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

TitleGenetically determined NLRP3 inflammasome activation associates with systemic inflammation and cardiovascular mortality.
Publication TypeJournal Article
Year of Publication2021
AuthorsSchunk, 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 AuthorseQTLGen consortium, BIOS Consortium
JournalEur Heart J
Date Published2021 05 07
KeywordsCardiovascular 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 JournalEur Heart J
PubMed ID33748830
PubMed Central IDPMC8244638
Grant ListR01 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