C10X polymorphism in the CARD8 gene is associated with bacteraemia

Abstract

The NLRP3 inflammasome is an intracellular multi-protein complex that triggers caspase-1 mediated maturation of interleukin-1β (IL-1β); one of the most potent mediators of inflammation and a major cytokine produced during severe infections, like sepsis. However, the excessive cytokine levels seem to stage for tissue injury and organ failure, and high levels of IL-1β correlates with severity and mortality of sepsis. Instead, recent data suggest caspase-1 to function as a guardian against severe infections. CARD8 has been implied to regulate the synthesis of IL-1β via interaction to caspase-1. In recent years, polymorphism of CARD8 (C10X) per se or in combination with NLRP3 (Q705K) has been implicated with increased risk of inflammation. The aim was to investigate the correlation of these polymorphisms with severe blood stream infection. Human DNA was extracted from blood culture bottles that were found to be positive for microbial growth (i.e. patients with bacteraemia). Polymorphisms Q705K in the NLRP3 gene and C10X in the CARD8 gene were genotyped using TaqMan genotyping assay. The results were compared to healthy controls and to samples from patients with negative cultures. The polymorphism C10X was significantly over-represented among patients with bacteraemia as compared to healthy controls, whereas patients with negative blood culture were not associated with a higher prevalence. No association was observed with polymorphism Q705K of NLRP3 in either group of patients. Patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation.

Association of CARD8 Activating Polymorphism With Bone Erosion in Cholesteatoma Patients

“…These results suggest that the host inflammatory state exerts a significant influence on the progression of cholesteatoma bone destruction. Increased severity of disease based on host inflammatory mutations for both NLRP3 and CARD8 has already been described for both Crohn disease and rheumatoid arthritis 12,14 . These results highlight the impact of the presence of the homozygous CARD8 mutant state in our study because the aforementioned studies demonstrated an impact on severity but not frequency of mutations compared to controls.…”

“…In this study, we focused on two commonly studied genetic variants: CARD8 C10X (accession number: rs2043211) and NLRP3 Q705K (rs35829419). The polymorphism C10X in CARD8 (rs2043211) causes a nonsense mutation in exon 5 that incapacitates inhibitory pathways of caspase‐1 activation, causing constitutive activation of downstream NLRP3 pathways and an increase in caspase‐1 production and cytokine release 12,13 . Meanwhile, the Q705K polymorphism in NLRP3 (rs35829419) achieves a similar phenotypic effect through a gain‐of‐function missense mutation in exon 3 14,15 …”

NLRP3 p.Q705K and CARD8 p.C10X single nucleotide polymorphisms are not associated with susceptibility to rheumatoid arthritis: a meta‐analysis

“…Such a termination mutation finally leads to a severely truncated protein. In addition to its reported association with inflammatory activity in RA patients, CARD8 p.C10X polymorphism also has associations with bacteriemia, Crohn's disease and ankylosing spondylitis …”

Association of NLRP3 and CARD8 Inflammasome Polymorphisms With Aseptic Loosening After Primary Total Hip Arthroplasty

“…There is evidence for association of gout with functional variants in CARD8—multiplicative interaction with CARD8 would be consistent with a synergy of greater inflammasome activity, resulting from reduced CARD8 . Also, patients carrying polymorphism C10X in the CARD8 gene are at increased risk of developing bacteraemia and severe inflammation . All these data combined suggest that certain polymorphisms create inflammasomes with an increased basal activation state, which might provide a more favorable innate immune response.…”

“…The nonsynonymous gain‐of‐function polymorphism NLRP3 rs35829419 (p. Q705K) leads to an overactive NLRP3 inflammasome, while caspase recruitment domain‐containing protein 8 (CARD8) rs2043211 (p. C10X) polymorphism encodes a truncated protein that does not inhibit the nuclear factor‐κB (NF‐κB) stimulation of inflammatory response . It was suggested that interaction between NLRP3 rs35829419 and CARD8 rs2043211 increases susceptibility to several inflammatory diseases and bacteriemia, but the results are inconclusive and have not been tested on patients with hip arthroplasty implants so far.…”