Unraveling the causal associations between systemic cytokines and six inflammatory skin diseases

Background: Previous observational studies have reported that systemic cytokines are associated with the risk of inflammatory skin diseases, but their conclusions remain controversial. Method: We conducted a two-sample Mendelian randomization analysis to assess the relationship between systemic cytokines and six inflammatory skin disorders (including alopecia areata (AA), acne, atopic dermatitis (AD), hidradenitis suppurativa (HS), psoriasis (PS) and vitiligo), based on datasets from EArly Genetics and Lifecourse Epidemiology (EAGLE) eczema consortium, acne GWAS conducted by Maris Teder Laving et al., IEU Open GWAS, and FinnGen database. Inverse-variance weighted (IVW) method was conducted in primary MR analysis, and supplemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO. Results: By integrating the findings from both primary and sensitivity analyses, we identified ten systemic cytokines linked to the risk of six skin diseases using the IVW method. Briefly, four cytokines increased the risk of corresponding skin diseases: beta-nerve growth factor (beta-NGF) to AA (p = 0.005) and HS (p = 0.001), interleukin-8 (p = 0.014) to acne; interleukin-5 (p = 0.042) to AD; interleukin-13 (p = 0.049) to PS. In the meantime, seven cytokines could have protective effect on specific skin diseases: interleukin-9 (p = 0.040) and interleukin-2 receptor subunit alpha (IL-2ra) (p = 0.020) on AA; macrophage inflammatory protein (MIP)-1 beta (p = 0.020) on acne; monokine induced by IFN-gamma (p = 0.006) on AD; interleukin-16 (p = 0.038), MIP-1 beta (p = 0.017) and IL2ra (p = 0.020) on PS. Conclusions: This study reveals 13 causal associations between systemic cytokines and 6 skin diseases, offering new perspectives on the prevention and management of widespread inflammatory skin disorders.