rs2066845
badMag 6.5This is a variant in the NOD2 gene that changes a glycine to an arginine.
Key Literature Trait Associations
Crohn's Disease
rs2066845 causes a missense change in NOD2 (G908R: glycine to arginine at position 908), located in the leucine-rich repeat domain that senses bacterial peptidoglycans. Like R702W, G908R impairs NOD2's immune sensing function. One copy increases Crohn's risk approximately 2.6-fold. Combined with other NOD2 variants, risk rises 15-40 fold. Found in ~1% of Europeans, essentially absent in East Asians. Crohn's associated with NOD2 variants typically has ileal predominance and fibrostenotic phenotype.
Inflammatory bowel disease
rs2066845 shows pleiotropic association across five chronic inflammatory diseases — ankylosing spondylitis, Crohn's disease, psoriasis, primary sclerosing cholangitis, and ulcerative colitis — at extreme genome-wide significance (p=6×10⁻⁹⁴) in a multi-disease GWAS framework. This pleiotropy reflects the central role of NOD2-mediated innate immune dysregulation in mucosal and systemic inflammation. A cross-disease analysis by Ellinghaus et al. (2016) examining over 86,000 Europeans identified shared genetic architecture across these conditions, with NOD2 representing a major pleiotropic locus. The variant is predominantly informative in European-ancestry populations.
Colorectal cancer
The NOD2 G908R variant has been associated with elevated colorectal cancer (CRC) susceptibility in Caucasian populations. A meta-analysis of 8 case-control studies (Tian et al. 2010; n=5,888) found an odds ratio of 1.98 (95% CI 1.14–3.44; p=0.01), representing the strongest individual NOD2 variant effect on CRC risk among those analyzed. The biological plausibility is consistent with the known role of impaired NOD2-mediated innate immunity in intestinal mucosal surveillance. Evidence is currently limited to Caucasian cohorts and the overall meta-analytic sample size is modest.
▶GWAS Catalog Trait Associations (1)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
GWAS Catalog Trait Associations (1)
Genome-wide significant associations (p < 5×10⁻⁸) from the NHGRI-EBI GWAS Catalog.
▶ClinVar annotation
Autoinflammatory syndrome; Blau syndrome (BLAUS); Inflammatory bowel disease 1 (IBD1); Psoriatic arthritis, susceptibility to; Regional enteritis; Yao syndrome; not specified
View on ClinVar →▶Research that mentions this SNP (7)
▶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.
▶Distinct and overlapping genetic loci in crohnʼs disease and ulcerative colitis: Correlations with pathogenesisAssociationN=3,431Matti Waterman et al.(2011)· Inflammatory Bowel Diseases
This study examined 40 SNPs (34 CD-associated and 6 UC-associated) in 2374 Canadian IBD patients (1144 CD, 1230 UC/IBDU) and 1057 healthy controls. While most immune-related variants showed similar frequencies between CD and UC, the two diseases diverged significantly in genes related to innate immunity and autophagy (NOD2, ATG16L1, IRGM), which were more prevalent in CD. In patients with colon-only CD, genetic overlap with UC was nearly complete, suggesting a shared genetic basis for colonic disease.
▶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.
▶CARD15 and IL23R influences Crohnʼs disease susceptibility but not disease phenotype in a Brazilian populationAssociationN=442Márcia Luiza Baptista et al.(2008)· Inflammatory Bowel Diseases
This case-control study examined the association of CARD15, IL23R, and ATG16L1 variants with Crohn's disease (CD) susceptibility in a Brazilian population of 187 CD patients and 255 controls. CARD15 variants R702W (OR=3.77) and 3020insC (OR=4.56) and IL23R variants rs1004819 (OR=1.46), rs11209026 (OR=0.36, protective), and rs10889677 (OR=1.38) showed significant associations with CD. However, no significant genotype-phenotype correlations were found for disease location, behavior, or severity in the Brazilian population.
▶Association of IL23R, TNFRSF1A, and HLA-DRB1*0103 allele variants with inflammatory bowel disease phenotypes in the Finnish populationAssociationN=7,457Maarit Lappalainen et al.(2008)· Inflammatory Bowel Diseases
PhD thesis describing comprehensive genome-wide association studies of acute anterior uveitis (AAU) in European (2,752 cases, 3,836 controls) and East Asian (821 cases, 4,898 controls) populations. European descent GWAS identified HLA-B at genome-wide significance plus 11 suggestive loci (ERAP1, NOS2, MERTK). East Asian GWAS identified HLA-B and ERAP1 at genome-wide significance plus 12 suggestive loci (GPR68, RHBDD2). Mendelian randomization confirmed ERAP1 as functionally relevant and showed genetically predicted CRP levels positively associated with AAU risk.
Gene information from NCBI Gene. Variant classifications from ClinVar.
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