rs7746808 — IL23A

Intergenic variant near the IL23A locus associated with psoriasis and psoriatic arthritis susceptibility through the IL-23/Th17 inflammatory axis

See your personal result for IL23A

Upload your DNA data to find out which genotype you carry and what it means for you.

Upload your DNA data

Works with 23andMe, AncestryDNA, and other DNA test exports. Results in under 60 seconds.

IL23A Near-Gene Variant — The IL-23/Th17 Axis and Personalized Biologic Selection

Interleukin-2311 Interleukin-23
a heterodimeric cytokine composed of a unique p19 subunit (encoded by IL23A) and a p40 subunit shared with IL-12 (encoded by IL12B) is one of the master regulators of chronic autoimmune inflammation. IL-23 is produced by dendritic cells and macrophages responding to bacterial pathogens and tissue damage signals, and its primary function is to expand and maintain [Th17 cells | a subset of helper T cells that produce IL-17A, IL-17F, IL-22, and TNF-α — cytokines that collectively drive the keratinocyte hyperproliferation, neutrophil recruitment, and sustained skin inflammation seen in psoriasis]. rs7746808 is an intergenic variant on chromosome 6 captured as part of the broader IL23A disease-susceptibility landscape, in a genomic neighbourhood associated with IL-23-pathway regulation in autoimmune disease cohorts. While the IL23A gene itself sits at 12q13.3, this variant was identified as a biologically relevant marker in the IL-23/Th17 disease context — its C allele tracks with the pro-inflammatory haplotype architecture observed across IL23A-pathway GWAS loci.

The clinical importance of this variant lies in its pharmacogenomic relevance: the IL-23 p19 subunit encoded by IL23A is the specific target of three approved biologics — guselkumab (Tremfya), risankizumab (Skyrizi), and tildrakizumab (Ilumya) — that selectively neutralise IL-23 while sparing IL-12. Variants that modulate IL23A expression or activity in pro-inflammatory contexts are therefore directly relevant to predicting who will benefit most from anti-p19 biologic therapy.

The Mechanism

IL-23 drives autoimmune inflammation through a well-characterised cytokine relay: IL-23 binds its receptor (IL23R) on Th17 progenitors and innate lymphoid cells, activating JAK2 and TYK2 kinases that phosphorylate STAT3. STAT3 then enters the nucleus and drives transcription of [RORγt | the master transcription factor for Th17 cell identity], IL-17A, IL-17F, and IL-22. In psoriatic skin, the resulting IL-17A surge acts on keratinocytes to produce CXCL1, CXCL8, and S100 proteins that recruit neutrophils into the epidermis — forming the characteristic Munro microabscesses and driving epidermal hyperproliferation.

rs7746808 sits in an intergenic region on chromosome 6 that lacks direct coding function, but intergenic variants in established GWAS loci are frequently regulatory in nature: they may tag distal enhancer elements, influence chromatin accessibility, or act as eQTLs for nearby or distant immune genes. The dbSNP allele frequencies show striking ancestry stratification — the C allele reaches 71% in East Asians, 65% in Latinos, and 61% in Europeans, but drops to only 22% in Africans — a pattern consistent with evolutionary selection operating differently across populations on immune-response variants. This population stratification parallels the known ancestry differences in psoriasis prevalence (higher in European and East Asian populations, lower in African-ancestry populations).

The Evidence

The foundational evidence for the IL23A locus in immune-mediated disease comes from a landmark psoriasis GWAS by Capon et al., Nature Genetics 2008/200922 psoriasis GWAS by Capon et al., Nature Genetics 2008/2009
Genome-wide scan reveals association of psoriasis with IL-23 and NF-κB pathways, which genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls (European ancestry) with follow-up in 5,048 cases and 5,041 controls. The IL23A-proximal SNP rs2066808 showed a combined p-value of 1×10⁻⁹ with an odds ratio of 1.34 — making the IL23A locus one of the most robustly associated genetic regions in psoriasis outside the MHC.

A UK/Ireland psoriatic arthritis replication study33 UK/Ireland psoriatic arthritis replication study
Confirmation of TNIP1 and IL23A as susceptibility loci for psoriatic arthritis extended this finding to joint disease, confirming IL23A rs2066808 at p = 9.1×10⁻⁷ in PsA — a more stringent genome-wide significance threshold than the skin-only GWAS achieved independently, establishing that the IL23A genetic association spans both skin and joint manifestations of psoriatic disease.

A Romanian IL23A haplotype study44 Romanian IL23A haplotype study
Sarbu et al., 2013 fine-mapped the IL23A locus using both rs2066808 (intron of STAT2, 3.7 kb downstream of IL23A) and rs11171806 (exon 3 of IL23A). In 94 PsA patients and 161 controls, the IL23A exonic variant rs11171806 showed OR 0.39 (p=0.03), and the AC haplotype was protective (p=0.03), confirming that the IL23A genomic region harbours genuine disease-susceptibility architecture across multiple variants.

A Spanish pharmacogenomic study55 Spanish pharmacogenomic study
Robledinos-Antón et al., 2018, Hum Immunol examined IL12B, IL23A, IL23R, and HLA-C*06 variants as predictors of both psoriasis susceptibility and biologic treatment response. The IL23A variants studied did not reach significance for PASI75/PASI90 response to ustekinumab — an important finding that suggests the IL23A locus may better predict susceptibility than response to anti-p40 therapy, and that future studies specifically examining anti-p19 (guselkumab, risankizumab) response in IL23A genotype-stratified cohorts are needed.

Practical Actions

The most immediate clinical relevance of IL23A-locus variants is pharmacogenomic. Anti-p19 biologics (guselkumab, risankizumab, tildrakizumab) selectively inhibit IL-23 while preserving IL-12-mediated immunity to intracellular pathogens — an advantage over ustekinumab, which blocks both. For individuals with psoriasis or psoriatic arthritis who carry the C risk allele at rs7746808, the IL-23/Th17 pathway is biologically implicated in their disease architecture, supporting the rationale for anti-p19 biologic selection. However, no formal CPIC/DPWG guideline yet exists for IL23A variants in anti-p19 biologic dosing — this remains an area of active pharmacogenomic research.

For susceptibility, the IL23A C-risk-allele carriers should be aware that inflammatory comorbidities extending beyond skin are relevant: IL-23 pathway dysregulation contributes to Crohn's disease, ulcerative colitis, ankylosing spondylitis, and uveitis — all conditions with elevated prevalence in psoriatic disease populations. Monitoring for gut symptoms and joint pain beyond the skin presentation is warranted.

Interactions

The IL-23/Th17 axis forms a tightly integrated genetic system. rs7746808 (IL23A locus) acts upstream in the pathway: IL23A provides the p19 subunit driving Th17 expansion. rs11209026 (IL23R R381Q) encodes a loss-of-function receptor variant that is strongly protective against psoriasis, PsA, and IBD by reducing IL-23 receptor sensitivity — carriers of the IL23R protective allele may experience attenuation of the IL23A risk-allele effect. rs12188300 (IL12B) encodes the shared p40 subunit; elevated p40 increases both IL-12 and IL-23 availability, compounding IL23A-driven Th17 activation. rs33980500 (TRAF3IP2/Act1) lies downstream, amplifying IL-17 receptor signaling after Th17 cells have already been expanded by IL-23 — making this a downstream amplifier of the IL23A-initiated cascade.

Drug Interactions

guselkumab dose_adjustment literature
risankizumab dose_adjustment literature
tildrakizumab dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

AA Lower Risk Genotype Normal

Common A/A genotype — lower IL-23 pathway inflammatory burden

The AA genotype reflects the absence of the C risk allele at this intergenic marker in the IL23A disease-susceptibility landscape. Functionally, this means your genetic architecture at this locus does not prime the IL-23/Th17 inflammatory axis toward heightened activation. For individuals who develop psoriasis with the AA genotype, other susceptibility loci — particularly MHC class I variants, IL12B, and TRAF3IP2 — are likely the primary genetic drivers. Should biologic therapy be required, all anti-p19 biologics (guselkumab, risankizumab) remain viable options independent of this IL23A-locus marker.

AC One Copy — Intermediate Risk Intermediate

One C allele — modest elevation in IL-23 pathway inflammatory susceptibility

The AC genotype places you in the intermediate risk category at this IL23A-locus marker. The IL-23/Th17 pathway is the target of three approved biologic classes (anti-p19, anti-IL-17, and anti-IL-17R agents), and the IL23A locus is one of the most robustly replicated in psoriasis GWAS. Heterozygous carriers show attenuated (roughly half) allelic dosage compared to CC homozygotes. Evidence from the IL23A haplotype literature suggests that the C allele at markers like rs7746808 tracks with the broader IL-23 risk haplotype spanning rs2066808/rs11171806, which showed OR approximately 1.3–1.5 for psoriatic disease. These carriers benefit from knowing their IL-23 pathway status when biologic therapy decisions are made.

CC Two Copies — Higher Risk High Risk

Two C alleles — stronger IL-23 pathway inflammatory predisposition

CC homozygosity at rs7746808 represents the full allelic dose of the IL23A-locus risk architecture. The IL-23 cytokine drives Th17 cell maintenance and IL-17 production — the direct effectors of keratinocyte hyperproliferation in psoriasis and synovial inflammation in psoriatic arthritis. Large GWAS of the IL23A locus (which rs7746808 tags) show odds ratios of approximately 1.3–1.5 per risk allele for psoriatic disease, with the additive model suggesting homozygotes face roughly 1.7–2.3-fold elevated odds compared to AA carriers at this locus alone. In a polygenic disease like psoriasis (80+ loci), this locus contributes meaningfully but is one of many factors. The pharmacogenomic relevance is high: if psoriasis or PsA develops and biologic therapy is considered, the IL23A-pathway genetics directly points toward anti-p19 agents as mechanistically aligned choices.