Abstract
BACKGROUND: Skin atrophy (SA) is a pathological condition marked by the thinning of the skin, decreased elasticity, and reduced functionality, often arising from aging, chronic glucocorticoid use, or autoimmune diseases. OBJECTIVE: This study investigates the role of the major histocompatibility complex (MHC) region on chromosome 6 in the development of SA. METHODS: We applied summary-data-based Mendelian randomization (SMR) using eQTL data of three skin-related tissues (whole blood, lower leg, and suprapubic) from the GTEx database, and SA genome-wide association study data from FinnGen. Further, we conducted functional enrichment, colocalization, and drug enrichment analyses on the core genes (intersection genes) to explore their functions and druggability. RESULTS: Six core genes (PSORS1C3, HLA-C, HLA-DRB5, HLA-DRB6, HLA-DQA1, and HLA-DQB1) located on chromosome 6p21 were consistently identified across all tissues. Functional enrichment, pathway, and protein-protein interaction analyses revealed that these genes are involved in antigen processing and immune response regulation. Drug enrichment analysis highlighted potential therapeutic targets, including interactions with palladium, azathioprine, and insulin. However, limitations in available data for PSORS1C3 and HLA-DRB6, as well as inconclusive colocalization results, suggest a need for further research. CONCLUSION: This study highlights the involvement of six core genes within the MHC region on chromosome 6 in the development of SA, emphasizing their roles in immune regulation and antigen presentation. These findings open new avenues for understanding SA and offer a foundation for future investigations into immune-related pathways in skin diseases.