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

R L Roberts1, R K G Topless, A J Phipps-Green

  • 1Department of Biochemistry, University of Otago, Dunedin, New Zealand. rebecca.roberts@otago.ac.nz

Genes and Immunity
|February 26, 2010
PubMed

Insights

Specific CARD8 and NALP3 gene variants protect against Crohn's disease by reducing gut inflammation. This interaction is most protective when nucleotide-binding oligomerization domain protein 2 (NOD2) mutations are absent.

Area of Science:

  • Genetics
  • Immunology
  • Gastroenterology

Background:

  • CARD8 is a candidate gene for inflammatory bowel disease (IBD) due to its role in the NALP3 inflammasome and as a nuclear factor (NF)-κB inhibitor.
  • Previous studies on the association between the CARD8 loss-of-function single-nucleotide polymorphism (SNP) rs2043211 and IBD have shown inconsistent results.
  • A recent study suggested that interactions between rs2043211, nucleotide-binding oligomerization domain protein 2 (NOD2) loss-of-function variants, and a NALP3 gain-of-function SNP (rs35829419) might explain the discordance.

Purpose of the Study:

  • To validate the interaction between CARD8 (rs2043211), NOD2, and NALP3 (rs35829419) in an independent inflammatory bowel disease (IBD) cohort.
  • To investigate the protective effects of specific genotype combinations against IBD, particularly Crohn's disease.

Main Methods:

  • Genotyping of CARD8 (rs2043211), NOD2, and NALP3 (rs35829419) in an independent sample set comprising 1009 IBD patients and 517 controls.
  • Statistical analysis to assess the association between genotype combinations and IBD, with a focus on Crohn's disease.
  • Conditional analysis to evaluate the interaction in the absence of NOD2 mutations.

Main Results:

  • The presence of the minor allele of rs2043211 with the major allele of rs35829419 showed a protective effect against Crohn's disease (odds ratio [OR]=0.66, 95% confidence interval [CI] [0.48–0.90]).
  • Conversely, the presence of the major allele of rs2043211 with the minor allele of rs35829419 also conferred protection (OR=0.35, 95% CI [0.15–0.82]).
  • These protective effects were more pronounced in individuals without NOD2 mutations, indicating a significant interaction (P(1,2/1,1)=0.009 and P(1,1/1,2)=0.015).

Conclusions:

  • Specific combinations of CARD8 and NALP3 genotypes, particularly in the absence of NOD2 mutations, offer protection against Crohn's disease.
  • These findings support the hypothesis that these genotype interactions modulate the NALP3 inflammasome pathway.
  • The proposed mechanism involves preventing excessive interleukin-1beta production, thereby protecting against gut inflammation in inflammatory bowel disease.

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