rs2066844 — NOD2 R702W

NOD2 R702W — Guardian of the Gut's Bacterial Balance

Your gut hosts trillions of bacteria, and your immune system must constantly distinguish friend from foe. The NOD2 gene encodes an intracellular bacterial sensor¹¹ intracellular bacterial sensor
NOD2 (nucleotide-binding oligomerization domain-containing protein 2) recognizes muramyl dipeptide (MDP), a component of bacterial cell walls that acts as a pattern-recognition receptor for bacterial peptidoglycans. When functioning normally, NOD2 helps maintain homeostasis in the gut²² homeostasis in the gut
balancing inflammatory and anti-inflammatory responses to commensal bacteria by modulating immune responses and regulating the composition of gut microbiota, particularly in the small intestine.

The R702W variant was among the first genetic risk factors discovered for Crohn's disease³³ first genetic risk factors discovered for Crohn's disease
identified in 2001 through linkage studies on chromosome 16 and remains the single strongest genetic predictor of this inflammatory bowel disease. This missense mutation changes arginine to tryptophan at position 702 in the leucine-rich repeat (LRR) domain, the part of the protein responsible for recognizing bacterial molecules.

The Mechanism

The R702W substitution occurs in the leucine-rich repeat domain⁴⁴ leucine-rich repeat domain
this domain recognizes muramyl dipeptide from bacterial peptidoglycan of the NOD2 protein, altering its ability to sense and respond to bacterial components. Unlike the more severe L1007fs frameshift mutation, R702W results in a partial loss of function⁵⁵ partial loss of function
retains some ability to activate NF-κB but with reduced efficiency rather than complete protein truncation. Studies show that R702W impairs the protein's ability to detect muramyl dipeptide and downregulate excessive TLR responses⁶⁶ downregulate excessive TLR responses
NOD2 normally suppresses Toll-like receptor signaling to prevent overreaction to gut bacteria.

NOD2 is highly expressed in ileal Paneth cells⁷⁷ highly expressed in ileal Paneth cells
specialized epithelial cells in the small intestine that secrete antimicrobial peptides, which produce antimicrobial defensins to regulate the bacterial load in the terminal ileum. The R702W variant is associated with reduced defensin production⁸⁸ reduced defensin production
though this may result from chronic inflammation rather than direct genetic effect, allowing increased colonization by potentially inflammatory bacterial species and creating a dysbiotic state that predisposes to intestinal inflammation.

The Evidence

A landmark meta-analysis of 75 case-control studies⁹⁹ A landmark meta-analysis of 75 case-control studies
18,727 Crohn's disease cases and 17,102 controls across multiple populations established that R702W carriers (CT genotype) have an odds ratio of 2.2 (95% CI 2.0-2.5) for developing Crohn's disease compared to non-carriers. The risk escalates dramatically with gene dosage¹⁰¹⁰ gene dosage
effect is codominant with increasing risk per copy of the risk allele: simple heterozygotes (one R702W) show 2.4-fold risk, while compound heterozygotes (R702W plus another NOD2 variant) have 9-fold risk and homozygotes (two R702W) reach 6.7-fold risk.

The variant shows strong genotype-phenotype correlation¹¹¹¹ strong genotype-phenotype correlation
R702W particularly predicts ileal disease location and stricturing behavior. A study of CD patients found ileal involvement in 90% of NOD2 variant carriers versus 73% of non-carriers (p<0.05), and stricturing or penetrating disease occurred in 88% versus 56% (p<0.01). The R702W variant specifically associates with ileal-predominant disease¹²¹² ileal-predominant disease
the terminal ileum is where Paneth cells expressing NOD2 are most abundant, with mutation frequency of 26.9% in ileal CD versus 12.7% in colonic CD.

Geographic variation is striking¹³¹³ Geographic variation is striking
R702W is virtually absent in Asian populations but common in Europeans. In European CD cohorts, the R702W allele frequency reaches 10%, compared to essentially 0% in Japanese and Chinese populations where Crohn's disease has different genetic architecture. This suggests population-specific disease mechanisms¹⁴¹⁴ population-specific disease mechanisms
environmental factors and other genetic pathways drive CD in non-European populations.

Recent studies have revealed a recessive inheritance pattern¹⁵¹⁵ recessive inheritance pattern
biallelic NOD2 variants act as single-gene cause in subset of patients for a subset of Crohn's disease patients. Approximately 8% of pediatric-onset IBD patients carry two NOD2 risk alleles (either homozygous or compound heterozygous), and these patients show a markedly severe phenotype with 11.5-fold increased risk of stricturing disease¹⁶¹⁶ 11.5-fold increased risk of stricturing disease
compared to patients without NOD2 mutations requiring surgical intervention.

Practical Implications

If you carry one or two copies of R702W, your lifetime risk of developing Crohn's disease is elevated but penetrance remains low¹⁷¹⁷ penetrance remains low
even two-mutation carriers have less than 10% lifetime risk. The majority of R702W carriers never develop IBD, indicating that environmental triggers and additional genetic factors are required. However, understanding your genotype allows proactive gut health strategies¹⁸¹⁸ proactive gut health strategies
microbiome modulation and early symptom monitoring.

The gut microbiome plays a central role. Studies show NOD2-deficient mice have increased bacterial load¹⁹¹⁹ NOD2-deficient mice have increased bacterial load
particularly in the ileum where NOD2 is highly expressed and altered microbial composition, with decreased beneficial Firmicutes²⁰²⁰ decreased beneficial Firmicutes
including butyrate-producing species like Faecalibacterium prausnitzii and increased potentially inflammatory Enterobacteriaceae. Probiotic supplementation, particularly with Lactobacillus strains producing DL-endopeptidase²¹²¹ Lactobacillus strains producing DL-endopeptidase
this enzyme generates muramyl dipeptide that can stimulate residual NOD2 function, has shown promise in mouse models of colitis.

For heterozygous carriers (CT), focus on maintaining gut barrier integrity and microbial diversity through fiber-rich diet²²²² fiber-rich diet
feeds beneficial bacteria that produce short-chain fatty acids, stress management, and judicious antibiotic use. For compound heterozygotes or homozygotes (those with two NOD2 risk alleles), more vigilant monitoring is warranted given the substantially elevated risk of complicated disease²³²³ substantially elevated risk of complicated disease
including strictures and fistulas requiring surgery.

Interactions

R702W commonly co-occurs with other NOD2 variants, particularly rs2066845 (G908R) and rs2066847 (L1007fs)²⁴²⁴ rs2066845 (G908R) and rs2066847 (L1007fs)
the three major CD-associated NOD2 mutations, creating compound heterozygotes with dramatically elevated risk. When an individual carries R702W on one chromosome and either G908R or L1007fs on the other, the combined effect produces a 9-fold increased risk of Crohn's disease²⁵²⁵ 9-fold increased risk of Crohn's disease
compared to 2-3-fold for single heterozygotes, with 98% specificity for complicated, stricturing disease requiring surgery.

NOD2 also interacts with ATG16L1 (rs2241880)²⁶²⁶ ATG16L1 (rs2241880)
another major CD risk gene involved in autophagy, a cellular process for degrading intracellular bacteria. NOD2 recruits ATG16L1 to sites of bacterial entry, and variants in both genes synergistically impair the intestinal epithelial response to bacterial invasion. Patients carrying risk variants in both NOD2 and ATG16L1 show additive risk beyond either variant alone²⁷²⁷ additive risk beyond either variant alone
suggesting convergent pathways in CD pathogenesis.

The interaction between NOD2 genotype and smoking is complex and counterintuitive²⁸²⁸ smoking is complex and counterintuitive
shows negative interaction with protective effect. While smoking increases CD risk in the general population, a case-only study found R702W carriers who smoke have lower risk than expected (OR 0.71, p=0.005), suggesting the genetic and environmental factors may operate through different mechanisms²⁹²⁹ genetic and environmental factors may operate through different mechanisms
biological interaction between NOD2 pathway and smoking-induced changes in gut immunity.