SO003LIFE-LONG NLRP3 INFLAMMASOME-MEDIATED SYSTEMIC INFLAMMATION ASSOCIATES WITH CARDIOVASCULAR MORTALITY: A GENETIC ASSOCIATION STUDY OF >500,000 INDIVIDUALS

Abstract Background and Aims Chronic kidney disease (CKD) represents one of the strongest cardiovascular risk factors. Recently, we have shown that activation of the NOD-like receptor protein-3 (NLRP3) inflammasome mediates progression of kidney injury and CKD-associated vascular disease (Zewinger et al. Nat Immunol 2013). Components of the NLRP3 inflammasome pathway such as interleukin-1β (IL-1β) can therapeutically be targeted. Associations of genetically determined life-long inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. Method We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 3,061 patients enrolled in the LURIC study undergoing coronary angiography in a gene-centric approach. Functional relevance of the rs10754555 NLRP3 variant was studied in freshly isolated human monocytes. Findings were validated in 39,755 participants from eight independent studies (CV risk populations) as well as in 483,258 participants of the UKBiobank study (general population). Results Genetic analyses identified the highly prevalent (MAF 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. Expression of NLRP3 mRNA and inflammasome-dependent effector responses of isolated human monocytes from rs10754555 carriers were significantly higher as compared to non-carriers. In homozygous rs10754555 carriers, the prevalence of coronary artery disease (CAD) was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age in LURIC and in UKBiobank. Importantly, in LURIC and in UKBiobank, homozygous rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up (HR 1.37, 95%-CI 1.08-1.74 and HR 1.13, 95%-CI 1.02-1.25, respectively). Consistently, rs10754555 was associated with higher cardiovascular mortality (HR 1.11, 95%-CI 1.05-1.16; P<0.001) in an additive model in patients with prevalent CAD. Conclusion The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent CAD and mortality. This study provides evidence for a substantial role of life-long, genetically-driven systemic inflammation in cardiovascular disease and highlights the NLRP3 inflammasome as a therapeutic target in the general population and particular in patients with CKD.