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Combined Polymorphisms in Genes Encoding the Inflammasome Components NALP3 and CARD8 Confer Susceptibility to Crohns Disease in Swedish Men
Linköping University, Department of Clinical and Experimental Medicine, Surgery . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
Örebro University Hospital.
Karolinska University Hospital.
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2009 (English)In: American Journal of Gastroenterology, ISSN 0002-9270, Vol. 104, no 5, 1180-1188 p.Article in journal (Refereed) Published
Abstract [en]

OBJECTIVES : Crohns disease (CD) is characterized by overproduction of proinflammatory cytokines like interleukin (IL)-1 beta. Production of mature IL-1 beta is dependent on a caspase-1-activating protein complex called the NALP3 inflammasome, composed of NALP3, ASC, and CARD8. NALP3 shares structural similarities with Nod2, and both of these proteins are required for bacteria-induced IL-1 beta secretion. The combination of the polymorphisms CARD8 (C10X) and NALP3 (Q705K) was recently shown to be associated with rheumatoid arthritis. Our aim was to investigate whether these combined polymorphisms play a role in the susceptibility to CD.

METHODS: The study included 498 CD patients in two cohorts from different regions and 742 control individuals from a Swedish population. DNA was isolated from whole blood. Polymorphisms of (Q705K) NALP3 and (C10X) CARD8, as well as the Nod2 variants, R702W and G908R, were genotyped using the Taqman single nucleotide polymorphism assay. The Nod2 frameshift mutation, L1007fs, was detected by Megabace SNuPe genotyping.

RESULTS: Our results show that men who have both the C10X and Q705K alleles in CARD8 and NALP3, and who express wild-type alleles of Nod2 are at an increased risk of developing CD (odds ratio, OR: 3.40 range: 1.32-8.76); P = 0.011). No association with these polymorphisms was found in women (OR: 0.89 (range: 0.44-1.77); P = 0.74).

CONCLUSIONS: We suggest a role for combined polymorphisms in CARD8 and NALP3 in the development of CD in men, with obvious sex differences in the genetic susceptibility pattern. These findings give further support to the importance of innate immune responses in CD.

Place, publisher, year, edition, pages
2009. Vol. 104, no 5, 1180-1188 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-18957DOI: 10.1038/ajg.2009.29OAI: diva2:222144
Available from: 2009-06-06 Created: 2009-06-05 Last updated: 2009-09-29Bibliographically approved
In thesis
1. Mechanisms of bacterial-epithelial interaction in Crohn’s disease
Open this publication in new window or tab >>Mechanisms of bacterial-epithelial interaction in Crohn’s disease
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Crohn’s disease (CD) is believed to be initiated when an individual, who has agenetic predisposition either leading to a disturbance in the barrier functionand/or the innate immune system is exposed to triggering environmentalfactors, the most important being intraluminal bacteria. Genetic and functionalstudies have confirmed the Pattern-recognition receptors (PRRs), Nod2, TLR4and NALP3, as important mediators of the inflammatory process associatedwith disease progression. However, the mechanisms that link enteric bacteriaand barrier function in a background of genetic predisposition to CD are justbeginning to emerge. The general aim of this thesis was therefore to morethoroughly investigate the mechanisms of bacterial-epithelial interaction in CD.

Here we present evidence suggesting that the small bowel is able to inducetranscytosis of antigens after short term exposure to Yersinia pseudotuberculosis. This suggests that small bowel enterocytes are able toattain follicle associated epithelial (FAE) abilities and contribute to the barrierdysfunction observed in CD. Furthermore we report a positive effect of anti-TNFα treatment (infliximab) on the translocation of adherent invasive E.coli (AIEC) across the colonic mucosa of patients suffering from severe CD.

We also confirm the importance of the Nod-like receptors (NLRs) in thepathogenesis of CD by showing that combined polymorphisms in the genesencoding NALP3 and CARD8 confer susceptibility to CD among Swedish menand in addition to previous published results add a gender aspect on thegenotype-phenotype relationship in CD. Finally, we show that Nod2 is rapidlysubjected to ubiquitination followed by proteasomal degradation, henceproviding important clues about how NLR regulation might occur in the cell,suggesting that the ubiquitin-proteasome pathway is an important factor toconsider in the development of the disease.

In conclusion we report novel insights into the bacterial-epithelial interactionsoccurring in CD and contribute important clues about the origin of this disease.ISBN: 978-

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2009. 71 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1113
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-21104 (URN)978-91-7393-667-5 (ISBN)
Public defence
2009-04-17, Berzeliussalen, Hälsouniversitetet, Campus US, Linköpings Universitet, Linköping, 13:00 (English)
Available from: 2009-09-29 Created: 2009-09-29 Last updated: 2009-09-29Bibliographically approved

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