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<sup>-7</sup>)were successfully replicated in an additional cohort of 623 RS individuals (IRF4, rs12203592, P<inf>combined</inf>=6.5×10<sup>-13</sup> and MC1R, rs139810560, P<inf>combined</inf>=4.1×10<sup>-9</sup>). Further, in an analysis of ten additionalwell-known human pigmentation genes, TYR also showed significant associationwith AK (rs1393350, P=5.3×10<sup>-4</sup>) 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.,
Human Molecular Genetics
Centre for Rotterdam Cultural Sociology (CROCUS)

Jacobs, L., Liu, F., Pardo Cortes, L., Hofman, A., Uitterlinden, A., Kayser, M., & Nijsten, T. (2014). IRF4, MC1R and TYR genes are risk factors for actinic keratosis independent of skin color. Human Molecular Genetics, 24(11), 3296–3303. doi:10.1093/hmg/ddv076