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This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers (NMSC). We aim to identify circulating proteins causally linked to MM and NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimate the impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identified proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identified proteins and existing cancer medication targets. The MR analysis has identified associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Specifically, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identified as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers. This study suggests that the circulating proteins ASIP, KRT5, CTSS, and TNFSF8 are causally associated with melanoma and non-melanoma skin cancer-related traits through a multicenter Mendelian randomization. [ABSTRACT FROM AUTHOR]

Objective: Several studies demonstrated potential associations between the telomere length (TL) in leukocytes and psoriasis or psoriatic arthritis (PsA). This study aimed to investigate whether there was the causal genetic relationship between TL and psoriatic diseases bidirectionally., Methods: Two-sample univariable MR (UVMR) analysis was applied to explore the bidirectional causal association of TL with overall psoriasis, psoriasis vulgaris (PV) and PsA. Multivariable MR (MVMR) and the mediation effects analysis were applied to test whether the bidirectional associations between TLs and psoriasis were mediated by body mass index (BMI), alcohol, and smoking status., Results: According to the UVMR results, a negative causal impact of TL on the risk of overall psoriasis was found (OR = 0.775; 95% CI: 0.646-0.931; P = 6.36 × 10-3), and a similar trend was observed in the reversed direction for psoriasis-TL (IVW-β = -0.0097; 95% CI: -0.0170 to -0.0024; P = 9.12 × 10-3). There were also negative genetic associations between TL and PV bidirectionally. The independent association of genetically predicted TL and overall psoriasis persisted in the MVMR results controlled for BMI, smoking, and alcohol consumption (ORMVMR = 0.736; 95% CI: 0.597 to 0.907; P = 0.004). An independent significant association of genetic predisposition to PsA with TL was also found (βMVMR = 0.006; 95% CI: 0.001 to 0.012; P = 0.033). The mediation analysis showed that BMI partially mediated the reverse association between PSO and TL., Conclusion: This MR study revealed an association between genetic indicators of shortened TL and risk of overall psoriasis and PV, and genetic predisposition to PsA was associated with longer TL. Key message What is already known on this topic?  Telomere length (TL) is acknowledged to reflect an individual's biological age but is also associated with dysregulated immune function and immunosenescence. The impact of aging on psoriasis is controversial. Existing evidence suggests that aging may influence pathological changes and clinical course but whether aging is an independent risk factor remains unclear. What this study adds?  The current study found an association between genetic indicators of shortened TL and the risk of overall psoriasis and psoriasis vulgaris (PV). There was a bidirectional link between genetically indicated overall psoriasis and shortened TL. A possible positive genetic association between PsA and TL was also found. How this study might affect research, practice, or policy?  Our study may provide evidence for TL as new diagnostic and therapeutic strategies in clinical practices for psoriasis. Greater efforts to psoriasis management may substantially reduce the aging attributable to TL shortening. Future large-scale GWAS and experimental studies are warranted to examine the mechanistic basis for links between TL and psoriasis to improve understanding and illuminate possible therapeutic targets for psoriatic disease., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine.)