HLA-DOB: A Key "Coordinator" Between Cutaneous Melanoma and Psoriasis.

Psoriasis is a chronic inflammatory skin disease associated with immune dysfunction, and its relationship to cutaneous melanoma is unclear. This study used Mendelian randomization (MR) to explore the causal link between the two and identify risk genes. SNPs from a psoriasis GWAS (5,072 cases, 478,102 controls) were used as instrumental variables, and melanoma GWAS data (3,751 cases, 372,016 controls) served as the outcome. Causal relationships were assessed using IVW, MR-Egger, and weighted median methods, with sensitivity tests. Co-localization and transcriptome analyses identified risk genes. Forward MR showed psoriasis significantly reduced melanoma risk (PIVW=0.040). The co-localization analysis revealed genes positively associated with the risk of psoriasis, including HLA-DOB, NOTCH4, and VARS2. HLA-DOB was the only risk gene of psoriasis that showed differential expression in cutaneous melanoma based on transcriptional analysis. HLA-DOB was downregulated in melanoma and associated with better prognosis (P=0.033). Single-cell analysis showed that HLA-DOB was mainly enriched in B cells (especially memory B cells) and myeloid cells (particularly DC: monocyte-derived). Our findings suggest an inverse causal relationship between melanoma and psoriasis. Importantly, we also found that HLA-DOB can be served as a key "coordinator" between cutaneous melanoma and psoriasis: a risk gene of psoriasis and a protective factor of cutaneous melanoma.