Key result
NLRP3 variant rs10754555 links to higher systemic inflammation, prevalent CAD, and cardiovascular mortality.
Why the study?
Although the NLRP3 inflammasome contributes to atherosclerosis in animal models and its pathway components can be therapeutically targeted, associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans were unknown.
Does the genetically determined NLRP3 variant rs10754555 increase systemic inflammation, prevalent coronary artery disease, and cardiovascular mortality in humans?
Observational (n=538,167)
Does the genetically determined NLRP3 variant rs10754555 increase systemic inflammation, prevalent coronary artery disease, and cardiovascular mortality in humans?
This large-scale genetic study demonstrates that the prevalent NLRP3 intronic variant rs10754555 is associated with heightened systemic inflammation, coronary artery disease, and cardiovascular mortality, supporting the NLRP3 inflammasome as a viable therapeutic target in cardiovascular disease.
Hypothesis-generating for NLRP3 inhibition trials in high-risk CAD; leaves open clinical utility of rs10754555 genotyping.
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.
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Schunk et al. (2021) conducted an observational in Cardiovascular disease and cardiovascular mortality (n=538,167). NLRP3 intronic variant rs10754555 carriage vs. Non-carriers of the rs10754555 variant was evaluated on Prevalent coronary artery disease and cardiovascular mortality. The NLRP3 intronic variant rs10754555 (minor allele frequency 39.9%) was associated with significantly higher systemic inflammation, prevalent coronary artery disease, and cardiovascular mortality in 538,167 subjects.
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