rs324013 — STAT6

Promoter variant in STAT6 that alters transcription factor binding; the T allele is associated with reduced IFN-γ production in response to herpes simplex virus, forming a 6.87-kb haplotype with rs167769 that confers a 3.3-fold increased risk of eczema herpeticum in atopic dermatitis patients

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STAT6 rs324013 — The Promoter Switch That Silences Your Antiviral Guard

STAT6 (Signal Transducer and Activator of Transcription 6)11 STAT6 (Signal Transducer and Activator of Transcription 6)
The central transcription factor activated by IL-4 and IL-13 signaling; when phosphorylated, it dimerizes, enters the nucleus, and switches on genes for IgE production, eosinophil recruitment, and Th2 cell differentiation — the molecular signature of allergic disease orchestrates the body's allergy response from a strategic position in the immune signaling hierarchy. The rs324013 variant sits in the promoter region of the STAT6 gene on chromosome 12q13 — approximately 7 kilobases upstream of the well-studied intron 2 variants rs167769 and rs324011. Where those intronic variants alter an NF-κB binding site and upregulate STAT6 transcription, rs324013 influences a separate regulatory element.

The Mechanism

The STAT6 promoter is the master on/off switch for Th2 immune programming. Variants in this region change transcription factor binding affinity at the promoter. He et al. 200822 He et al. 2008
Genes & Immunity; electrophoretic mobility shift assay (EMSA) in PHA-stimulated PBMCs showed differential transcription factor binding between the C and T alleles at rs324013, confirming functional regulatory activity at this locus.

The T allele's most clinically significant consequence is suppression of IFN-γ (interferon gamma33 interferon gamma
the primary antiviral cytokine produced by Th1 cells and NK cells; IFN-γ activates macrophages and dendritic cells to clear viral infections and suppresses Th2 polarization — its reduction tilts the immune balance toward allergic over antiviral responses) production in response to herpes simplex virus exposure. When the rs167769-C allele and rs324013-T allele occur on the same chromosome — forming the 6.87-kb "CT haplotype" in the STAT6 promoter region — the result is underproducing the IFN-γ needed to suppress HSV replication in the skin.

The Evidence

The primary evidence for rs324013's clinical significance comes from a 2011 study by Howell et al.44 Howell et al.
J Allergy Clin Immunol 2011; 278 white atopic dermatitis patients from the ADVN consortium; 10 STAT6 SNPs genotyped across the 12q13 locus investigating why some patients with atopic dermatitis (AD) develop disseminated HSV skin infections — eczema herpeticum (EH) — while others do not. The rs167769-C / rs324013-T two-SNP haplotype spanning the STAT6 promoter region was present in 24.9% of ADEH+ patients but only 9.2% of ADEH− controls (OR 3.33, 95% CI 1.39–8.55, P = 5.17×10⁻⁶). Carriers of the T allele at rs324013 showed significantly reduced IFN-γ production when their peripheral blood mononuclear cells were stimulated with HSV.

A parallel strand of evidence comes from immune defense against parasitic infection. He et al. 200855 He et al. 2008
Genes Immun; 841 subjects in two Mali villages with endemic Schistosoma haematobium; rs324013 associated with higher infection burden (P=0.04); additive interaction with IL13 promoter SNP rs1800925 (P=0.011) found that C/T heterozygotes at rs324013 carried higher parasite loads than CC or TT homozygotes. The EMSA data from this study confirm that both alleles bind transcription factors differently, consistent with a functional regulatory role.

The broader STAT6 promoter-region haplotype block provides strong contextual support. Weidinger et al. 200466 Weidinger et al. 2004
J Med Genet; 1,407 German adults; STAT6 risk haplotype OR 1.7 for IgE ≥100 kU/L and OR 2.54 for 90th-percentile IgE established that variants in this region collectively drive elevated serum IgE.

Practical Actions

Carriers of the T allele — particularly TT homozygotes — face a blunted IFN-γ response to herpes simplex virus. For atopic dermatitis patients, this translates to heightened vigilance for early HSV skin involvement and awareness of triggers that simultaneously suppress antiviral immunity (topical corticosteroids, calcineurin inhibitors applied during active flares).

Interactions

rs324013 operates within a 6.87-kb STAT6 promoter haplotype block that also contains rs167769 (intron 2). The two-SNP haplotype rs167769-C / rs324013-T is the primary risk unit for eczema herpeticum. Both variants are in linkage disequilibrium with rs324011, the best-characterized STAT6 regulatory SNP that creates a functional NF-κB binding site. Separately, rs324013 shows an additive interaction with the IL13 promoter variant rs1800925.

Drug Interactions

dupilumab dose_adjustment literature

Genotype Interpretations

What each possible genotype means for this variant.

CC Normal

Standard STAT6 promoter — balanced Th1/Th2 immune activity

You carry two copies of the reference C allele at the STAT6 promoter, the most common configuration in European populations (approximately 26% of people are CC). Your IFN-γ responses to herpes simplex virus are not suppressed by the rs324013/rs167769 haplotype.

CT Intermediate

One T allele — moderately elevated Th2 tone and reduced antiviral IFN-γ

The rs324013 T allele suppresses IFN-γ (interferon gamma) production in response to herpes simplex virus stimulation. IFN-γ is the primary cytokine that activates macrophages and dendritic cells to clear viral infections and that suppresses Th2 polarization. When IFN-γ is reduced, HSV replicates more efficiently in skin.

TT High Risk

Two T alleles — elevated Th2 drive and suppressed antiviral IFN-γ response

The IFN-γ suppression is the clinically underappreciated risk. IFN-γ normally acts as the Th2 "brake" — it inhibits IL-4-driven STAT6 phosphorylation and competes with Th2 differentiation at the T-cell level. When IFN-γ production falls in response to viral challenge, the immune system loses this brake precisely when Th2 suppression is most needed, allowing herpes simplex virus to replicate in already-inflamed skin. This mechanism is supported by ex vivo PBMC data showing reduced IFN-γ production in T allele carriers after HSV stimulation.