Interleukin-1 Receptor Antagonist as a Potential Mediator Linking Psoriasis and Non-Alcoholic Fatty Liver Disease: Insights From Mendelian Randomization and Experimental Evidence.

BACKGROUND

Epidemiological studies have revealed a close association between psoriasis and non-alcoholic fatty liver disease (NAFLD), but the causal relationship and underlying mechanisms remain unclear.

MATERIALS AND

METHODS

In this study, we used genome-wide association study (GWAS) data from the MRC Integrative Epidemiology Unit (MRC-IEU) to investigate the causal relationship between psoriasis and NAFLD, as well as potential mediators. Two-sample and two-step MR analyses were conducted, followed by bulk and single-cell transcriptomic analyses to validate our MR findings. In vivo validation was performed using Enzyme-Linked Immunosorbent Assay (Sample of patients (n=10)), immunohistochemistry, and liver bulk transcriptomic analysis.

RESULTS

The two-sample MR analysis revealed that genetically predicted psoriasis significantly increased the risk of NAFLD (OR = 1.07, 95% CI = 1.03-1.12, p = 0.001). Mediation analysis suggested that psoriasis was associated with elevated plasma Interleukin-1 receptor antagonist protein (IL-1RA) levels (OR = 1.02, 95% CI = 1.00-1.05, p = 0.031), which in turn raised the risk of NAFLD (OR = 1.15, 95% CI = 1.04-1.27, p = 0.006). In vivo experiments demonstrated elevated IL-1RA levels in the skin and plasma of psoriasis patients. Similarly, imiquimod (IMQ)-induced psoriasis mouse models exhibited increased IL-1RA levels in plasma and liver, accompanied by liver inflammation. MR and colocalization analysis indicated a positive correlation between IL-1RA, apolipoprotein B, and cholesterol.

CONCLUSION

Our study demonstrates that genetically predicted psoriasis increases the risk of NAFLD, and plasma IL-1RA may serve as a potential mediator between psoriasis and NAFLD.