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Circulating Protein-Mediated Pathways in Basal Cell Carcinoma: Mendelian Randomization Reveals STAT3 and GUCA1A as
1Clinical Medical College, Qinghai University, Xining, Qinghai Province, People's Republic of China.
Objective:
To integrate protein quantitative trait loci (BD pQTL) data from the UK Biobank (UKB) and the Icelandic population to investigate the causal relationship between circulating proteins and basal cell carcinoma (BCC), as well as their mediation mechanisms.
Methods:
Bidirectional Mendelian randomization (MR) was performed to assess the causal association between UKB-derived pQTLs and BCC. Protein-protein interaction networks and functional enrichment analyses were applied to identify core pathways. A mediation MR framework was further constructed to model the regulatory axis of "upstream proteins-mediator proteins-BCC", and sensitivity analyses were conducted to ensure robustness.
Results:
Circulating proteins have a unidirectional causal effect on BCC, and the associated proteins are significantly enriched in immune and inflammatory pathways. A total of 13 UKB pQTLs were identified to potentially affect the risk of BCC through 6 BD pQTLs, and the robustness of the results was confirmed. Among them, STAT3 and GUCA1A emerged as key mediator hubs, each mediating multiple protein pathways (with the highest mediation proportion reaching 15.2%).
Conclusion:
This study reveals the causal associations between certain UKB pQTLs, BD pQTLs, and BCC, and identifies six BD pQTLs that mediate the effect of UKB pQTLs on BCC through STAT3 and GUCA1A as core mediator proteins, providing new genetic evidence for the precise stratification and targeted intervention of BCC.
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