS / United States
KL2 TR001429 / TR / NCATS NIH HHS / United States
R01 NR013396 / NR / NINR NIH HHS / United States