rs10045431 — IL12B

Upstream tagging SNP at the IL12B locus; the C allele is associated with increased susceptibility to psoriasis and other IL-12/IL-23-mediated autoimmune conditions

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IL12B Upstream — Th1/Th17 Risk at the IL-12p40 Locus

The IL12B gene11 IL12B gene
located at chromosome 5q33.3, encodes the 40-kDa p40 subunit shared by interleukin-12 and interleukin-23. This shared subunit means genetic variation at IL12B influences both cytokine axes simultaneously: IL-12 (p40 + p35) drives Th1 differentiation and IFN-γ production, while IL-23 (p40 + p19) sustains Th17 expansion and IL-17 production. Both arms converge on inflammatory skin disease, gut inflammation, and joint inflammation. rs10045431 lies approximately 57 kb upstream of IL12B and is associated with increased risk for psoriasis (OR ~1.41), and other Th1/Th17-mediated autoimmune conditions22 increased risk for psoriasis (OR ~1.41), and other Th1/Th17-mediated autoimmune conditions
Capon et al. identified rs10045431 specifically as an independent signal from rs3212227 in the IL12B locus.

The Evidence

The initial identification of rs10045431 as an independent IL12B psoriasis-risk SNP came from Capon et al. 200733 Capon et al. 2007
Sequence variants in IL23R and IL12B confer protection against psoriasis; rs10045431 OR 1.41, p=0.0001 in North American + UK cohorts. A 2021 meta-analysis Wang et al. 202144 Wang et al. 2021 confirmed that rs10045431 significantly increased risk in UC.

The additive effect size at this locus is modest, consistent with a polygenic susceptibility variant rather than a Mendelian cause. Over 80 loci contribute to psoriasis susceptibility; rs10045431 represents one component of the IL12B contribution, with independent signals from rs3212227 (3′ UTR) and rs6887695 (upstream regulatory).

Practical Actions

For carriers who have not yet developed disease, awareness of the IL12B locus's breadth of associations is valuable: this variant is part of the shared genetic architecture underlying psoriasis, psoriatic arthritis, ulcerative colitis, and ankylosing spondylitis — all of which share Th1/Th17 inflammatory pathophysiology and respond to the same class of biologics.

Interactions

rs11209026 (IL23R R381Q) encodes a loss-of-function receptor variant strongly protective against psoriasis and IBD by dampening IL-23 signaling. rs12188300 is another IL12B near-gene variant with partially overlapping psoriasis associations; individuals carrying risk alleles at both SNPs may have compounded susceptibility via independent regulatory mechanisms at the same locus.

Drug Interactions

ustekinumab altered_response literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Standard Risk Normal

Common IL12B genotype — typical Th1/Th17 background and population-average autoimmune susceptibility

The CC genotype at rs10045431 represents the population-common configuration of the IL12B upstream regulatory region.

AC One Risk Allele Intermediate

One copy of the IL12B risk variant — modestly elevated psoriasis susceptibility

You carry one copy of the C risk allele and one copy of the protective A allele at rs10045431. This genotype is present in approximately 41% of individuals of European descent. The C allele is associated with modestly increased susceptibility to psoriasis (OR ~1.41 per allele, Capon 2007).

AA Protective Variant Decreased

Two copies of the minor IL12B allele — reduced Th1/Th17 drive and lower susceptibility to IL-12/IL-23-mediated conditions

The AA genotype at rs10045431 means you carry two copies of the protective minor allele. The protective A allele effect at rs10045431 represents roughly a mirror image of the C risk effect: per-allele OR for psoriasis protection is approximately the inverse of the C allele's OR (~1/1.41 ≈ 0.71 protective effect).

While this confers reduced susceptibility, it is not absolute protection — psoriasis and ankylosing spondylitis are polygenic, and the IL12B locus is one of many contributors.