rs6693831 — IL23R

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.