Unraveling the Link between Air Pollution and Psoriasis Subtypes: Genetic Architecture of Epigenetic Insights and Mediating Cytokines

The impact of air pollution on psoriasis is poorly understood. We conducted a prospective cohort study and used epigenetic Mendelian randomization (MR) to dissect the pathogenic effects of air pollution. We first investigated the associations between air pollution and the incidence of skin psoriasis and psoriatic arthritis (PsA) within the UK Biobank cohort. We then used MR analyses to identify potential causal relationships between blood DNA methylation changes due to air pollution and psoriasis risk. To validate MR associations, we conducted genetic colocalization, gene-air pollutant interaction, and mediation analyses. Exposures to air pollutants were associated with skin psoriasis only, not PsA, with effects amplified by daily alcohol consumption. PM_2.5 and NO₂-related methylation alteration at CpG sites in the <i>ZMIZ1</i> locus are correlated with psoriasis risk. Air pollutants show dose-response effects in relation to the <i>ZMIZ1</i> genotypes. Furthermore, <i>ZMIZ1</i> gene variation-associated cytokines (IL-15, IL-19, and IL-22) significantly mediated the link between air pollution and skin psoriasis risk, with the proportion mediated ranging from 4.55 to 19.94%. Our findings suggest that air pollution contributes to psoriasis through <i>ZMIZ1</i> epigenetic modifications and subsequent inflammatory cytokine activation, revealing a key pathway linking environmental exposure to the disease.