rs11465770 — IL23R

IL23R rs11465770 — A Protective Haplotype Tag in the IL-23/Th17 Pathway

The immune system uses the interleukin-23 (IL-23) signalling axis as a master switch for chronic inflammatory responses. When IL-23 binds the IL-23 receptor (IL23R) on Th17 cells¹¹ Th17 cells
T helper 17 cells — a subset of CD4+ T cells that produce interleukin-17A and interleukin-17F; their chronic activation drives gut and joint inflammation in IBD, ankylosing spondylitis, and psoriasis, it sustains production of the pro-inflammatory cytokine IL-17A and drives the kind of persistent mucosal inflammation that characterises Crohn's disease (CD) and ulcerative colitis (UC). The rs11465770 variant in IL23R sits within an intronic region on chromosome 1, position 67,168,280 (GRCh38)²² chromosome 1, position 67,168,280 (GRCh38)
The IL23R gene spans chromosome 1p31.3; rs11465770 is located in the 5' portion of the gene near the block containing the well-studied protective variants. The T allele at this position marks a protective haplotype that co-segregates with other IL23R variants known to dampen receptor signalling, and it is this haplotype that reduces susceptibility to inflammatory bowel disease.

The Mechanism

rs11465770 is itself an intronic substitution (C>T on the plus strand) with no direct coding consequence. Its biological relevance lies in linkage disequilibrium (LD)³³ linkage disequilibrium (LD)
Two variants are in LD when they are inherited together on the same chromosomal stretch far more often than chance would predict; knowing one allele reliably predicts the other within a population with functional IL23R variants in the same haplotype block. The IL23R gene contains two major LD blocks: a centromeric block (containing exons 5–11) harbouring the most significant GWAS signals, and a 5' region block. The T allele at rs11465770 tags a haplotype architecture where reduced receptor activity is the net effect.

The biological mechanism of protection is best understood through the functional IL23R variants this haplotype accompanies. The key coding variant rs11209026 (R381Q) disrupts the cytoplasmic signalling domain of IL23R. When IL-23 binds the receptor, it normally phosphorylates the transcription factor STAT3, driving IL-17A transcription in Th17 cells. T cells carrying the protective haplotype produce only 5.5 pg/mL IL-17A after IL-23 stimulation, compared with 36.0 pg/mL in non-carriers⁴⁴ 36.0 pg/mL in non-carriers
6.5-fold reduction measured in Th17 effector cells; Th17 differentiation itself is unaffected, meaning pathogen defence is preserved while the chronic inflammatory overdrive is attenuated. More broadly, protective IL23R variants act through impaired protein stability and intracellular trafficking⁵⁵ impaired protein stability and intracellular trafficking
The R381Q, G149R, and V362I protective variants all display reduced cell-surface receptor expression due to ER retention or accelerated degradation, limiting the number of receptors available to respond to IL-23 stimulation. rs11465770 T, as a haplotype tag, identifies individuals who carry this reduced-receptor architecture on at least one chromosomal copy.

This mechanism is clinically validated by the pharmaceutical success of anti-IL-23 biologics. Drugs such as risankizumab, guselkumab, and mirikizumab — all targeting the IL-23 p19 subunit that binds IL23R — are now first-line or second-line treatments for moderate-to-severe Crohn's disease and ulcerative colitis, achieving remission rates of 40–60% in clinical trials. Carriers of protective IL23R haplotypes are, in effect, born with a partial pharmacological blockade of the same pathway these drugs target.

The Evidence

The IL23R locus was identified as an IBD susceptibility region in the landmark 2006 GWAS published in Science⁶⁶ published in Science
Duerr et al. — genome-wide discovery in 547 CD cases and 548 controls, with replication in Jewish and non-Jewish cohorts; the IL23R centromeric haplotype block showed P values as low as 10⁻¹³ for Crohn's disease. Multiple intronic IL23R variants in the same haplotype block as rs11465770 achieved protective odds ratios of 0.30–0.70 for CD, with protective allele frequencies in European controls reaching 10% or higher.

A meta-analysis of 60 CD case-control studies⁷⁷ meta-analysis of 60 CD case-control studies
Xu et al. Scientific Reports 2015; 22,820 CD cases and 27,401 controls across multiple populations confirmed that IL23R intronic variants — particularly rs7517847, a member of the same haplotype architecture — reduce CD risk with OR = 0.70 (95% CI 0.66–0.74, P<0.001) in Caucasian populations. The protective signal is not present in East Asian populations, consistent with the near-absence of the T allele at rs11465770 in East Asian gnomAD data (allele frequency <0.04%).

For ulcerative colitis, a meta-analysis of 33 studies⁸⁸ meta-analysis of 33 studies
Zhong et al. Oncotarget 2016; 10,527 UC cases, 15,142 controls; OR=0.76 (95% CI 0.64–0.90, P=0.002) for protective IL23R alleles vs risk alleles in Caucasians confirmed a consistent 24% reduction in UC risk among carriers of the protective haplotype. The effect size is smaller for UC than for CD, mirroring the pattern seen across all IL23R variants in the gene — the locus has a stronger and more consistently replicated association with CD than with UC across populations.

The T allele at rs11465770 is found at approximately 10% allele frequency in Europeans and South Asians (~8%), is exceedingly rare in East Asians (<0.1%), and uncommon in Africans (~1.4%). This population structure — high frequency in populations with high IBD prevalence, very low frequency in East Asian populations where IBD incidence is rising but was historically low — is consistent with a variant under modest balancing selection in environments where the IL-23/Th17 pathway plays a critical host-defence role.

Practical Actions

Carrying the T allele at rs11465770 represents a genuinely favourable finding with respect to gut inflammatory disease risk. Heterozygous CT carriers have partial haplotype protection on one chromosomal copy; TT homozygotes carry the maximum protection available at this locus. This does not eliminate IBD risk — other genetic contributors (NOD2, ATG16L1, CARD9) and environmental factors are also important — but it meaningfully shifts the baseline.

For individuals who develop IBD despite carrying the protective T allele, or who have a family history of IBD alongside this protective genotype, the IL-23/Th17 biology is still directly relevant to treatment selection. Anti-IL-23 biologics (risankizumab, guselkumab, ustekinumab for the IL-12/23 p40 subunit) target the exact pathway in which this haplotype confers its protection, and carriers of protective IL23R haplotypes may show differential pharmacological responses — though this remains an area of active research rather than established clinical guidance.

Interactions

rs11465770 is in linkage disequilibrium with the principal IL23R protective variants: rs11209026 (R381Q, the functional coding change), rs11465804, rs7517847, rs10489629, and rs1343151. Individuals carrying the T allele at rs11465770 are likely to also carry protective alleles at one or more of these correlated positions, though LD is not perfect and each provides independent information. Combining haplotype data across all typed IL23R markers gives a more complete picture of IL23R protective coverage than any single variant.

Beyond IL23R itself, the IL-23/Th17 pathway involves upstream (IL12B, STAT3, JAK2) and downstream (IL17A, IL17RA, IL22) genes whose variants interact epistatically with IL23R haplotypes. Studies of the IL23/IL17 pathway in CD have documented significant gene-gene interactions between IL23R risk haplotypes and IL17A, IL17RA, and IL12RB2 haplotypes: combined carrier status of multiple pathway risk alleles pushes CD odds ratios to 4.3 or higher, while protective IL23R haplotypes partially buffer against these epistatic risks.