IRF4 variants have age-specific effects on nevus count and predispose to melanoma.
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).
Duffy
David L
DL
Queensland Institute of Medical Research, Brisbane 4029, Australia.
Iles
Mark M
MM
Glass
Dan
D
Zhu
Gu
G
Barrett
Jennifer H
JH
Höiom
Veronica
V
Zhao
Zhen Z
ZZ
Sturm
Richard A
RA
Soranzo
Nicole
N
Hammond
Chris
C
Kvaskoff
Marina
M
Whiteman
David C
DC
Mangino
Massimo
M
Hansson
Johan
J
Newton-Bishop
Julia A
JA
Bataille
Veronique
V
Hayward
Nicholas K
NK
Martin
Nicholas G
NG
Bishop
D Timothy
DT
Spector
Timothy D
TD
Montgomery
Grant W
GW
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D002648:Child; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D009506:Nevus / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000235:genetics*; D055815:Young Adult; D000099218:Interferon Regulatory Factor-4
D019941:Cyclin-Dependent Kinase Inhibitor p16; D050835:Interferon Regulatory Factors; D000099218:Interferon Regulatory Factor-4