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Multicenter Study
. 2010 Jul 9;87(1):6-16.
doi: 10.1016/j.ajhg.2010.05.017. Epub 2010 Jun 17.

IRF4 variants have age-specific effects on nevus count and predispose to melanoma

David L Duffy  1 , Mark M Iles, Dan Glass, Gu Zhu, Jennifer H Barrett, Veronica Höiom, Zhen Z Zhao, Richard A Sturm, Nicole Soranzo, Chris Hammond, Marina Kvaskoff, David C Whiteman, Massimo Mangino, Johan Hansson, Julia A Newton-Bishop; GenoMEL; Veronique Bataille, Nicholas K Hayward, Nicholas G Martin, D Timothy Bishop, Timothy D Spector, Grant W Montgomery
Affiliations
Multicenter Study

IRF4 variants have age-specific effects on nevus count and predispose to melanoma

David L Duffy et al. Am J Hum Genet. .

Abstract

High melanocytic nevus count is a strong predictor of melanoma risk. A GWAS of nevus count in Australian adolescent twins identified an association of nevus count with the interferon regulatory factor 4 gene (IRF4 [p = 6 x 10(-9)]). There was a strong genotype-by-age interaction, which was replicated in independent UK samples of adolescents and adults. The rs12203592(*)T allele was associated with high nevus counts and high freckling scores in adolescents, but with low nevus counts and high freckling scores in adults. The rs12203592(*)T increased counts of flat (compound and junctional) nevi in Australian adolescent twins, but decreased counts of raised (intradermal) nevi. In combined analysis of melanoma case-control data from Australia, the UK, and Sweden, the rs12203592(*)C allele was associated with melanoma (odds ratio [OR] 1.15, p = 4 x 10(-3)), most significantly on the trunk (OR = 1.33, p = 2.5 x 10(-5)). The melanoma association was corroborated in a GWAS performed by the GenoMEL consortium for an adjacent SNP, rs872071 (rs872071(*)T: OR 1.14, p = 0.0035; excluding Australian, the UK, and Swedish samples typed at rs12203592: OR 1.08, p = 0.08).

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Figures

Figure 1
Figure 1
Manhattan Plot of GWAS p Values for Counts of All Moles, Macular Moles, and Papular Moles Dark points represent results for directly measured SNP genotypes, lighter points represent those for imputed SNP genotypes. The lower line represents results from linkage analysis of the same data set.
Figure 2
Figure 2
Nevus Counts versus Age and IRF4 Genotype Lines represent cubic-polynomial-smoothed predictions from the best-fitting linear model (dotted lines are 95% confidence intervals). The three sets of lines represent Australian adolescent twins (BTNS), combined data from the UK control populations, and UK melanoma cases. Likelihood-ratio tests showed that the three UK control groups could be combined (p = 0.94).
Figure 3
Figure 3
Adolescent Macular and Papular Mole Counts versus rs12203592 Genotype, Stratified on the Four Levels of Freckling Score The association between papular counts and genotype is highly statistically significant in all cells except the first (no freckling).
Figure 4
Figure 4
Self-Reported Mole Scores in Queensland Melanoma Cases versus Age and Genotype at rs12203592 in IRF4 Bar shading represents the proportion reporting each of the four possible responses, from “none” (no shading) to “very many” (solid shading). Differences between genotypes are highly significant (see Table S1).
Figure 5
Figure 5
Combined Analysis of Melanoma Case-Control Data from Australia, the UK, and Sweden for rs12203592 by Tumor Site, Showing the Strongest Association with Melanoma on the Trunk: OR = 1.32, p = 2.5 × 10−5
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