Proteomic signatures of ambient air pollution and risk of non-alcoholic fatty liver disease: A prospective cohort study in the UK Biobank

Air pollution has been linked with non-alcoholic fatty liver disease (NAFLD), but the underlying mechanisms characterized by perturbations in the circulating proteome profile are largely unknown. Therefore, we included 51,357 participants from the UK Biobank with 2941 plasma proteins measured in blood samples collected between 2006 and 2010, measurements of annual fine particular matter <2.5 μm in diameter (PM_2.5) and nitrogen dioxide (NO₂), and follow-up data on NAFLD (743 incident cases occurred over a median follow-up of 13.6 years). Multiple linear regression was used to identify proteins associated with PM_2.5 and NO₂. Cox proportional hazards models were applied to assess associations of PM_2.5 and NO₂ and identified proteins with incident NAFLD. Mediation analyses were conducted to explore the mediation role of proteins in the associations between air pollution and incident NAFLD. After adjusting for selected covariates, PM_2.5 (hazard ratio [HR] = 2.57, 95%CI:1.27, 5.21, per ln increase) and NO₂ (HR = 1.43, 95%CI: 1.10, 1.84, per ln increase) were positively associated with incident NAFLD. We identified 138 proteins associated with PM_2.5 (92 positively, 46 inversely, FDR <0.05) and 143 with NO₂ (100 positively, 43 inversely). Of the proteins that were significantly associated with both PM_2.5 and NO₂, 93 (79 positively, 14 inversely) and 79 (69 positively, 10 inversely) were significantly associated with incident NAFLD. Furthermore, 84 PM_2.5-associated proteins and 66 NO₂-associated proteins significantly mediated the corresponding association between air pollutants and incident NAFLD, with the proportion of mediation effects ranging from 3.2 % to 27.3 % for PM_2.5 and 2.6 % to 20.8 % for NO₂, respectively. Of note, the majority of significant mediating proteins were enriched in pathways of cytokine-cytokine receptor interaction, viral protein interaction with cytokine and cytokine receptor. Our findings suggested that long-term exposure to PM_2.5 and NO₂ was associated with an increased risk of NAFLD partially by perturbating circulating proteins involved in pathways of inflammation and immunity responses.