rs7746808 — IL23A

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.