title: Evidence of interaction of CARD8 rs2043211 with NALP3 rs35829419 in Crohn's disease.
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)kappaB 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 (P(1,2/1,1)=0.009, odds ratio (OR)=0.66, 95% confidence interval (CI) (0.48-0.90); P(1,1/1,2)=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-1beta.
authors.affiliation: Department of Biochemistry, University of Otago, Dunedin, New Zealand. rebecca.roberts@otago.ac.nz
authors.forename: R L
authors.initials: RL
authors.lastname: Roberts
authors.forename: R K G
authors.initials: RK
authors.lastname: Topless
authors.forename: A J
authors.initials: AJ
authors.lastname: Phipps-Green
authors.forename: R B
authors.initials: RB
authors.lastname: Gearry
authors.forename: M L
authors.initials: ML
authors.lastname: Barclay
authors.forename: T R
authors.initials: TR
authors.lastname: Merriman
mesh_terms: D000328:Adult; D053468:CARD Signaling Adaptor Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics*; D003424:Crohn Disease / Q000235:genetics*; D004843:Epistasis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009363:Neoplasm Proteins / Q000235:genetics*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D020641:Polymorphism, Single Nucleotide
chemical_list: D053468:CARD Signaling Adaptor Proteins; C455623:CARD8 protein, human; D002352:Carrier Proteins; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C429018:NOD2 protein, human; D009363:Neoplasm Proteins; D053473:Nod2 Signaling Adaptor Protein