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

• Published in: Genes and immunity Vol. 11; no. 4; pp. 351 - 356
• Main Authors: Roberts, R L, Topless, R K G, Phipps-Green, A J, Gearry, R B, Barclay, M L, Merriman, T R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.06.2010; Nature Publishing Group
• Subjects: 631/208/2490; 631/250/127/1213; 631/250/256/2177; 692/699/1503/1581/257/1402; Adult; Alleles; Apoptosis; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; CARD Signaling Adaptor Proteins - genetics; Carrier Proteins - genetics; Confidence intervals; Crohn Disease - genetics; Crohn's disease; Crohns disease; Cytokines; Development and progression; Discordance; DNA binding proteins; Epistasis, Genetic; Female; Gene Expression; Gene polymorphism; Genes; Genetic aspects; Genetic polymorphisms; Genotype & phenotype; Health aspects; Human Genetics; Humans; IL-1β; Immunology; Inflammasomes; Inflammatory bowel disease; Inflammatory bowel diseases; Male; Middle Aged; Mutation; Neoplasm Proteins - genetics; NLR Family, Pyrin Domain-Containing 3 Protein; NOD2 protein; Nod2 Signaling Adaptor Protein - genetics; Oligomerization; Physiological aspects; Polymorphism; Polymorphism, Single Nucleotide; Proteins; Risk factors; short-communication; Single-nucleotide polymorphism; New Zealand; inflammasome; ulcerative colitis; inflammatory bowel disease
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2010.11

The location of CARD8 within an inflammatory bowel disease (IBD) locus and its role in the NALP3 inflammasome and as a nuclear factor (NF) κ B 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-1 β .