Genetically predicted TWEAK mediates the association between lipidome and Keratinocyte Carcinomas

BackgroundReports suggest that lipid profiles may be linked to the likelihood of developing skin cancer, yet the exact causal relationship is still unknown.ObjectiveThis study aimed to examine the connection between lipidome and skin cancers, as well as investigate any possible mediators.MethodsA two-sample Mendelian randomization (MR) analysis was conducted on 179 lipidomes and each skin cancer based on a genome-wide association study (GWAS), including melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma (SCC). Then, Bayesian weighted MR was performed to verify the analysis results of two-sample MR. Moreover, a two-step MR was employed to investigate the impact of TNF-like weak inducer of apoptosis (TWEAK)-mediated lipidome on skin cancer rates.ResultsMR analysis identified higher genetically predicted phosphatidylcholine (PC) (17:0_18:2) could reduce the risk of skin tumors, including BCC (OR = 0.9149, 95% CI: 0.8667-0.9658), SCC (OR = 0.9343, 95% CI: 0.9087-0.9606) and melanoma (OR = 0.9982, 95% CI: 0.9966-0.9997). The proportion of PC (17:0_18:2) predicted by TWEAK-mediated genetic prediction was 6.6 % in BCC and 7.6% in SCC. The causal relationship between PC (17:0_18:2) and melanoma was not mediated by TWEAK.ConclusionThis study identified a negative causal relationship between PC (17:0_18:2) and keratinocyte carcinomas, a small part of which was mediated by TWEAK, and most of the remaining mediating factors are still unclear. Further research on other risk factors is needed in the future.