rs2066844
badMag 6.5This is a protein-altering variant in the NOD2 gene.
Key Literature Trait Associations
Crohn's Disease
rs2066844 is a missense change in NOD2 (R702W: arginine to tryptophan at position 702). NOD2 is a key innate immune sensor that detects bacterial peptidoglycans in the gut. The R702W change impairs NOD2's ability to activate NF-κB. One copy approximately doubles Crohn's disease risk; two NOD2 risk variants (homozygous or compound het with G908R or 3020insC) increase risk 15-40 fold. Found in ~3-4% of Europeans and extremely rare in East Asians.
Inflammatory bowel disease
NOD2 rs2066844 (R702W) is significantly associated with inflammatory bowel disease broadly, driven primarily by its Crohn's disease signal. A large trans-ancestry GWAS meta-analysis (n=96,486) confirmed NOD2 as an IBD susceptibility locus at genome-wide significance, with population-level heterogeneity noted across European and non-European cohorts. The variant is not consistently associated with ulcerative colitis in European populations, and null results have been reported in non-European populations including Mexican and Iraqi cohorts, highlighting strong ancestry-specificity of this risk allele.
Cancer risk
A meta-analysis of 30 case-control studies found that carriers of the NOD2 rs2066844 T allele (TT+CT genotypes) had modestly increased cancer risk compared to CC homozygotes (OR=1.32, 95% CI 1.01–1.72, p=0.041), though borderline significance and heterogeneity across cancer types limit this inference. Subsequent updated systematic reviews for colorectal cancer specifically (13 studies, 5,013 cases) found no statistically significant association with rs2066844. The cancer signal may reflect chronic inflammatory predisposition in IBD-adjacent contexts rather than a direct carcinogenic effect of this variant.
▶GWAS Catalog Trait Associations (4)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (4)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Autoinflammatory syndrome; Blau syndrome (BLAUS); Crohn disease; Inflammatory bowel disease 1 (IBD1); Regional enteritis; Yao syndrome; not specified
View on ClinVar →▶Research that mentions this SNP (6)
▶Gene Variants, mRNA and NOD1/2 Protein Levels in Tunisian Childhood AsthmaAssociationN=763Rafik Belhaj et al.(2019)· Lung
Case-control study of 338 Tunisian asthmatic children and 425 healthy controls examining NOD1/NOD2 polymorphisms. The NOD1 rs2075820 (E266K) AA genotype was a significant risk factor for childhood asthma (OR 4.6, p=0.0001), with higher effect in males. NOD1 mRNA and protein expression were significantly elevated in asthma patients (p<0.001).
▶TLR4, IL10RA, and NOD2 mutation in paediatric Crohn’s disease patients: an association with Mycobacterium avium subspecies paratuberculosis and TLR4 and IL10RA expressionAssociationN=108Josef Wagner et al.(2013)· Medical Microbiology and Immunology
This study investigated 34 SNPs in 18 Crohn's disease susceptibility genes in 62 pediatric CD patients and 46 controls with known Mycobacterium avium subspecies paratuberculosis (MAP) status. Mutations in TLR4 (rs4986790, Asp299Gly) and IL10RA (rs2229113, Gly330Arg) were significantly associated with MAP-positive CD (27.6% vs 6.1%, p=0.021 and 62.1% vs 33.3%, p=0.024, respectively), with a synergistic interaction (OR=7.39, 95% CI 2.25-24.27). Functional studies showed IL-10 and TNFα production were significantly lower in CD patients with NOD2 mutations, and IL10R and TLR4 receptor expression were elevated on NK cells and NK T cells harboring NOD2 mutations.
▶Contribution of higher risk genes and European admixture to Crohnʼs disease in African AmericansAssociationN=708Ming-Hsi Wang et al.(2012)· Inflammatory Bowel Diseases
Study of 354 African American Crohn's disease cases and 354 controls examined the contribution of European admixture and major established CD risk genes. Mean European ancestry was similar between cases (20.9%) and controls (20.4%, p=0.58). Significant associations were found with NOD2 carrier status (OR 3.28, p=0.007), ATG16L1 Thr300Ala (p=0.003), IBD5 locus genes SLC22A4 L503F (p=0.05) and SLC22A5 g-207c (p=0.03), and IL23R rs2201841 (p=0.03), but not IRGM variants.
▶NOD2/CARD15 Mutations Correlate With Severe Pouchitis After Ileal Pouch-Anal AnastomosisAssociationN=387Rishabh Sehgal et al.(2010)· Diseases of the Colon & Rectum
This case-control association study examined NOD2/CARD15 mutations in IPAA patients with various post-surgical complications. NOD2 mutations were found in 67% of severe pouchitis patients (P<0.001), compared to 5.4% in asymptomatic IPAA patients and 8.5% in healthy controls, suggesting a genetic basis for severe pouchitis due to compromised host immune response to enteric bacteria.
▶Autoinflammatory genes and susceptibility to psoriatic juvenile idiopathic arthritisAssociationN=950Day TG et al.(2008)· Arthritis & Rheumatism
This case-control study investigated the association of autoinflammatory genes (NLRP3, NOD2, MEFV, PSTPIP1) with juvenile idiopathic arthritis (JIA) in 950 UK Caucasian patients and 728 controls. After Bonferroni correction, two SNPs remained significantly associated with psoriatic JIA: MEFV rs224204 (corrected P = 0.025) and NLRP3 rs3806265 (corrected P = 0.04). The findings suggest a shared disease mechanism between hereditary periodic fever syndromes and psoriatic JIA involving abnormal IL-1β production.
▶Common variants in genes that mediate immunity and risk of multiple myelomaAssociationN=672Elizabeth E. Brown et al.(2007)· International Journal of Cancer
A case-control study of 127 multiple myeloma (MM) cases and 545 controls examined 82 common variants in 45 genes mediating immunity. IL4R rs2107356 (−28120T homozygotes, OR=1.91, 95% CI 1.08-3.38) and FCGR2A rs1801274 (−120G homozygotes, OR=1.95, 95% CI 1.06-3.60) were significantly associated with increased MM risk. A haplotype in the LTA*TNF complex (LTA −82C/−90G*TNF −1036C/−487G/−417G, OR=1.63, 95% CI 1.02-2.61) was also associated with increased MM risk compared to controls.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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