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 examinationwas 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.AGWAS forAK severitywas 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, P<inf>combined</inf>=6.5×10^-13 and MC1R, rs139810560, P<inf>combined</inf>=4.1×10^-9). Further, in an analysis of ten additionalwell-known human pigmentation genes, TYR also showed significant associationwith AK (rs1393350, P=5.3×10^-4) after correction formultiple 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.

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