Effect of the blood cells, inflammatory cytokines, antibodies, circulating metabolome, and immune cells on skin cancers: A bidirectional 2-sample Mendelian randomization study and mediation analysis

Abstract

Previous research has highlighted the involvement of several human blood cells in skin cancer, but large-scale studies are lacking to explore their relationship and avoid confounding factors. Here, we comprehensively investigated the causal effect of blood cells on skin cancer subtypes across 4 different human microenvironments through 2-sample Mendelian randomization (MR) analysis and mediation analysis. Summary statistics of 91 human blood cells, 233 circulating metabolites, 731 immune cells, 46 antibody immune responses, 91 inflammatory cytokines, and 4 skin cancer traits (including cutaneous melanoma, nonmelanoma skin cancer, basal cell carcinoma, and squamous cell carcinoma) were derived from genome-wide association studies. The bidirectional 2-sample MR was used to determine the causality between exposures and outcomes. Additionally, comprehensive sensitivity analyses were performed to ensure the robustness of MR findings. Finally, the mediation analysis was applied to identify the role of blood cells in skin cancers mediated by 4 different microenvironments. MR revealed causal associations between 18 different types of human blood cells, 30 different types of circulating metabolites, 136 different types of immune cells, 17 different types of antibodies immune responses, 17 different types of inflammatory cytokines with skin cancers. Reverse MR analysis indicated skin cancers were causally associated with the levels of 4 different types of human blood cells. Mediation analysis revealed 19 mediation correlations during the causal effect from blood cells to skin cancers. Among them, 13 belonged to immune cells, 3 belonged to inflammatory cytokines, and 3 belonged to antibodies immune responses. Sensitivity analyses confirmed the consistency of these findings. This study represents the first comprehensive evaluation demonstrating causal relationships among human blood cells, circulating metabolites, immune cells, antibodies immune responses, inflammatory cytokines, and skin cancers, thereby providing novel insights and potential intervention targets for skin cancer treatment.

Keywords: Mendelian randomization; antibodies immune responses; blood cells; circulating metabolites; immune cells; inflammatory cytokines; skin cancer.

Figure 1.

Schema of the study.

Figure 2.

IVW analysis showed the causal associations between blood cells and skin cancers (A) OMNS, (B) BCC, (C) MM, and SCC. BCC = basal cell carcinoma, IVW = inverse variance-weighted, MM = malignant melanoma, OMNS = other malignant neoplasms of skin, SCC = squamous cell carcinoma.

Figure 3.

Reverse MR analysis showed the causal role of skin cancers on blood cells. MR = Mendelian randomization.