Abstract
Actinic keratosis (AK) is a keratinocyte-derived precancerous lesion that arises on skin exposed to chronic ultraviolet radiation. AK is highly prevalent, afflicting >58 million Americans, and its treatment costs are estimated at >$1 billion per year. AK can progress to keratinocyte carcinoma, including cutaneous squamous cell carcinoma (cSCC). Genetic risk has been implicated in AK, as evidenced by a genome-wide association study (GWAS), which identified 3 susceptibility loci (IRF4, TYR, and MC1R) among Europeans. To identify additional AK-associated loci, we performed a GWAS in non-Hispanic white participants of the Kaiser Permanente Genetic Epidemiology Research on Adult Health and Aging cohort. Participants with a physician-rendered diagnosis of AK were classified as cases (n=16,251), and the non-cases (n=46,454) were assigned to the control group. Genome-wide genotype data were generated on the Affymetrix Axiom European array and imputed to the 1000 Genomes reference panel. Genetic association analysis with AK was performed using logistic regression adjusted for age, sex, and ancestry principal components, and we identified ten genome-wide significant loci for AK (P<5×10-8), including 8 novel loci. Identified loci are implicated in the pigmentation pathway (IRF4, TYR, SLC45A2, BNC2, and HERC2), the Notch signaling pathway (FOXP1), the TGF-ß pathway (SPIRE2), immune regulation (HLA), coactivating receptors including retinoid and vitamin D receptors (NCOA6), and an additional locus DLGAP4 whose biologic relevance to AK risk is currently unknown. Interestingly, some of our AK-associated loci have been previously reported to be cSCC-associated loci (IRF4, TYR, SLC45A2, BNC2, HERC2, FOXP1, and HLA), suggesting common biological pathways in keratinocyte carcinogenesis. Study findings provide new insight into the genetic basis of AK susceptibility and may help identify subjects at higher risk for developing AK and cSCC. Further studies replicating our findings in an independent cohort are needed.
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