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C10X polymorphism in the CARD8 gene is associated with bacteraemia
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
Örebro University, School of Health and Medical Sciences, Örebro University, Sweden. Department of Clinical Medicine.
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2014 (English)In: Immunity, inflammation and disease, E-ISSN 2050-4527, Vol. 2, no 1, 13-20 p.Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
West Sussex, UK: John Wiley & Sons, 2014. Vol. 2, no 1, 13-20 p.
Keyword [en]
Bacteraemia, blood culture, gene variants, infection, inflammasomes, inflammation, innate immunity, leukocytes, polymorphisims, sepsis
National Category
Clinical Laboratory Medicine Microbiology in the medical area Immunology in the medical area
Identifiers
URN: urn:nbn:se:oru:diva-42421DOI: 10.1002/iid3.14PubMedID: 25400921OAI: oai:DiVA.org:oru-42421DiVA: diva2:786315
Available from: 2015-02-05 Created: 2015-02-05 Last updated: 2017-03-14Bibliographically approved
In thesis
1. Inflammasome polymorphisms and the Inflammatory Response to Bacterial Infections
Open this publication in new window or tab >>Inflammasome polymorphisms and the Inflammatory Response to Bacterial Infections
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

NLRP3 inflammasome; a key component of the innate immune system, can be activated by a number of pathogens and other threats of the body. Activation of the NLRP3 inflammasome triggers caspase-1 mediated maturationof IL-1β and IL-18. Polymorphisms Q705K and C10X are two gene variants of the NLRP3 inflammasome that combined or per se have been associated with higher risk and severity of chronic inflammation and excessive production of IL-1β. Host genetic factors have been found an important determinants of susceptibility of infectious diseases and disease outcome. The aims of this thesis were to investigate the association between polymorphisms Q705K and C10X with bacterial infections and the inflammatory response, moreover to determine the inflammasome activation state in healthy carriers of these polymorphisms. The data of the thesis show higher levels of IL-1β and IL-33 in healthy carriers of combined polymorphisms of Q705K and C10X as compared to non-carrier controls. This may provide individuals with combined polymorphisms a more robust innate immune response against pathogens, but could also lead to the onset of chronic inflammation, and excessive inflammation during acute infection. In addition, individuals with C10X polymorphism per se showed association with the presence of bacteremia as compared withhealthy blood donors. No association was found in severely ill patients with negative blood culture bottle. In addition, the results show that LOS of N. meningitidis is responsible for the priming and activating steps of the inflammasome. The non-LOS components were found to contribute to the priming step. A higher inflammatory response to N. meningitidis was found in individuals who were non-carriers of the polymorphisms than individuals with the Q705K and C10X per se or combined regardless of the strain of bacteria. Taken together, the gene variations of the NLRP3 inflammasome are of importance in explaining inter-individual variation in susceptibility to infectious diseases.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2016. 75 p.
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 149
Keyword
Bacteremia, Cytokines, Gene variants, Inflammasome, Inflammation, Innate immunity, Neutrophils, Meningitis, Neisseria meningitidis
National Category
Other Basic Medicine
Research subject
Biomedicine
Identifiers
urn:nbn:se:oru:diva-50581 (URN)978-91-7529-154-3 (ISBN)
Public defence
2016-09-16, Campus USÖ, Hörsal C3, Södra Grev Rosengatan 30, Örebro, 09:00 (English)
Opponent
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Available from: 2016-06-07 Created: 2016-06-07 Last updated: 2016-12-12Bibliographically approved

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Citation style
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