Interaction of the inflammasome genes CARD8 and NLRP3 in abdominal aortic aneurysms

Abstract

Objective: Cholesterol crystals have been shown to cause inflammation, and ultimately atherosclerotic lesions through the activation of the NLRP3 inflammasome. As cholesterol crystals have also been found in the walls of patients with abdominal aortic aneurysms (AAA), it is possible that the NLRP3 inflammasome is involved in AAA and genetic variability within this protein complex could alter disease risk. The primary objective of this study was to assess whether there is genetic evidence for a role of the NLRP3 inflammasome in AAA by testing for association of AAA with functional single nucleotide polymorphisms (SNPs) in the CARD8 and NLRP3 genes.

Methods: AAA patients (n=1151) and controls (n=727) were genotyped for CARD8 SNP rs2043211 and NLRP3 SNP rs35829419 using TaqMan SNP assays. IL1-β, C-reactive protein (CRP), and lipoprotein (a) [Lp(a)] were measured in the plasma of a subset of study participants. The Kruskal-Wallis Rank test was conducted to test for differences in mean concentration of IL1-β, CRP and Lp(a). Logistic regression was used to test for interaction between CARD8 and NLRP3.

Results: Significantly higher mean concentration of plasma IL1-β was observed in study participants who were homozygous for the common C allele of NLRP3 rs35829419 (p=0.010). Interaction between rs2043211 and rs35829419 was observed in this dataset (χ(2)=6.22; p=0.044), which strengthened when adjusted for age, gender, smoking, diabetes, hypertension, and dyslipidemia (χ(2)=14.75; p=0.012); and separately for NOD2 genotype (χ(2)=14.06; p=0.015).

Conclusion: Our finding suggests genetic variability within the NLRP3 inflammasome may be important in the pathophysiology of AAA.