rs11465804 — IL23R

Intronic IL23R variant in strong linkage disequilibrium with the functional R381Q variant (rs11209026); the minor G allele tags the protective haplotype that dampens IL-23 receptor signalling, reducing risk for ankylosing spondylitis, Crohn's disease, ulcerative colitis, and psoriasis

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IL23R — The Protective Haplotype That Tamps Down the IL-23/Th17 Axis

Your immune system walks a narrow line between fighting infection and attacking its own tissues. One of the most critical molecular checkpoints along that line is the IL-23/Th17 axis11 IL-23/Th17 axis
The signalling pathway in which the cytokine IL-23 binds to the IL-23 receptor (IL23R) on T helper 17 (Th17) cells, sustaining their inflammatory effector function and driving chronic inflammation in the skin, gut, and joints. Dysregulation of this pathway is a root cause of ankylosing spondylitis (AS), Crohn's disease (CD), ulcerative colitis (UC), and psoriasis. The rs11465804 variant in the IL23R gene is a tag SNP that co-segregates with the most studied protective IL23R haplotype — and carries one of the strongest single-locus protective signals identified in immune-mediated disease genetics.

The Mechanism

rs11465804 is an intronic variant located at chromosome 1, position 67,236,843 (GRCh38). It lies in high linkage disequilibrium (LD)22 high linkage disequilibrium (LD)
Linkage disequilibrium means the two variants are inherited together on the same chromosomal segment so frequently that knowing one variant's identity predicts the other; r²=0.84 between rs11465804 and rs11209026 in the IBD case-control dataset with rs11209026, the missense variant encoding the p.Arg381Gln (R381Q) substitution in the cytoplasmic domain of the IL-23 receptor. The R381Q change is the biologically active element: replacing arginine with glutamine at position 381 partially impairs the receptor's ability to transduce IL-23 signals.

Mechanistically, R381Q dampens IL-23-induced STAT3 phosphorylation33 STAT3 phosphorylation
STAT3 is a transcription factor activated when IL-23 binds its receptor; phosphorylated STAT3 enters the nucleus and drives expression of inflammatory cytokines including IL-17A; lower pSTAT3 means less downstream inflammation specifically in Th17 effector cells. T cells from carriers of the protective allele produced a median of 5.5 pg/ml IL-17A after IL-23 stimulation, compared with 36.0 pg/ml in non-carriers — a 6.5-fold reduction. Crucially, this reduced effector response did not affect Th17 cell differentiation or baseline cytokine production, meaning that protective-allele carriers retain Th17-mediated host defence against pathogens while being protected from the chronic Th17 hyperactivation that drives spondyloarthritis and IBD. This receptor hypomorphism is precisely the mechanism that pharmaceutical anti-IL-23 biologics (guselkumab, risankizumab, mirikizumab) try to recapitulate pharmacologically.

The Evidence

The IL23R locus was first identified as an IBD gene by a landmark GWAS published in Science in 200644 Science in 2006
Duerr et al. Science 313:1461–3; genome-wide discovery in 567 CD cases and 571 controls, with replication in additional Jewish and non-Jewish cohorts. In that study, the G allele at rs11465804 was present in 6.3% of non-Jewish healthy controls but only 2.0% of CD cases — a striking frequency difference. The resulting odds ratio was 0.30 (95% CI 0.18–0.51, P=7.52×10⁻⁷), meaning G allele carriers had roughly 70% lower odds of Crohn's disease. In the Jewish cohort, where G allele frequency is higher (~10%), the protective OR was 0.47 (95% CI 0.31–0.71).

The protective signal extends across inflammatory diseases. A meta-analysis of 25 AS case-control studies55 meta-analysis of 25 AS case-control studies
Zhong et al. Expert Rev Clin Immunol 2018; 8,431 AS cases and 8,972 controls from multiple European cohorts confirmed that the G allele frequency was significantly lower in AS patients than controls (P<0.001), placing rs11465804 among the four protective IL23R polymorphisms in ankylosing spondylitis. In ulcerative colitis, a meta-analysis of 33 studies66 meta-analysis of 33 studies
Zhong et al. Oncotarget 2016; 10,527 UC cases and 15,142 controls found the G vs T comparison OR=0.76 (95% CI 0.64–0.90, P=0.002), a consistent 24% reduction in UC risk. The protective associations are most robust in European populations; East Asian populations carry the G allele at near-zero frequency (~0.01%) and have not shown significant association.

The protective effect size is consistent with the IL-23/Th17 pathway being a principal driver of these diseases — and with the clinical success of IL-23 inhibitor drugs as highly effective treatments for the same conditions.

Practical Implications

Carriers of the G allele have measurably dampened IL-23-driven Th17 effector responses, which translates to reduced lifetime risk for AS, Crohn's disease, UC, and psoriasis. This is especially relevant for individuals with a family history of spondyloarthritis or inflammatory bowel disease. The protection is partial and additive — GG homozygotes (extremely rare globally at ~0.3%) carry the greatest degree of protection; GT heterozygotes carry intermediate protection.

It is important to understand what this variant does not protect against: conditions driven by IL-12/Th1 pathways or other arms of the immune system remain unaffected. Additionally, the protective signal is strongest for the conditions listed above and should not be extrapolated to all autoimmune diseases.

Interactions

rs11465804 tags the same protective IL23R haplotype block as rs10489629, rs1343151, and rs11209026 (R381Q). These variants are in strong LD and typically co-inherited, so individuals who carry the G allele at rs11465804 will almost always also carry the protective alleles at rs10489629 and rs1343151 — they represent the same underlying biology. The independent functional variant remains rs11209026 (R381Q), with rs11465804 serving as a reliable proxy in genotyping studies.

Within the broader IL-23 pathway, several other IL23R variants (rs2201841, rs1004819) confer increased susceptibility and represent distinct haplotypes; individuals may carry both protective alleles at rs11465804 and susceptibility alleles at these other loci on separate chromosomal copies, making the net haplotype architecture complex. The rs7517847 variant, also intronic in IL23R, marks a susceptibility haplotype and is tracked separately in this database.

Genotype Interpretations

What each possible genotype means for this variant.

TT Common Genotype Normal

Standard IL-23 receptor signalling — common genotype without protective IL23R haplotype

You have two copies of the T (reference) allele at rs11465804. This is the most common genotype, carried by approximately 89% of people globally (and over 99% in East Asian populations). The T allele does not tag the protective IL23R haplotype (which includes the functional R381Q substitution), meaning your IL-23 receptor signals at typical intensity when stimulated by IL-23. Your susceptibility to ankylosing spondylitis, Crohn's disease, ulcerative colitis, and psoriasis is at the population baseline — neither elevated nor reduced by this variant.

GT Protective Haplotype Carrier Beneficial

One copy of the IL23R protective haplotype — associated with reduced inflammatory disease risk

You carry one copy of the G allele at rs11465804, which tags the IL23R protective haplotype. This haplotype co-segregates with the functional R381Q (rs11209026) substitution that partially impairs IL-23 receptor signalling in Th17 effector cells. Functional studies show that one copy of the protective allele significantly reduces IL-23-induced IL-17A production and STAT3 phosphorylation. In large population studies, this genotype is associated with approximately 50–70% reduced odds of Crohn's disease (OR ~0.47 in Jewish cohorts, ~0.30 in non-Jewish) and 24% reduced odds of ulcerative colitis. Protective signals for ankylosing spondylitis are consistent across multiple European cohorts. About 10% of people of European ancestry carry this genotype; it is rare in East Asian populations.

GG Dual Protective Haplotype Beneficial

Two copies of the IL23R protective haplotype — maximum attenuation of IL-23/Th17 signalling at this locus

You carry two copies of the G allele at rs11465804, which tags the IL23R protective haplotype on both chromosomes. This is an extremely rare genotype (approximately 0.3% of the global population; roughly 1 in 1,000 people of European ancestry). Both copies of your IL-23 receptor carry the functional R381Q modification that dampens Th17 effector cell responses to IL-23 stimulation. Functional studies suggest this double-dose reduction in IL-23 signalling confers the greatest degree of protection against IL-23/Th17-driven diseases at this locus — consistent with an additive inheritance model where each G allele contributes independently to reduced risk. Your genetic risk from this specific variant for ankylosing spondylitis, Crohn's disease, ulcerative colitis, and psoriasis is substantially below population average.