rs10489629 — IL23R

Intronic IL23R variant in LD block 2 where the T allele is associated with increased susceptibility to Crohn's disease and ankylosing spondylitis while the C allele is protective — a signal distinct from the rs1004819/rs7517847 haplotype block

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IL23R rs10489629 — The LD Block 2 Signal: Crohn's, AS, and a Second Entry Point to the IL-23 Axis

The IL23R gene does not speak with one genetic voice. Scattered across a 36-kilobase region of chromosome 1, at least two independent haplotype blocks carry disease-associated variants that modulate interleukin-23 receptor activity through distinct mechanisms. rs10489629 sits in the larger of those blocks — LD block 211 LD block 2
a 36-kb region of co-inherited alleles including rs11209026, rs1343151, rs10489629, and rs10889677; it is structurally and statistically independent from LD block 1, which contains rs1004819 and rs7517847 — and tags a protective haplotype against Crohn's disease and ankylosing spondylitis22 Crohn's disease and ankylosing spondylitis
two IL-23/Th17-driven inflammatory diseases with overlapping genetic architecture at this locus.

The C allele at rs10489629 (reported as the G or A allele in papers using coding-strand notation, because the IL23R gene runs on the plus strand at this position) is the minor allele in most populations — present in roughly 46% of Europeans, 26% of East Asians, and 56% of Africans. Its lower frequency in Crohn's disease and ankylosing spondylitis patients compared to healthy controls is a consistent finding across multiple independent meta-analyses.

The Mechanism

rs10489629 is an intronic variant at position 67,222,666 on chromosome 1 (GRCh38). It does not alter the IL-23 receptor protein sequence. Like other non-coding variants in the IL23R locus, its mechanism is regulatory33 regulatory
intronic variants within this locus are thought to influence IL23R mRNA expression levels, splicing efficiency of alternative isoforms, or transcription factor binding within intronic regulatory elements. The C allele at rs10489629 is in strong linkage disequilibrium with the well-characterized R381Q protective missense variant rs1120902644 R381Q protective missense variant rs11209026
the Arg381Gln substitution that directly reduces IL-23 receptor surface expression and blunts Th17 cell differentiation — the most functionally characterized IL23R variant, meaning the rs10489629 C allele frequently co-segregates with the protective Q381 allele within this block. This LD relationship partly explains why rs10489629 shows consistent protective associations — it tags a broader protective haplotype — though it may also have independent regulatory effects.

The T allele represents the ancestral, higher-activity baseline state of the IL-23/Th17 signaling axis. Carriers lacking the C allele do not benefit from the haplotype-level dampening that co-inheritance with the R381Q-bearing haplotype may provide. The net result, seen across multiple inflammatory disease GWAS, is modestly elevated susceptibility to the spectrum of Th17-driven conditions: Crohn's disease, ulcerative colitis, and ankylosing spondylitis.

The Evidence

For Crohn's disease, a meta-analysis of 12 studies55 meta-analysis of 12 studies
Du et al. Scientific Reports 2015, including >9,000 CD cases and >12,000 controls from the IL23R IBD literature found that the protective C allele (reported as G in papers using coding-strand notation) was significantly less frequent in CD cases: OR=0.791 (95% CI 0.706–0.887, P<0.001) overall, and OR=0.775 (95% CI 0.690–0.869, P<0.001) in Caucasians specifically. A single Asian study showed no significant association (OR=0.998), consistent with the pattern seen for most IL23R non-coding variants — predominantly a European signal.

For ankylosing spondylitis, a meta-analysis of 25 studies (8,431 AS cases, 8,972 controls)66 meta-analysis of 25 studies (8,431 AS cases, 8,972 controls)
Zhong et al. Expert Review of Clinical Immunology 2018 confirmed that the minor allele frequency of rs10489629 was significantly lower in AS patients (p=0.002), establishing a protective role for the C allele in AS susceptibility, again predominantly in Caucasian populations. An updated 2018 meta-analysis77 updated 2018 meta-analysis
Associations between interleukin-23R polymorphisms and ankylosing spondylitis susceptibility — an updated meta-analysis, Rheumatologie 2018 confirmed rs10489629 followed the same pattern as other IL23R markers, with a significant protective association in Europeans but not Asians.

A study of 334 ankylosing spondylitis patients88 334 ankylosing spondylitis patients
de Hooge et al. Rheumatology Advances in Practice 2019 reported the protective C allele (A in coding strand notation) at a frequency of 56% in AS patients vs. 52% in the CEU reference cohort, with OR=0.83 for the protective allele, and found no statistically significant correlation with serum IL-17A levels — suggesting the variant's primary disease-modifying effect is upstream at the receptor level rather than directly detectable in downstream cytokine output.

The evidence for rheumatoid arthritis is less consistent. A European-population meta-analysis in 2012 found the C allele slightly elevated in RA patients (OR=1.092 for C vs. T), while a 2023 updated meta-analysis found the G allele (=C on plus strand) protective (OR=0.901). This directional inconsistency across RA studies — contrasted with the more consistent protective signal in CD and AS — means the RA association should be interpreted cautiously and is not considered a primary actionable finding for this variant.

Practical Implications

The clinical implications of rs10489629 closely parallel those of its LD block neighbor rs1004819 and the broader rs7517847 signal. Carriers of the TT genotype at rs10489629 lack the protective C allele and have modestly elevated genetic susceptibility to Crohn's disease and ankylosing spondylitis in the context of European ancestry. The actionable implications are awareness-based: early recognition of IBD symptoms and prompt evaluation for inflammatory back pain (the hallmark of ankylosing spondylitis) are the most clinically meaningful responses to this genetic signal.

The IL-23/Th17 pathway that rs10489629 tags is directly targeted by approved biologics — IL-23 inhibitors (risankizumab, guselkumab, ustekinumab) for IBD, and IL-17 inhibitors (secukinumab, ixekizumab) along with IL-23 inhibitors for AS — meaning that if inflammatory disease does develop, effective pathway-targeted therapies are available.

Interactions

rs10489629 sits in LD block 2 of the IL23R locus, which also contains the well-characterized protective missense variant rs11209026 (R381Q). The rs10489629 T allele and the rs11209026 common C allele (the non-protective allele) tend to co-segregate on the same haplotype, meaning TT carriers at rs10489629 are also less likely to carry the protective Q381 allele at rs11209026. This haplotype-level co-inheritance means the two variants reinforce each other's directional effects rather than being strictly independent risk signals.

LD block 1 variants — rs1004819 and rs7517847 — are in low linkage disequilibrium with rs10489629 and represent structurally independent risk signals. Carriers of risk alleles at both blocks (TT at rs10489629 AND AA at rs1004819) face additive IBD and AS susceptibility from independent genetic signals within the same gene.

The IL23R × NOD2/CARD15 gene-gene interaction documented for other IL23R variants is biologically expected to apply at rs10489629 as well: TT carriers who also carry NOD2 risk alleles (rs2066844, rs2066845) may face amplified Crohn's disease susceptibility, though this specific combination has not been quantified directly for rs10489629.

Genotype Interpretations

What each possible genotype means for this variant.

CC Protective Genotype Beneficial

Two copies of the protective C allele — reduced susceptibility to Crohn's disease and ankylosing spondylitis

You carry two copies of the protective C allele at rs10489629. This genotype is present in approximately 21% of Europeans (Hardy-Weinberg estimate from ~46% C allele frequency). Meta-analyses consistently show the C allele is significantly less common in Crohn's disease and ankylosing spondylitis patients compared to healthy controls in European populations (OR ~0.775–0.791 for CD; OR ~0.83 for AS). Your CC genotype reflects a favorable position at this IL23R locus for these conditions.

CT One Protective Copy Intermediate

One copy of the protective C allele — moderately elevated Crohn's disease and AS susceptibility

The protective signal at rs10489629 is part of a 36-kb LD block that also harbors the well-characterized R381Q missense variant (rs11209026). The C allele at rs10489629 tends to co-segregate with the protective Q381 allele within this block — meaning CT carriers have one chromosome carrying the protective haplotype and one chromosome carrying the risk haplotype. The partial protection from the single C allele does not fully eliminate the T allele's contribution to baseline IL-23 signaling tone.

The association with CD (OR=0.791 for C allele) and AS (OR=0.83 for C allele) in Caucasian populations is well-replicated. The absolute risk increase for a CT carrier compared to CC is modest, and most CT carriers will never develop Crohn's disease or AS. However, awareness of early symptoms is clinically valuable given the established genetic signal.

TT Two Risk Copies High Risk

Two copies of the risk T allele — highest susceptibility at this IL23R locus for Crohn's disease and ankylosing spondylitis

rs10489629 TT genotype means both copies of your chromosome 1 carry the risk haplotype at LD block 2 of the IL23R locus. This block is in low linkage disequilibrium with LD block 1 (containing rs1004819 and rs7517847), so rs10489629 captures a partially independent genetic contribution to IL-23 pathway activity. The TT genotype is associated with slightly elevated or more easily activated IL-23 receptor signaling — the molecular basis for the observed associations with Th17-driven inflammatory diseases.

This does not mean TT carriers will develop Crohn's disease or AS — the absolute lifetime risks remain modest, and the majority of TT carriers will never develop these conditions. However, TT status is meaningful in the context of other risk alleles: additional IL23R variants (rs1004819 AA, rs7517847 TT), NOD2/CARD15 variants, and HLA-B27 positivity compound the risk substantially. The IL-23/Th17 pathway your genotype reflects is directly targeted by multiple approved biologics (IL-23 inhibitors: risankizumab, guselkumab, ustekinumab; IL-17 inhibitors: secukinumab, ixekizumab) — so if inflammatory disease does develop, effective pathway-targeted treatments exist.

The protective association is predominantly established in Caucasian populations; in East Asian populations the evidence is weaker, possibly because the C allele frequency is lower (~26% vs ~46% in Europeans), reducing statistical power.