rs6693831 — IL23R

Intronic IL23R variant where the minor T allele is associated with increased ankylosing spondylitis susceptibility and the common C allele confers protection across several IL-23/Th17-driven inflammatory diseases in Asian populations

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IL23R rs6693831 — A Protective C Allele in the IL-23 Receptor

The interleukin-23 receptor (IL-23R) sits at the center of the IL-23/Th17 axis11 IL-23/Th17 axis
A cytokine signaling pathway linking innate immune sensing to adaptive T-helper 17 cell responses; the primary target of anti-IL-23 biologics including risankizumab, guselkumab, and ustekinumab used in IBD, psoriasis, and ankylosing spondylitis, one of the most therapeutically targeted pathways in modern inflammatory disease. When IL-23 binds its receptor on CD4+ T cells, innate lymphoid cells, and natural killer cells, it drives differentiation and survival of Th17 cells that produce IL-17A — the cytokine responsible for the neutrophil-dominated tissue inflammation seen in psoriasis, ankylosing spondylitis, psoriatic arthritis, and Crohn's disease. rs6693831 is an intronic variant within the IL23R gene on chromosome 1, where the minor T allele (~21.8% globally) is associated with increased susceptibility to ankylosing spondylitis, while the common C allele confers a substantial protective effect.

The Mechanism

rs6693831 lies within an intron of IL23R (NM_144701.3:c.1149-653T>C, GRCh38 position chr1:67255184) on the plus strand of the gene. As an intronic variant, it does not directly alter the IL-23R protein sequence. However, intronic variants in this gene frequently act as linkage disequilibrium tags22 linkage disequilibrium tags
Intronic SNPs that co-segregate with nearby functional variants on the same chromosomal haplotype, so that the intronic SNP captures the disease association even when it is not itself the causal variant for regulatory elements or coding variants on the same IL23R haplotype block. The IL23R locus contains multiple independent association signals organized into haplotype blocks; rs6693831 tags a signal distinct from the well-characterized rs11209026 (R381Q, Arg381Gln) missense variant, which is the primary IL23R protective allele studied across European populations.

Whether rs6693831 acts through direct regulation of IL23R expression levels or through LD with a nearby functional element has not been resolved experimentally. Given the large allele frequency differences across ancestries — the T allele is notably rarer in African (~7.6%) compared to European (~26.4%) and American (~37.7%) populations — the clinical signal is most robustly established in East Asian cohorts where the majority of studies have been conducted.

The Evidence

The most statistically compelling data for rs6693831 comes from a case-control study in Southwest China33 case-control study in Southwest China
Yang et al. Oncotarget 2017, PMID 29050281 — 486 ankylosing spondylitis patients and 480 healthy controls genotyped using high-resolution melting analysis, which found the C allele strongly protective against AS (p=3.206×10⁻³¹) and the CC genotype independently associated with reduced AS susceptibility (p=8.574×10⁻⁸). These extremely significant p-values place rs6693831 among the most robustly associated IL23R variants tested in this Chinese cohort for AS.

In the direction of risk for rheumatoid arthritis, a 2024 case-control study in Western China44 2024 case-control study in Western China
Ren et al. Int J Immunogenet 2024, PMID 38196067 — 246 RA patients and 362 controls found the C allele and CC genotype were more frequent in RA patients than in controls (OR=7.797 for CC vs TT, OR=5.984 for allele C vs T). This finding runs in the opposite direction from the AS study, suggesting rs6693831 may have disease-specific bidirectional effects — a pattern documented at the IL2RA locus and other immune-regulatory genes where the same pathway component plays opposing roles in different autoimmune disease contexts. The RA study's small sample (n=608) and unusually large odds ratios for a common intronic variant warrant replication before firm RA-specific guidance can be offered.

A third study examining alcohol-induced osteonecrosis of the femoral head55 alcohol-induced osteonecrosis of the femoral head
Wang et al. Oncotarget 2017, PMID 28422712 — 355 male cases and 355 controls in a Chinese Han population found the TC heterozygous genotype to function as a protective factor (p=0.046), consistent with a broadly modulatory role for this variant in inflammatory susceptibility.

The evidence base for rs6693831 is currently anchored in Chinese Han populations from three small-to-moderate case-control studies. The extraordinary significance of the AS association (p~10⁻³¹) suggests a real biological effect in that population, but independent replication in European and other ancestries is lacking. The evidence level is accordingly rated moderate.

Practical Implications

For carriers of two T alleles (TT genotype, ~4.8% of people globally), the AS association data from Chinese cohorts suggests meaningfully elevated susceptibility to ankylosing spondylitis — an axial spondyloarthropathy characterized by chronic back pain, progressive spinal fusion, and systemic inflammation. Early recognition of AS symptoms enables timely rheumatology referral and initiation of disease-modifying therapy that can prevent irreversible structural damage. The IL-23/Th17 axis is directly targeted by approved biologics for AS (secukinumab, ixekizumab for IL-17A; ustekinumab, risankizumab for IL-23), making pathway-level genetic risk genuinely informative for treatment planning.

The contradictory RA signal from the smaller Ren 2024 study means the TT genotype should not be considered protective against RA on current evidence. The most defensible interpretation is: TT = elevated AS risk (robust finding), uncertain RA implications (requires replication).

For CT heterozygotes (~34.1% of people), one copy of the T allele confers intermediate risk for AS under an additive model, with less data available to quantify the effect precisely.

Interactions

rs6693831 is one of six IL23R variants in this research batch, tagging an independent haplotype signal distinct from the canonical rs11209026 R381Q missense protective allele and from other intronic IL23R markers (rs7517847, rs10489629, rs2201841, rs1004819). Multiple IL23R variants can be present simultaneously on different haplotypes; their combined effect has not been formally modeled in the studies available for rs6693831. Given the IL23R gene's complex haplotype structure with at least three independent disease-association blocks documented in European and Asian populations, individuals carrying risk alleles at multiple IL23R SNPs may have compounded susceptibility beyond what any single variant predicts.

The IL-23/Th17 pathway interacts functionally with HLA-B*27 in ankylosing spondylitis (HLA-B*27 is the dominant AS genetic risk factor, present in ~90% of AS patients) — the combined effect of HLA-B*27 and IL23R risk alleles has not been quantified for rs6693831 specifically. A compound action describing IL23R × HLA-B*27 interaction should be considered if data emerge for this specific SNP.

Genotype Interpretations

What each possible genotype means for this variant.

CC Common Protective Genotype Normal

Common genotype — typical IL23R background; population-level AS susceptibility

You carry two copies of the common C allele at rs6693831, the most frequent genotype globally (~61% by Hardy-Weinberg estimate from gnomAD v4 frequencies). In the largest study of this variant, the CC genotype was strongly associated with reduced ankylosing spondylitis susceptibility compared to TT carriers (p=8.574×10⁻⁸ in a Chinese cohort of 966 individuals). Your IL23R background risk for AS at this specific locus is at or below average. C allele frequency varies substantially by ancestry: ~74% in Europeans, ~92% in Africans, and ~62% in East Asians.

CT One Risk Allele Intermediate

One T risk allele — modestly elevated ankylosing spondylitis susceptibility

rs6693831 is an intronic IL23R variant tagging a haplotype signal in the IL-23 receptor gene distinct from the well-studied rs11209026 (R381Q) missense protective allele. The AS association observed in Chinese cohorts (Yang 2017, n=966, p~10⁻³¹ for allele C) places this among the more significant IL23R signals tested in that population, though independent replication in non-Asian populations is lacking. Under a log-additive model, CT heterozygotes would carry approximately one half the per-allele AS risk increment of TT homozygotes. For CT individuals, the most actionable response is awareness of the early warning signs of axial spondyloarthropathy: inflammatory-pattern back pain before age 45 (improves with movement, not rest), prolonged morning stiffness, enthesitis (tendon/ligament insertion tenderness at heel or knee), uveitis, and elevated inflammatory markers (CRP, ESR). Formal HLA-B*27 testing provides complementary genetic context — the combination of IL23R risk alleles and HLA-B*27 positivity substantially raises pre-test probability for AS.

TT Two Risk Alleles High Risk

Two T risk alleles — higher ankylosing spondylitis susceptibility at this IL23R locus

The TT genotype at rs6693831 represents maximum T-allele dosage at this IL23R intronic position. The extraordinary significance of the AS association in Chinese cohorts (allele p~10⁻³¹) places this among the most statistically compelling IL23R signals tested in this population. Extrapolation to European and other non-Asian ancestries is limited by the absence of large replication studies. However, because rs6693831 tags a haplotypic signal in the broader IL23R disease-association region — the same gene implicated in AS pathogenesis across all studied ancestries — a biological effect in non-Asian populations is plausible.

A contradictory signal was reported in a smaller study of rheumatoid arthritis (Ren 2024, n=608) where the C allele was associated with increased RA risk — the opposite direction. This bidirectional pattern at immune-regulatory genes is documented elsewhere in the literature (e.g. IL2RA variants protect against T1D but raise Graves' disease risk); the mechanistic basis for disease-specific allelic direction reversal is not fully resolved for rs6693831. Given the much larger and more significant AS dataset, the TT genotype is classified as high-risk primarily for spondyloarthropathy.

Ankylosing spondylitis is a member of the spondyloarthropathy spectrum that includes psoriatic arthritis, reactive arthritis, and IBD-associated arthritis. IL23R variants influence the entire spectrum; AS is the condition with the most published data for rs6693831 specifically. HLA-B*27 status is the single most important genetic risk factor for AS (~90% of AS patients are positive) and should be tested alongside IL23R risk assessment for comprehensive spondyloarthropathy risk profiling.