rs12203592 — IRF4 T allele

IRF4 Enhancer Variant — Freckling, Sun Sensitivity, and Melanoma Risk

The rs12203592 variant sits in intron 4 of the IRF4 gene on chromosome 6, within a melanocyte-specific enhancer element that regulates IRF4 expression .

The T allele is most common in individuals of European descent and is not seen in sub-Saharan Africans or East Asians , making it one of the population-specific variants that emerged during human migration out of Africa. IRF4 (Interferon Regulatory Factor 4) is primarily known as an immune transcription factor, but

ENCODE data shows rs12203592 overlaps a peak of DNase I hypersensitivity in human primary melanocytes and melanoma lines , revealing its critical role in pigmentation biology ¹¹ Praetorius et al. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell, 2013.

The Mechanism

The rs12203592 variant affects enhancer-promoter chromatin looping: the enhancer physically interacts with the IRF4 promoter through an allele-dependent chromatin loop, and the T allele disrupts TFAP2A binding, reducing IRF4 transcription

²² Visser et al. Allele-specific transcriptional regulation of IRF4 in melanocytes. Hum Mol Genet, 2015.

TFAP2A and MITF cooperatively activate IRF4, with TFAP2A binding the ancestral C allele but not the T allele; melanocytes from individuals with TT genotype express considerably less IRF4 .

IRF4 in turn regulates tyrosinase (TYR), the rate-limiting enzyme in melanin synthesis, by binding MITF-flanked sites in the TYR promoter; when IRF4 is knocked down in melanocyte and melanoma cell lines, TYR expression likewise reduces . This creates a regulatory cascade: T allele → reduced TFAP2A binding → lower IRF4 expression → decreased tyrosinase → altered pigmentation phenotypes.

The Evidence

The pigmentation associations are among the strongest in human genetics.

In 95,085 Icelanders, rs12203592-T showed the strongest association in the IRF4 region with freckles (p=2.0×10⁻¹²⁰), brown hair, and high skin sun sensitivity

³³ Han et al. GWAS identifies novel alleles associated with hair color and skin pigmentation. PLoS Genet, 2008.

The T allele was associated with high nevus counts and high freckling in adolescents, but with low nevus counts and high freckling in adults, and increased counts of flat nevi but decreased counts of raised nevi

⁴⁴ Duffy et al. IRF4 variants have age-specific effects on nevus count and predispose to melanoma. Am J Hum Genet, 2010.

The melanoma associations are concerning.

In a pooled analysis of 3,673 melanoma patients from GEM and WAMHS studies, IRF4 rs12203592*T was associated with increased Breslow thickness (β=0.09, p=5.47×10⁻⁵), the most important prognostic indicator

⁵⁵ Gibbs et al. Functional melanoma-risk variant IRF4 rs12203592 associated with Breslow thickness. Br J Dermatol, 2017.

In 3,303 melanoma cases of European ancestry, each copy of the T allele significantly increased melanoma-specific death (HR 1.35, 95% CI 1.09–1.67, p=0.006) , with

70% of this association mediated through Breslow thickness

⁶⁶ Ward et al. Association of IRF4 SNP rs12203592 with melanoma-specific survival. Br J Dermatol, 2020.

In two independent European cohorts, the T allele increased the risk of dying from melanoma (Barcelona: OR 6.53, p=0.032; Essen: OR 1.68, p=0.035)

⁷⁷ Potrony et al. IRF4 rs12203592 functional variant and melanoma survival. Int J Cancer, 2017.

Practical Implications

If you carry one or two copies of the T allele, your melanocyte biology differs in ways that increase sun sensitivity and melanoma risk independent of your overall skin tone.

Melanomas in TT individuals are associated with increased Breslow thickness , meaning thicker, more advanced tumors at diagnosis. This is not simply about having fair skin — the association between rs12203592*T and Breslow thickness remained significant even after adjusting for number of nevi, hair color, eye color, and ability to tan . The T allele appears to affect melanoma biology directly, possibly through

IRF4's role in both melanocytes and immune cells .

Sun protection is non-negotiable. Use broad-spectrum SPF 30+ daily, reapply every two hours when outdoors, seek shade between 10am-4pm, and wear protective clothing. Establish a relationship with a dermatologist for annual full-body skin exams, more frequently if you have many moles or a family history of melanoma. Learn the ABCDE features of melanoma (Asymmetry, Border irregularity, Color variation, Diameter >6mm, Evolution/change) and perform monthly self-exams.

The "EFG" addition (Elevated, Firm, Growing for more than a month) may be particularly relevant for TT individuals whose melanomas present with increased thickness .

Interactions

This variant interacts with other pigmentation genes in complex ways. It clusters with MC1R variants (red hair/fair skin), SLC45A2 (light skin tone), HERC2/OCA2 (eye color), and ASIP (pigmentation) in determining overall sun sensitivity and melanoma risk. The combination of IRF4 rs12203592*T with MC1R red hair variants or SLC45A2 light skin variants creates compound sun sensitivity that exceeds either variant alone. These interactions affect not just baseline pigmentation but also dynamic responses to UV exposure — tanning ability, inflammatory response to sunburn, and the molecular pathways that lead from UV damage to malignant transformation. Compound implications for individuals carrying multiple high-risk pigmentation variants should address the multiplicative rather than additive nature of melanoma risk.