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Interferon regulatory factor 4 gene

Authors: Dr Jenna E. Rayner, Dermatology Registrar; Dr David L. Duffy, Statistical Geneticist; Dr Richard A. Sturm, Principal Research Fellow, Dermatology Research Centre, University of Queensland Diamantina Institute, University of Queensland, Brisbane, Queensland, Australia. DermNet NZ Editor in Chief: Adjunct A/Prof Amanda Oakley, Dermatologist, Hamilton, New Zealand. Copy edited by Gus Mitchell. January 2020.


Introduction

The physical features of hair, skin, and eye colour, freckling, melanocytic naevi and the skin’s response to the sun are influenced by major gene polymorphisms.

Sun exposure stimulates tanning, where melanocytes produce the biopolymer melanin and transfer it to keratinocytes.

What is the IRF4 gene?

The interferon regulatory factor 4 (IRF4) gene belongs to a family of DNA-binding proteins that play an important role in immune system development and function [1].

IRF4 polymorphisms have been independently associated with pigmentation and age-specific effects on melanocytic naevus count in European-derived populations [2,3].

A single nucleotide polymorphism (SNP) within intron 4 of IRF4, rs12203592*C/T, plays a major role in pigmentation.

IRF4 is one of only 2 genes, along with tyrosinase (TYR), known to affect the skin, eye, hair, and together with the melanocortin 1 receptor (MC1R), freckling. IRF4 independently affects total body naevus counts [4].

IRF4 is predominantly expressed in blood cells with key roles in lymphoid, myeloid and dendritic cell lineages and adipocytes. IRF4 is also expressed in melanocytes in naevi and primary melanomas [5,6].

What are the variants of IRF4?

Asian and African populations are fixed for the ancestral rs12203592*C allele, being monomorphic. In European populations, the rs12203592*T allele is found at around 17% allele frequency. This allele frequency is 40% in Ireland.

What are the IRF4-related phenotypes?

The rs12203592*T allele was statistically and significantly associated with dark hair colour, light eye colour, and decreased ability to tan [2,3,7]. Figure 1 shows the frequency of this phenotype by rs12203592 genotype in 1200 individuals from South-east Queensland. Figure 2, 3 and 4 demonstrate the blue eye and freckling phenotype of IRF4 rs12203592*T/T patients. IRF4 has also been one of the few genes linked to hair greying [8].

Phenotype of individuals

A strong genotype-by-age interaction for total body naevus count has also been reported for this SNP, which is also a predictor of melanoma risk (Table 1). Compared to rs12203592*C/C or C/T carriers, homozygous T/T individuals have higher naevus counts as adolescents, which reverses with age so that adults have lower naevus counts. The rs12203592*T allele was also associated with decreased counts of raised (papular and dermal) melanocytic naevi and increased counts of flat (compound and junctional) naevi [3].

The Study of Nevi in Children (SONIC) identified five significant associations (p < 0.005) between IRF4 rs12203592 variants and the clinical appearance of naevi. SNPs in IRF4 showed significant associations with globular patterns [9]. The IRF4 rs12203952 polymorphism was very strongly associated with naevus counts (p < 0.0001). T alleles, compared with C, are linked to increased naevus counts at any level of sun exposure.

What are the clinical features of IRF4 variants?

Table 1: Clinicopathologic features and IRF4 phenotype associations

IRF4 rs12203592*C= 83% IRF4 rs12203592*T =17%
Low adolescent naevus count a, e, f High adolescent naevus count a, e, f
High adult naevus count a, e, f Low adult naevus count a, e, f
Darker skin colour b Lighter skin colour b
Brown/dark eye colour b Blue/light eye colour b, g
Better tanning b Reduced tanning b
Melanoma naevus remnant b Melanoma solar elastosis b
Melanoma with lower Breslow thickness c Melanoma with greater Breslow thickness c
Increased survival in melanoma d Reduced survival in melanoma d
Lower incidence of nodular melanoma h Higher incidence of nodular melanoma h

Table 1: rs12203592*T carriers have a reduced number of naevi with age, a fairer phenotype and an increased melanoma Breslow thickness with localised chronic UV solar damage.

a (Duffy et al. 2010) [3], b (Gibbs et al. 2016) [7], c (Gibbs et al. 2017) [10], d (Potrony et al. 2017) [11], e (Kvaskoff et al. 2011) [12], f (Orlow et al. 2015) [9], g (Pena-Chilet et al. 2013) [13], h (Rayer et al. 2019) [16]

How are IRF4 variants diagnosed?

Genetic testing for IRF4 variants is most often undertaken for research purposes and forensic analysis of DNA samples [14]. As of 2019, the entire coding region is assessed on an Illumina Infinium HumanCoreExome-24 Microarray or through a bi-directional Sanger sequence analysis of intron 4.

Does IRF4 status affect patient management?

People likely to carry IRF4 rs12203592*T variants have a phenotype which demonstrates high adolescent naevus count, lighter skin and eye colour, and a reduced ability to tan. These patients’ melanomas are frequently associated with solar elastosis, increased Breslow thickness (Figure 3), and reduced survival in melanoma.

Sun protection includes wearing sun-protective clothing when outdoors, applying sunscreen at regular intervals, and avoiding intense or frequent sunburn.

People carrying the IRF4 variant gene should be advised to arrange skin checks by a trained health professional. Self skin examination education should emphasise lesions that are enlarging or changing in colour, shape and structure. Awareness of the ABCDE features of melanoma can be useful; these features are:

  • Asymmetry
  • Border irregularity
  • Colour variation
  • Diameter > 6 mm (large size)
  • Evolution (change).

The proposed addition of “EFG” (Elevated, Firm and Growing for more than a month) to the ABCD acronym aids clinical assessment of lesions. This may be particularly relevant for patients with an IRF4 rs12203592*T/T genotype, whose melanomas are associated with an increased Breslow thickness [15].

See smartphone apps to check your skin.
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Related information

 

References

  1. Paun A, Pitha PM. The IRF family, revisited. Biochimie 2007; 89: 744–53. PubMed Central
  2. Han J, Qureshi AA, Nan H, Zhang J, Song Y, Guo Q, et al. A germline variant in the interferon regulatory factor 4 gene as a novel skin cancer risk locus. Cancer Res 2011; 71: 1533–9. PubMed Central
  3. Duffy DL, Iles MM, Glass D, Zhu G, Barrett JH, Hoiom V, et al. IRF4 variants have age-specific effects on nevus count and predispose to melanoma. Am J Hum Genet 2010; 87: 6–16. PubMed Central
  4. Ainger SA, Jagirdar K, Lee KJ, Soyer HP, Sturm RA. Skin Pigmentation Genetics for the Clinic. Dermatology 2017; 233: 1–15. PubMed
  5. Praetorius C, Grill C, Stacey SN, Metcalf AM, Gorkin DU, Robinson KC, et al. A polymorphism in IRF4 affects human pigmentation through a tyrosinase-dependent MITF/TFAP2A pathway. Cell 2013; 155: 1022–33. PubMed Central 
  6. Chhabra Y, Yong HXL, Fane ME, Soogrim A, Lim W, Mahiuddin DN, et al. Genetic variation in IRF4 expression modulates growth characteristics, tyrosinase expression and interferon-gamma response in melanocytic cells. Pigment Cell Melanoma Res 2018; 31: 51–63. PubMed
  7. Gibbs DC, Orlow I, Bramson JI, Kanetsky PA, Luo L, Kricker A, et al. Association of Interferon Regulatory Factor-4 Polymorphism rs12203592 With Divergent Melanoma Pathways. J Natl Cancer Inst 2016; 108: djw004. PubMed Central
  8. Adhikari K, Fontanil T, Cal S, Mendoza-Revilla J, Fuentes-Guajardo M, Chacon-Duque JC, et al. A genome-wide association scan in admixed Latin Americans identifies loci influencing facial and scalp hair features. Nat Commun 2016; 7: 10815. PubMed Central
  9. Orlow I, Satagopan JM, Berwick M, Enriquez HL, White KA, Cheung K, et al. Genetic factors associated with naevus count and dermoscopic patterns: preliminary results from the Study of Nevi in Children (SONIC). Br J Dermatol 2015; 172: 1081–9. PubMed Central
  10. Gibbs DC, Ward SV, Orlow I, Cadby G, Kanetsky PA, Luo L, et al. Functional melanoma-risk variant IRF4 rs12203592 associated with Breslow thickness: a pooled international study of primary melanomas. Br J Dermatol 2017; 177: e180–e2. PubMed Central
  11. Potrony M, Rebollo-Morell A, Gimenez-Xavier P, Zimmer L, Puig-Butille JA, Tell-Marti G, et al. IRF4 rs12203592 functional variant and melanoma survival. Int J Cancer 2017; 140: 1845–9. PubMed Central
  12. Kvaskoff M, Whiteman DC, Zhao ZZ, Montgomery GW, Martin NG, Hayward NK, et al. Polymorphisms in Nevus-Associated Genes MTAP, PLA2G6, and IRF4 and the Risk of Invasive Cutaneous Melanoma. Twin Res Hum Genet 2011; 14: 422–32. PubMed Central
  13. Pena-Chilet M, Blanquer-Maceiras M, Ibarrola-Villava M, Martinez-Cadenas C, Martin-Gonzalez M, Gomez-Fernandez C, et al. Genetic variants in PARP1 (rs3219090) and IRF4 (rs12203592) genes associated with melanoma susceptibility in a Spanish population. BMC Cancer 2013; 13: 160. PubMed Central
  14. Walsh S, Chaitanya L, Breslin K, Muralidharan C, Bronikowska A, Pospiech E, et al. Global skin colour prediction from DNA. Hum Genet 2017; 136: 847–63. PubMed Central
  15. Kelly JW, Chamberlain AJ, Staples MP, McAvoy B. Nodular melanoma. No longer as simple as ABC. Aust Fam Physician 2003; 32: 706–9. PubMed
  16. Rayner JE, McMeniman EK, Duffy DL, De'Ambrosis B, et al. IRF4 rs12203592*T/T genotype is associated with nodular melanoma. Melanoma Res. 2019 Aug;29(4):445-446. doi: 10.1097/CMR.0000000000000596. PubMed.

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