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Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn's disease

Genes & Immunity volume 11, pages 351–356 (2010)Cite this article

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Abstract

The location of CARD8 within an inflammatory bowel disease (IBD) locus and its role in the NALP3 inflammasome and as a nuclear factor (NF)κB inhibitor make it an attractive candidate risk gene for IBD. However, studies testing for the association of the CARD8 loss-of-function single-nucleotide polymorphism (SNP) rs2043211 with IBD have yielded mixed results. A recent study provided evidence that this discordance may result from an interaction of rs2043211 with loss-of-function variants in nucleotide-binding oligomerization domain protein 2 (NOD2) and a gain-of-function SNP (rs35829419) in NALP3. To confirm this interaction, we conducted a replication in an independent IBD sample set (n=1009 patients, n=517 controls). We found that the presence of the minor allele of rs2043211 with the major allele of rs35829419 conferred a protective effect against Crohn's disease (and vice versa), which intensified in the absence of NOD2 mutations (P1,2/1,1=0.009, odds ratio (OR)=0.66, 95% confidence interval (CI) (0.48–0.90); P1,1/1,2=0.015, OR=0.35, 95% CI (0.15–0.82)). We propose that these genotype combinations protect against gut inflammation by preventing the NALP3 inflammasome from producing excessive interleukin-1β.

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Acknowledgements

We thank the people of Canterbury with IBD who generously gave of their time to take part in the study. We also thank Rhondda Brown and Judy Hoar for their assistance in coordinating the recruitment of patients to the Canterbury IBD sample set, and Pip Shirley, Megan Reilly, David Tan, Ramez Ailabouni and Charlotte Duncan for entering patient details into the clinical database. This study was supported by the Health Research Council (HRC) of New Zealand, the New Zealand Lottery Health Board and the University of Otago. RLR is the recipient of a Sir Charles Hercus Health Research Fellowship (HRC).

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Authors and Affiliations

  1. Department of Biochemistry, University of Otago, Dunedin, New Zealand

    R L Roberts, R K G Topless, A J Phipps-Green & T R Merriman

  2. Department of Medicine, University of Otago, Christchurch, New Zealand

    R L Roberts, R B Gearry & M L Barclay

  3. Department of Gastroenterology, Christchurch Hospital, Christchurch, New Zealand

    R B Gearry & M L Barclay

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  1. R L Roberts
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Correspondence to R L Roberts.

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Roberts, R., Topless, R., Phipps-Green, A. et al. Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn's disease. Genes Immun 11, 351–356 (2010). https://doi.org/10.1038/gene.2010.11

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