Crohn's disease susceptibility

The NOD2 gene helps the gut immune system sense bacteria. A NOD2 variant modestly raises susceptibility to Crohn's disease, but most carriers never develop it.

What this NOD2 variant does

NOD2 is an intracellular sensor that recognises a fragment of bacterial cell wall and triggers an immune response. It is especially active in Paneth cells, which sit in the small intestine and release antimicrobial peptides that shape which bacteria live there.

This variant, R702W, weakens that sensing. The prevailing model is that impaired bacterial handling in the ileum lets the gut wall and its microbes interact in ways that provoke chronic inflammation, which is consistent with NOD2-associated Crohn's disease typically involving the ileum.

How strong the evidence is

NOD2 was the first Crohn's disease gene identified, in 2001, and remains the strongest common genetic contributor in European-ancestry populations. The catalogued association here, from a study of 5,962 people, gives an odds ratio of about 2.2 per copy.

Meta-analysis across the three main NOD2 variants gives the clearer picture: roughly 2.4 times the risk for a single copy, and around 17 times for people carrying two damaged copies, whether the same variant twice or two different ones. Risk of complicated disease, meaning stricturing or fistulising, was raised by about 8% in heterozygotes and 41% in those with two.

This page reads one of three variants

The three main NOD2 risk variants are R702W, which is read here, G908R, and the 1007fs frameshift, which is the strongest of them. A consumer DNA file does not reliably carry the other two, so a result showing no R702W does not mean no NOD2 risk.

That matters because the large risk figures above apply to people with two damaged copies across any combination of the three, which cannot be established from this single position.

How common it is, and what it means in absolute terms

In 1000 Genomes reference data, about 9% of European-ancestry individuals carry one copy of R702W. It is essentially absent in East Asian samples, which is part of why NOD2 explains little of Crohn's disease in East Asian populations despite rising incidence there.

Crohn's disease affects a few hundred people per 100,000 in Western countries, so even a doubling of relative risk leaves absolute risk low. Persistent diarrhoea, blood in the stool, unexplained weight loss, night-time symptoms or ongoing abdominal pain are what warrant medical attention, with or without this variant.

What matters alongside genetics

Smoking is the clearest modifiable factor in Crohn's disease, and unusually it points the opposite way in ulcerative colitis, where it associates with lower risk. In people with two damaged NOD2 copies, active smoking has been linked to a particularly aggressive ileal course.

The IL23R protective variant on this site sits in the same disease pathway from the other direction, and the site's inflammatory bowel disease polygenic score aggregates many more common variants, though notably not the NOD2 coding variants.

What each rs2066844 genotype means

rs2066844 has three possible genotypes: CC, CT and TT.

No Crohn's risk variant (rs2066844 CC). You don't carry this NOD2 variant linked to Crohn's disease, so from what this gene shows your risk is at baseline. Crohn's is shaped by many genes and environmental factors together.

Slightly higher Crohn's risk (rs2066844 CT). You carry one copy of a NOD2 variant that modestly raises susceptibility to Crohn's disease, an inflammatory bowel condition. Most people who carry it never develop Crohn's, since it's only one of several risk factors. It's a small nudge in risk, not a prediction.

Higher Crohn's risk (rs2066844 TT). You have two copies of this NOD2 Crohn's variant, which raises susceptibility more than a single copy. Even so, most carriers stay healthy, because Crohn's depends on a mix of genes and environment. Worth being aware of if you have persistent gut symptoms.

Evidence & sources

Across global populations, fewer than 1% of people carry two copies of this variant, and about 93% carry none.

This variant appears in 2 published genetic studies: PubMed 28067908 · PubMed 41661118.

Common questions

Does carrying R702W mean I will get Crohn's disease? No. One copy roughly doubles a risk that starts low, and most carriers never develop Crohn's disease. The much larger figures in the literature apply to people carrying two damaged NOD2 copies, which this single position cannot establish.

Should I be screened for Crohn's disease? There is no screening test for Crohn's disease in people without symptoms, and a genotype does not change that. Diagnosis follows symptoms, blood and stool tests and endoscopy.

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