rs2066845 — NOD2 G908R

NOD2 G908R — A Key Bacterial Sensor Variant in Crohn's Disease

The NOD2 gene encodes an intracellular pattern recognition receptor that detects bacterial cell wall fragments¹¹ detects bacterial cell wall fragments
NOD2 specifically recognizes muramyl dipeptide (MDP), a conserved component found in peptidoglycan from both Gram-positive and Gram-negative bacteria. When bacteria are present, NOD2 triggers immune responses through the NF-κB pathway, producing antimicrobial peptides and recruiting immune cells to fight infection. The G908R variant (rs2066845), one of the three major Crohn's disease-associated NOD2 mutations, substitutes glycine with arginine at amino acid position 908²² substitutes glycine with arginine at amino acid position 908
This missense mutation occurs in the leucine-rich repeat (LRR) domain, the bacterial-sensing region of the NOD2 protein, impairing its ability to detect bacterial signals.

The Mechanism

NOD2 is primarily expressed in intestinal epithelial cells and immune cells³³ primarily expressed in intestinal epithelial cells and immune cells
Particularly concentrated in Paneth cells of the small intestine, which secrete antimicrobial compounds to control gut bacteria. When functioning normally, NOD2 detects muramyl dipeptide from bacterial cell walls and activates the NF-κB signaling cascade, leading to production of inflammatory cytokines and alpha-defensins—powerful antimicrobial peptides that keep bacterial populations in check. The G908R mutation disrupts this process: the amino acid change in the bacterial-sensing LRR domain reduces NOD2's ability to bind muramyl dipeptide⁴⁴ reduces NOD2's ability to bind muramyl dipeptide
Studies show G908R shares a common signaling defect with other CD-associated NOD2 variants, exhibiting impaired NF-κB activation in response to bacterial components. This leads to decreased production of antimicrobial peptides, allowing bacterial populations to grow unchecked and potentially triggering chronic inflammation.

The Evidence

G908R is one of three NOD2 variants strongly associated with Crohn's disease⁵⁵ G908R is one of three NOD2 variants strongly associated with Crohn's disease
First identified in 2001, these variants account for over 80% of NOD2-associated Crohn's disease cases. The variant's impact follows a clear dose-response pattern: a comprehensive meta-analysis of 75 case-control studies⁶⁶ a comprehensive meta-analysis of 75 case-control studies
Included 18,727 Crohn's disease cases and 17,102 controls across multiple populations found odds ratios of 2.2 for simple heterozygotes, 9.0 for compound heterozygotes (carrying two different NOD2 mutations), and 6.7 for homozygotes compared to non-carriers. The effect is most pronounced for ileal Crohn's disease—the form affecting the small intestine—where NOD2 mutations confer a 2-4 fold increased risk with one copy, and 20-40 fold with two copies⁷⁷ NOD2 mutations confer a 2-4 fold increased risk with one copy, and 20-40 fold with two copies.

G908R carriers show specific disease characteristics⁸⁸ G908R carriers show specific disease characteristics
A retrospective study of 202 Crohn's disease patients found G908R heterozygosity associated with ileal involvement and smoking. A recent meta-analysis demonstrated⁹⁹ recent meta-analysis demonstrated
Examining studies from the last decade, focusing on surgical outcomes that G908R specifically increases odds of surgical recurrence following intestinal resection by 64%, making it crucial for predicting disease course and treatment planning. The variant also affects the gut microbiome before disease onset: studies of first-degree relatives of Crohn's patients¹⁰¹⁰ studies of first-degree relatives of Crohn's patients
Analysis of 1,546 healthy subjects with known NOD2 genotypes showed that C allele carriers (the risk variant) have significantly increased levels of Erysipelotrichaceae bacteria in their stool, suggesting the genetic variant alters the microbiome composition years before inflammation appears.

Practical Implications

Knowing your G908R status provides actionable information about gut health and disease risk. For carriers, the impaired bacterial sensing¹¹¹¹ impaired bacterial sensing
NOD2-deficient mice show increased bacterial loads and reduced ability to prevent pathogenic bacterial colonization means extra attention to gut microbiome health is warranted. Unlike some genetic risk factors, NOD2 variants don't doom you to disease—only 30-40% of Crohn's disease patients carry at least one NOD2 mutation¹²¹² only 30-40% of Crohn's disease patients carry at least one NOD2 mutation
Conversely, 6-7% of healthy controls carry these mutations without developing disease, highlighting the importance of environmental and microbial factors.

For those with Crohn's disease who carry G908R, the variant has clinical implications: it predicts ileal location¹³¹³ ileal location
The terminal ileum, where Paneth cells are concentrated and NOD2 is most highly expressed, more aggressive disease course, and increased risk of needing surgery. This information can guide treatment decisions, with some evidence suggesting NOD2 mutation carriers may benefit more from early aggressive therapy to prevent complications.

Interactions

G908R frequently co-occurs with other NOD2 variants in compound heterozygous states, which dramatically amplifies risk. The most clinically significant combinations involve G908R with R702W (rs2066844) or with the L1007fs frameshift mutation (rs2066847). When someone carries two different NOD2 risk variants—one from each parent—the odds ratio for Crohn's disease jumps to 9.0, compared to 2.2 for a single variant. This multiplicative effect suggests the variants work through the same pathway, with each defective copy further impairing bacterial sensing.

Beyond NOD2 itself, G908R interacts with variants in genes involved in autophagy—the cellular process that digests intracellular bacteria. The ATG16L1 variant (rs2241880) is particularly relevant: NOD2 recruits ATG16L1 to bacterial entry sites¹⁴¹⁴ NOD2 recruits ATG16L1 to bacterial entry sites
This interaction is crucial for packaging invaded bacteria into autophagosomes for destruction. When both NOD2 and ATG16L1 are defective, bacterial clearance is severely compromised, potentially explaining why some NOD2 carriers develop disease while others don't. Studies of double-deficient mice show they develop spontaneous intestinal inflammation only when specific bacteria like Mucispirillum schaedleri are present, reinforcing that disease requires both genetic susceptibility and microbial triggers.