A lifelong inflammatory bowel disease that can affect any part of the digestive tract. Its genetics are unusually well mapped — NOD2 was the first susceptibility gene ever found for a common complex disease, and IL23R showed a drug class where to aim.
Crohn's disease is a long-term condition in which the immune system attacks the lining of the digestive tract. Anywhere from the mouth to the anus can be involved, though the end of the small intestine and the start of the colon are the most common sites. It comes in flares and remissions rather than steadily, and it is a disease people live with for decades rather than one they recover from.
The everyday reality of it is diarrhoea, abdominal pain that often settles in the lower right, weight loss and a fatigue that is out of proportion to everything else. Because the inflammation goes through the whole thickness of the bowel wall rather than staying on the surface, it can also tunnel — forming narrowings that block the bowel, or channels between the bowel and other organs or the skin. That depth is the main thing that distinguishes it from ulcerative colitis, which stays on the inner lining and stays in the colon.
Crohn's disease occupies an unusual place in the history of human genetics. In 2001, NOD2 became the first susceptibility gene identified for any common complex disease — before that, genetics had been good at rare single-gene conditions and had almost nothing to say about the ordinary ones. NOD2 is a sensor inside cells that recognises a fragment of bacterial cell wall. That a bacterial sensor turned out to be the first Crohn's gene reframed the disease: not the immune system misfiring at random, but a misjudged conversation between the gut and the bacteria living in it.
The second landmark was IL23R, found in 2006. One coding change in it, rs11209026, swaps arginine for glutamine at position 381 of the receptor, and the glutamine version substantially protects against Crohn's disease. Protective findings are rare and valuable: they say that turning this pathway down is safe and beneficial in people who are born that way. Drugs that block interleukin-23 were developed and are now in use for Crohn's disease. This is one of the clearest examples anywhere of a genetic finding leading to a treatment.
Less than that history might suggest. A 2012 meta-analysis of more than 75,000 people brought the count of inflammatory bowel disease loci to 163, and most of them affect both Crohn's disease and ulcerative colitis rather than one alone. Together they explain only a modest share of who develops the disease. Incidence has risen sharply over decades in which the gene pool cannot have changed, which by itself shows how much of the risk is environmental.
The two variants on this site are among the strongest of the 163, and they are still probabilistic:
Neither is a test. Most people carrying either will never develop Crohn's disease, and plenty of people who have it carry neither.
Nothing diagnostic. Crohn's disease is diagnosed by endoscopy, biopsy and imaging, and genotype plays no part in that. If you have symptoms that fit — persistent diarrhoea, unexplained weight loss, blood in the stool, abdominal pain that does not settle — those are worth a doctor's attention regardless of what any variant says, and the same symptoms with a normal genotype deserve exactly the same attention.
Disease definition. Crohn's disease is a chronic, relapsing transmural inflammatory bowel disease that may affect any segment of the gastrointestinal tract, most often the terminal ileum and proximal colon, with discontinuous ("skip") involvement. Transmural inflammation underlies the stricturing and penetrating (fistulising) behaviours that distinguish it from ulcerative colitis, which is mucosal and continuous and confined to the colon and rectum. Diagnosis is clinical, endoscopic, histological and radiological; there is no genetic diagnostic test.
NOD2 rs2076756. An intron variant in NOD2 (16q12.1; the gene was originally reported as CARD15). In the GWAS Catalog the G allele is reported as the risk allele with an odds ratio of 1.53 (95% CI 1.46-1.60, p = 4 x 10-69) at a risk allele frequency of about 0.26, with independent reports of 1.66 (95% CI 1.48-1.88, p = 1 x 10-37) and 1.71 (95% CI 1.42-2.05, p = 1 x 10-21). NOD2 encodes an intracellular pattern-recognition receptor for muramyl dipeptide, a bacterial peptidoglycan fragment. The classical coding risk alleles in this gene (R702W, G908R and the 1007fs frameshift) are separate variants that are not covered on this site; rs2076756 is a common intronic marker at the same locus and is not a substitute for them.
IL23R rs11209026. A missense variant in IL23R (1p31.3), NM_144701 / ENST00000347310, p.Arg381Gln, alleles G/A. The A allele encodes Gln381 and is the protective allele; the GWAS Catalog reports rs11209026-G as the risk allele for Crohn disease with an odds ratio of 2.66 (95% CI 2.36-3.00, p = 1 x 10-64) and for inflammatory bowel disease at 2.56 (95% CI 1.92-3.45, p = 7 x 10-11). The association is directionally consistent with the clinical efficacy of IL-12/IL-23 and selective IL-23 pathway inhibitors in Crohn's disease, and is a standard example of human genetics validating a drug target prospectively.
Genetic architecture. Jostins et al. (Nature 2012; PMID 23128233) reported 71 new associations for a total of 163 IBD loci in a meta-analysis of more than 75,000 cases and controls; most loci contribute to both Crohn's disease and ulcerative colitis, and the authors reported significant overlap between IBD susceptibility loci and loci for mycobacterial infection. Heritability is substantial but the identified common variants account for a minority of it, and the marked secular rise in incidence establishes a large environmental component. Familial aggregation is real but risk to relatives is far below Mendelian expectation.
Clinical status of genotype. None of these variants is used diagnostically, prognostically or for treatment selection in routine practice. NOD2 genotype has been studied in relation to ileal, stricturing and early-onset disease, and IL23R in relation to treatment response, but neither is established as a clinical decision aid. Genotype should not influence when a person seeks assessment for symptoms.
What a 23andMe/AncestryDNA export or raw VCF can and can't tell you about Crohn's Disease comes down to these specific, well-studied positions — not a diagnosis.
Crohn's disease can affect any part of the digestive tract, goes through the full thickness of the bowel wall, and typically appears in patches with normal bowel in between. Ulcerative colitis is confined to the colon and rectum, involves only the inner lining, and spreads continuously upward from the rectum. They share many of the same genetic risk loci, which is why both sit under the umbrella term inflammatory bowel disease.
No. These are common variants with modest effects. Most people who carry them never develop the disease, and many people who have it carry neither of the two on this site. Incidence has risen steeply over decades in which the gene pool cannot have changed, which shows how much of the risk is environmental.
Because it is protective rather than harmful. People born with the glutamine version of the receptor at position 381 get Crohn's disease substantially less often, which is evidence that turning this pathway down is both safe and useful. Drugs blocking interleukin-23 were developed and are now used in Crohn's disease — one of the clearest cases anywhere of a genetic finding leading to a treatment.
It was the first susceptibility gene found for any common complex disease, in 2001. Until then genetics could explain rare single-gene conditions and had almost nothing to say about ordinary ones. NOD2 senses a fragment of bacterial cell wall, which reframed Crohn's disease as a misjudged conversation between the gut and its bacteria rather than an immune system misfiring at random.
There is no clinical reason to. Crohn's disease is diagnosed by endoscopy, biopsy and imaging, and no guideline uses genotype to diagnose it, predict its course or choose treatment. Symptoms that fit the disease deserve medical assessment whatever your genotype says.
Free to reuse. This page's text is original writing from freely-available research, licensed CC BY 4.0 — reuse it, including commercially, with attribution to MyGeneLog. It's general research-derived information, not medical advice or a diagnosis — see Terms of Use.