Introduction and methods

Life-long genetically driven NLRP3 inflammasome activation associated with mortality: A genetic association study of >500,000 individuals

Presented at ERA-EDTA during the virtual meeting by Stefan Schunk (Homburg/Saar, Germany)

Inflammation plays a role in the development of CKD and CKD-associated CVD. The active NLRP3 inflammasome cleaves pro-cytokines into their biological active secreted form and is an important player of the innate immune system. The NLRP3 inflammasome can be activated by endogenous mediators such as lipoproteins. It has been recently shown that ApoC3 activates human monocytes, leading to NLRP3 inflammasome activation and systemic inflammation. In humanized mice, ApoC3 induces kidney injury and promotes CKD-associated CVD. The aim of the study was to explore the effect of life-long genetically driven NLRP3 inflammasome activation on the risk of coronary artery disease (CAD) and CV mortality.

The NLRP3 gene locus was screened for single nucleotide polymorphisms (SNPs) with a plausible biological function. Functional validation of the rs10754555 NLRP3 variant was investigated in isolated human monocytes. Furthermore, the association between the rs10754555 NLRP3 variant and the risk of CAD and mortality was investigated in 3,061 patients undergoing coronary angiography who were enrolled in the LURIC study. Findings on the association of the rs10754555 NLRP3 variant with mortality was validated in 489,258 participants of the UK Biobank study (general population) and in 39,755 participants from eight independent studies (CV risk populations).

Main results

• First the association between the rs10754555 NLRP3 variant and markers of systemic inflammation was assessed. Heterozygous as well as homozygous carriers of this variant showed significantly higher C-reactive protein and serum amyloid A plasma levels.
• Isolated human monocytes from heterozygous and homozygous rs10754555 NLRP3 variant carriers showed significantly higher NLRP3 mRNA expression and released significantly higher amounts of IL-1β, which indicates that the rs10754555 NLRP3 variant is associated with NLRP3 inflammasome activation.
• The association between the rs10754555 NLRP3 variant carrier status and CAD risk was assessed in 3,061 patients enrolled in the LURIC trial. The rs10754555 NLRP3 variant was associated with risk of CAD, with a strong age-dependent effect. Homozygous rs10754555 NLRP3 variant carriers <60 years of age, had a significantly higher risk of CAD, compared to non-carriers. The rs10754555 NLRP3 variant was also associated with all-cause mortality and CV mortality. This association was more pronounced in younger subjects.
• Validation of these findings in 483,258 participants of the UK Biobank study showed that homozygous rs10754555 NLRP3 carriers had a significantly higher risk of CV mortality, compared with non-carriers.
• A meta-analysis of trials that included patients with prevalent CAD showed that the rs10754555 NLRP3 variant was significantly associated with higher CV mortality.

Conclusions

The rs10754555 NLRP3 variant was associated with higher C-reactive protein and serum amyloid A plasma levels, which indicate that this SNP is associated with increased systemic inflammation. Homozygous rs10754555 NLRP3 carriers had a significantly higher risk of CV mortality, compared with non-carriers.

- Our reporting is based on the information provided at the ERA-EDTA congress -