IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color.
Actinic keratosis (AK) is a pre-malignant skin disease, highly prevalent in elderly Europeans. This study investigates genetic susceptibility to AK with a genome-wide association study (GWAS). A full body skin examination was performed in 3194 elderly individuals from the Rotterdam Study (RS) of exclusive north-western European origin (aged 51-99 years, 45% male). Physicians graded the number of AK into four severity levels: none (76%), 1-3 (14%), 4-9 (6%) and ≥10 (5%), and skin color was quantified using a spectrophotometer on sun-unexposed skin. A GWAS for AK severity was conducted, where promising signals at IRF4 and MC1R (P < 4.2 × 10(-7)) were successfully replicated in an additional cohort of 623 RS individuals (IRF4, rs12203592, Pcombined = 6.5 × 10(-13) and MC1R, rs139810560, Pcombined = 4.1 × 10(-9)). Further, in an analysis of ten additional well-known human pigmentation genes, TYR also showed significant association with AK (rs1393350, P = 5.3 × 10(-4)) after correction for multiple testing. Interestingly, the strength and significance of above-mentioned associations retained largely the same level after skin color adjustment. Overall, our data strongly suggest that IRF4, MC1R and TYR genes likely have pleiotropic effects, a combination of pigmentation and oncogenic functions, resulting in an increased risk of AK.
Department of Dermatology.
Leonie C
LC
Jacobs
Department of Forensic Molecular Biology.
Fan
F
Liu
Department of Dermatology.
Luba M
LM
Pardo
Department of Epidemiology and.
Albert
A
Hofman
Department of Epidemiology and Department of Internal Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
André G
AG
Uitterlinden
Department of Forensic Molecular Biology.
Manfred
M
Kayser
Department of Dermatology t.nijsten@erasmusmc.nl.
Tamar
T
Nijsten
D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D055623:Keratosis, Actinic / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D012307:Risk Factors; D012880:Skin Pigmentation; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D014442:Monophenol Monooxygenase; D044102:Receptor, Melanocortin, Type 1; D000099218:Interferon Regulatory Factor-4