rs2546890 — LOC285626 LOC285626 rs2546890

Regulatory variant upstream of IL12B associated with increased risk of multiple sclerosis, psoriasis, and primary biliary cholangitis

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LOC285626 rs2546890 — IL12B Regulatory Variant and Multi-Disease Autoimmune Risk

The rs2546890 variant sits approximately 2,000 base pairs upstream of the IL12B gene11 IL12B gene
located at chromosome 5q33.3, encodes the p40 subunit shared by interleukin-12 and interleukin-23, within a non-coding RNA locus designated LOC285626. IL-12 and IL-23 are cytokines produced by dendritic cells and macrophages that act as master switches for adaptive immune responses: IL-12 drives naive T cells toward the Th1 (IFN-γ-producing) lineage, while IL-23 sustains the Th17 (IL-17-producing) lineage. Both arms are implicated in autoimmune demyelination, psoriatic inflammation, and immune-mediated liver disease. The rs2546890 A allele has been associated in large genome-wide studies with elevated risk of multiple sclerosis, psoriasis, and primary biliary cholangitis — three immunologically distinct diseases unified by shared IL-12/IL-23 pathway dysregulation.

The Mechanism

rs2546890 is annotated as a non-coding transcript variant in the LOC285626 locus. Its position in the IL12B upstream regulatory region places it within a genomic neighborhood that contains multiple independently replicated autoimmune susceptibility signals. The IL12B locus at 5q33.3 harbors several GWAS-identified variants (including rs6887695 in the upstream region and rs3212227 in the 3′ UTR) that form a risk haplotype functionally linked to elevated p40 subunit expression in monocytes and dendritic cells. Carriers of the IL12B risk haplotype show increased IL12B mRNA and protein in antigen-presenting cells, leading to higher serum IL-12 and a Th1-polarized immune milieu22 increased IL12B mRNA and protein in antigen-presenting cells, leading to higher serum IL-12 and a Th1-polarized immune milieu.

The Evidence

The association of rs2546890 with multiple sclerosis has been established across multiple large GWAS cohorts. The 2011 International MS Genetics Consortium (IMSGC) study33 2011 International MS Genetics Consortium (IMSGC) study
Sawcer et al., Nature 2011, PMID 21833088 analysed 9,772 MS cases and 16,849 controls of European ancestry across 23 research groups and identified the IL12B locus region among at least 29 novel susceptibility signals. The 2019 IMSGC genomic map44 2019 IMSGC genomic map
International MS Genetics Consortium, Science 2019, PMID 31604244 expanded this to 47,429 MS cases and 68,374 controls, confirming rs2546890 among 200 autosomal susceptibility variants, with an odds ratio of approximately 1.11 (p = 1×10⁻¹¹). An independent Italian cohort study Leone et al., PLOS ONE 2013, PMID 2378540155 Leone et al., PLOS ONE 2013, PMID 23785401 found that rs2546890 near IL12B was the only non-HLA variant significantly associated with cerebrospinal fluid oligoclonal bands — a biomarker of CNS-compartmentalised inflammation — in 925 Italian MS patients (OR 1.45, 95% CI 1.09–1.92).

For psoriasis, the IL12B locus is one of the most robustly replicated susceptibility signals. GWAS Catalog records for rs2546890 show associations at p = 1×10⁻²⁰ (OR 1.54, 95% CI 1.32–1.79) and p = 3×10⁻³⁵ (OR 1.39, 95% CI 1.32–1.47) across separate European cohorts. Pharmacogenomic studies link rs2546890 to biologic treatment response: Ovejero-Benito et al., Pharmacogenomics 2017, PMID 2847012766 Ovejero-Benito et al., Pharmacogenomics 2017, PMID 28470127 found association with etanercept response at 6 months (n=68), and the same group Pharmacogenomics 2018, PMID 2919255277 Pharmacogenomics 2018, PMID 29192552 found that rs2546890 was among five SNPs associated with PASI75 response to adalimumab or infliximab at 3 months (n=95). For primary biliary cholangitis, an international GWAS meta-analysis Cordell et al., 2015, PMID 2639426988 Cordell et al., 2015, PMID 26394269 identified the locus. The convergence of three immunologically distinct conditions on the same variant underscores its role as a broad immune-regulatory signal rather than a disease-specific variant.

Practical Actions

For individuals carrying one or two A alleles, the primary actionable implications are: (1) heightened monitoring for early signs of MS, psoriasis, and autoimmune liver disease; (2) awareness of the pharmacogenomic relevance to IL-12/IL-23 pathway-targeting biologics.

Interactions

The IL23R rs11209026 (R381Q) loss-of-function variant provides strong protection against MS, psoriasis, IBD, and ankylosing spondylitis by reducing IL-23 receptor signaling downstream of the p40-containing IL-23 heterodimer.

Drug Interactions

ustekinumab altered_response literature
etanercept altered_response literature
adalimumab altered_response literature
infliximab altered_response literature

Genotype Interpretations

What each possible genotype means for this variant.

GG Protective Genotype Normal

Two protective G alleles — lowest genetic risk from this IL12B regulatory variant

Note that autoimmune conditions such as MS and psoriasis are highly polygenic — this variant is one of many contributing loci — so GG status at rs2546890 does not eliminate risk from the overall polygenic background.

AG Intermediate Risk Intermediate

One A risk allele — modestly elevated autoimmune risk from IL12B regulatory region

The pharmacogenomic angle is relevant: IL12B genotype is associated with response to etanercept (anti-TNF), adalimumab, and infliximab in psoriasis — share this result with your dermatologist if biologic therapy is considered.

AA Elevated Risk High Risk

Two copies of the A risk allele — highest genetic risk from this IL12B regulatory variant

The p40 subunit is shared by IL-12 and IL-23 — the cytokines that respectively drive Th1 (IFN-γ-mediated, relevant to MS demyelination and PBC) and Th17 (IL-17-mediated, relevant to psoriatic skin and joint disease) immune responses. The 2019 IMSGC study (47,429 MS cases) confirmed the IL12B locus among 200 autosomal susceptibility variants. For psoriasis, the association reaches p = 3×10⁻³⁵ in pooled GWAS data.

Pharmacogenomically, this is the most clinically relevant genotype: studies in psoriasis show that IL12B genotype predicts response to etanercept, adalimumab, and infliximab. Share this result with any specialist considering biologic therapy for an autoimmune condition.