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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-1? (IL-1?); 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-1? 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-1? 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.

SUBMITTER: Asfaw Idosa B

PROVIDER: S-EPMC4220665 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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C10X polymorphism in the CARD8 gene is associated with bacteraemia.

Asfaw Idosa Berhane B Sahdo Berolla B Balcha Ermias E Kelly Anne A Söderquist Bo B Särndahl Eva E

Immunity, inflammation and disease 20131105 1

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 i ...[more]

PMID: 25400921

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Project description:ObjectivesWe compared the incidence of polymorphisms activating the NLRP3 inflammasome between controls and patients with cholesteatoma and its potential association with bone erosion in patients with cholesteatoma.MethodsThis is a case-control study assessing the mutation rates in genes of interest in patients with and without cholesteatoma. A total of 133 saliva samples from control (n = 65) and cholesteatoma (n = 68) patients were collected for DNA extraction. Caspase recruitment domain family member 8 (CARD8) (AA: homozygous wild type, AT: heterozygous, TT: homozygous mutant polymorphism) and NLRP3 (CC: homozygous wild type, CA: heterozygous, AA: homozygous mutant) polymorphisms were analyzed with TaqMan single-nucleotide polymorphism (SNP) quantitative polymerase chain reaction (ThermoFisher Scientific, Waltham, MA). Mutation status was correlated with a novel bone erosion scoring model developed as a part of this study. Summary statistics, including frequencies (%) and median (Q1, Q3) were used to describe the sample.ResultsThe presence of CARD8 and NLRP3 homozygous wild-type polymorphisms were generally similar for the control and cholesteatoma patient groups. CARD8 homozygous TT polymorphisms were an exception, occurring more frequently in patients who developed a cholesteatoma compared to the control group (29% vs. 10%, P = .009). Those patients with CARD8 homozygous TT polymorphism had higher median scores of bone erosion as compared to subjects with nonhomozygous mutant genotypes (median [interquartile range]: 4.0 [3.0, 5.5] vs. 2.5 [1.0, 3.5], P = .0142).ConclusionCholesteatoma patients have a significant, twofold higher incidence of CARD8 homozygous TT polymorphism. Furthermore, cholesteatoma patients with this homozygous polymorphism had greater bone erosion rates than controls. These findings suggest that genetic mutations may increase host susceptibility to cholesteatomas. Specifically, the CARD8 TT polymorphism may influence the severity of cholesteatoma-induced bone erosion.Level of evidence3B.

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C10X polymorphism in the CARD8 gene is associated with bacteraemia.

Publications

C10X polymorphism in the CARD8 gene is associated with bacteraemia.

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