rs11209026 — IL23R R381Q

IL23R R381Q — A Powerful Shield Against Inflammatory Bowel Disease

The IL23R gene encodes the interleukin-23 receptor, a key player in immune regulation that pairs with IL12RB1 to form the functional receptor for IL-23, a pro-inflammatory cytokine. IL-23 drives the differentiation and survival of Th17 cells¹¹ IL-23 drives the differentiation and survival of Th17 cells
immune cells that produce IL-17 and contribute to chronic inflammation. The R381Q variant (rs11209026) is one of the most protective genetic variants ever identified for inflammatory bowel disease, reducing risk for Crohn's disease by more than 50% and ulcerative colitis by about 30-50%. This single amino acid change — arginine to glutamine at position 381 — fundamentally alters how your immune system responds to inflammatory signals.

The Mechanism

The R381Q variant is a [missense mutation | changes one amino acid in the protein sequence] that replaces arginine with glutamine in the cytoplasmic tail of the IL-23 receptor, between the transmembrane domain and the JAK2 binding site. This arginine is absolutely conserved across species²² absolutely conserved across species
present in the same position in mice, rats, and other mammals, indicating its critical importance for normal receptor function. The R381Q variant creates a loss-of-function receptor through multiple mechanisms. First, it alters mRNA splicing by reducing binding of the SF2 splicing enhancer³³ alters mRNA splicing by reducing binding of the SF2 splicing enhancer
promoting exon 9 skipping, which increases expression of a soluble IL-23R isoform that acts as a decoy receptor, soaking up IL-23 before it can activate cells. Second, the variant reduces surface expression of the receptor⁴⁴ reduces surface expression of the receptor
through impaired protein stability and trafficking, meaning fewer functional receptors reach the cell membrane. Third, even when the R381Q receptor does reach the surface, it shows reduced IL-23-induced STAT3 phosphorylation⁵⁵ reduced IL-23-induced STAT3 phosphorylation
weaker downstream signaling, blunting the inflammatory cascade.

The Evidence

The protective effect of R381Q was first discovered in a landmark 2006 genome-wide association study⁶⁶ landmark 2006 genome-wide association study
Duerr et al., A genome-wide association study identifies IL23R as an inflammatory bowel disease gene that scanned the genomes of 547 patients with ileal Crohn's disease. The A allele (encoding glutamine) was found in 7% of healthy controls but only 1.9% of Crohn's disease patients, yielding an odds ratio of 0.45 for disease protection. This has been replicated in dozens of independent cohorts⁷⁷ replicated in dozens of independent cohorts
representing tens of thousands of individuals. A 2019 meta-analysis of 41 studies encompassing 13,803 Crohn's disease patients, 5,876 ulcerative colitis patients, and over 27,000 controls confirmed the variant as a protective factor against IBD. The protective effect extends beyond IBD: R381Q also reduces risk for psoriasis (OR 0.49)⁸⁸ reduces risk for psoriasis (OR 0.49)
Capon et al., Sequence variants in the genes for the interleukin-23 receptor, ankylosing spondylitis, and other immune-mediated diseases that involve the IL-23/Th17 pathway.

Functional studies have clarified why the variant is protective. Primary T cells from R381Q carriers⁹⁹ Primary T cells from R381Q carriers
both heterozygotes and homozygotes show reduced surface IL-23R expression and decreased IL-23-induced STAT3 phosphorylation, translating to less IL-17 and IL-22 production — key inflammatory cytokines in the gut. Macrophages from R381Q carriers¹⁰¹⁰ Macrophages from R381Q carriers
also show reduced IL-23-dependent bacterial clearance, which may seem paradoxical given the protective effect, but likely reflects a trade-off: slightly reduced antimicrobial capacity in exchange for dramatically lower chronic inflammation. The net effect is protective, as excessive Th17 responses cause more damage than benefit in the context of IBD.

Practical Implications

If you carry one or two copies of the A allele at rs11209026, your baseline risk for inflammatory bowel disease is substantially lower than the general population. This doesn't mean you're immune — environmental factors, diet, gut microbiome composition, stress, and other genetic variants all contribute — but your genetic predisposition is significantly more favorable. For Crohn's disease specifically, each copy of the A allele reduces risk by about 50-60%, meaning AA homozygotes have approximately 70-75% lower risk than GG individuals.

The variant's protective effect is mediated through the IL-23/Th17 pathway, which is now a major therapeutic target in IBD. Biologics targeting IL-12/IL-23 (ustekinumab) and IL-23 specifically (risankizumab, guselkumab)¹¹¹¹ Biologics targeting IL-12/IL-23 (ustekinumab) and IL-23 specifically (risankizumab, guselkumab)
have shown efficacy in Crohn's disease and ulcerative colitis, essentially mimicking the effect of the R381Q variant pharmacologically. If you're GG (standard risk) and develop IBD, you may be a particularly good candidate for IL-23-targeted therapies, as you lack the natural protection the A allele provides. Conversely, if you're AA and still develop IBD, other pathways are likely more important in your disease, and IL-23 blockade may be less effective.

Beyond IBD, the R381Q variant's effects on immune regulation suggest broader implications for autoimmune disease risk. The IL-23/Th17 axis is implicated in psoriasis, psoriatic arthritis, ankylosing spondylitis, rheumatoid arthritis, and multiple sclerosis. Carriers of the A allele may have modestly reduced risk for these conditions as well.

Interactions

IL23R sits at a critical node in the inflammatory cascade, downstream of pattern recognition receptors (like NOD2, another major Crohn's disease gene) and upstream of Th17 cell differentiation. The protective effect of IL23R R381Q appears to be independent of other IBD risk variants — it's not simply tagging a protective haplotype but is itself the causal variant. Studies have found no epistatic interaction between IL23R and CARD15 (NOD2)¹²¹² no epistatic interaction between IL23R and CARD15 (NOD2)
the two genes act independently, meaning their effects are additive rather than synergistic. However, given that both genes feed into overlapping inflammatory pathways, individuals with favorable variants in both genes (e.g., IL23R R381Q plus wild-type NOD2) would have the lowest IBD risk, while those with risk variants in both would have compounded susceptibility.

The IL-23 receptor is also expressed on innate lymphoid cells, NK cells, and macrophages, not just T cells. The R381Q variant affects all these cell types, contributing to its broad protective effect across multiple immune-mediated diseases. The variant's impact on macrophage function — reducing IL-23-dependent bacterial clearance — raises interesting questions about infection susceptibility, though no increased infection risk has been documented in R381Q carriers¹³¹³ no increased infection risk has been documented in R381Q carriers
likely because multiple redundant antimicrobial pathways exist.