Autoimmune protection (IL23R R381Q)

IL23R is a receptor that drives a branch of the immune system involved in inflammation. A relatively uncommon variant (R381Q) turns that signal down and is protective against several immune diseases, including Crohn's disease, psoriasis and ankylosing spondylitis.

What the IL23R R381Q variant does

IL23R is the receptor for interleukin-23, a signalling molecule that maintains a class of inflammatory T cells central to gut and skin inflammation. This variant changes one amino acid and reduces the receptor's responsiveness, which dampens that inflammatory pathway.

Unusually for the variants on this site, its effect is protective rather than risk-increasing, and substantially so.

How strong the evidence is

The catalogued association comes from a study of 394,626 European-ancestry individuals with a p-value below 1e-17 and 19 supporting publications, and the effect size corresponds to roughly a halving of Crohn's disease odds for carriers.

The same protective direction has been reported for ulcerative colitis, psoriasis and ankylosing spondylitis, which is what marked out the interleukin-23 pathway as shared across these conditions.

Why this variant changed how these diseases are treated

This is one of the clearest cases of human genetics validating a drug target. The discovery that a naturally occurring variant which weakens interleukin-23 signalling protects against inflammatory bowel disease and psoriasis provided evidence that blocking the same pathway pharmacologically should work.

Drugs that do exactly that, including ustekinumab, risankizumab and guselkumab, are now standard treatments for Crohn's disease, ulcerative colitis and psoriasis. Carrying the protective variant does not predict how you would respond to them, but the connection is why the pathway was pursued.

How common it is, and what it means

About 12% of European-ancestry individuals carry one protective copy in reference data, and it is close to absent in East Asian samples. Because the underlying conditions are uncommon, halving the odds still leaves most of the protection unnoticeable in an individual life.

Protection here also does not extend to the rest of the immune system. It shifts one pathway, not general immune competence.

What each rs11209026 genotype means

rs11209026 has three possible genotypes: GG, AG and AA.

Typical IL23R (no protective variant) (rs11209026 GG). You have the common version of IL23R, so as far as this gene goes, your inflammatory immune signalling is at the typical baseline. You don't carry the protective variant, which is the most common situation and says nothing unusual.

Some autoimmune protection (IL23R) (rs11209026 AG). You carry one copy of the protective IL23R variant, which dampens a pro-inflammatory immune signal and is linked to lower risk of Crohn's disease, psoriasis and ankylosing spondylitis. It's a favorable variant, though it only shifts the odds.

Strong autoimmune protection (IL23R) (rs11209026 AA). You have two copies of the protective IL23R variant (uncommon), strongly linked to lower risk of Crohn's disease, psoriasis and ankylosing spondylitis. The same immune pathway is the target of several modern anti-inflammatory drugs, a sign of how relevant it is.

Evidence & sources

Across global populations, fewer than 1% of people carry two copies of this variant, and about 89% carry none.

This variant appears in 19 published genetic studies: PubMed 17447842 · PubMed 18758464 · PubMed 19122664 · PubMed 19915572 · PubMed 20062062 · PubMed 20953190 · PubMed 21102463 · PubMed 21297633 · PubMed 21743469 · PubMed 22293688 · PubMed 22412388 · PubMed 22936669 · PubMed 23128233 · PubMed 23749187 · PubMed 25574825 · PubMed 28008999 · PubMed 37377963 · PubMed 39789286 · PubMed 41661118.

Common questions

Does the protective IL23R variant mean I cannot get Crohn's disease? No. It roughly halves the odds in carriers, which still leaves the possibility open, and inflammatory bowel disease has many other genetic and environmental contributors including smoking.

Does this variant predict how I would respond to ustekinumab or risankizumab? No. The variant is why the interleukin-23 pathway became a drug target, but it is not used to select treatment, and no established pharmacogenomic test uses it.

Related

Age-related macular degeneration risk · Breast cancer (female) · Depression · Diastolic blood pressure · Inflammatory bowel disease · Type 2 diabetes protection (PPARG Pro12Ala) · Venous thromboembolism (clots)