Genetically predicted levels of circulating cytokines and the risk of six immune skin diseases: a two-sample Mendelian randomization study

BACKGROUND: Circulating cytokines play a crucial role in the onset and progression of immune skin diseases. However, the causal relationships and the direction of causal effects require further investigation. METHODS: Two-sample Mendelian randomization (MR) analyses were conducted to assess the causal relationships between 41 circulating cytokines and six immune skin diseases including alopecia areata, chloasma, hidradenitis suppurativa (HS), lichen planus (LP), seborrheic dermatitis, and urticaria, using summary statistics from genome-wide association studies. Reverse MR analyses was performed to test for the reverse causation. Pleiotropy and heterogeneity tests were conducted to assess the robustness of the findings. RESULTS: Twelve unique cytokines showed a suggestive causal relationship with the risk of six immune skin diseases. Among them, the causal effects between 9 unique cytokines and immune skin diseases have strong statistical power. Additionally, the concentrations of six cytokines might be influenced by LP and urticaria. After Bonferroni correction, the following associations remained significant: the causal effect of beta-nerve growth factor on HS (odds ratio [OR] = 1.634, 95% confidence interval [CI] = 1.226-2.177, p = 7.97e-04), interleukin (IL)-6 on LP (OR = 0.615, 95% CI = 0.481-0.786, p = 1.04e-04), IL-4 on LP (OR = 1.099. 95% CI = 1.020-1.184, p = 1.26e-02), and IL-2 on urticaria (OR = 0.712, 95% CI = 0.531-0.955, p = 2.33e-02). CONCLUSION: This study provides novel perspectives on the relationship between circulating cytokines and immune skin diseases, potentially providing valuable insights into their etiology, diagnostic approaches, and treatment.