Adenosine 5'monophosphate-activated protein kinase activation reduces the risks of psoriasis and its comorbidities: a Mendelian randomization study in the UK Biobank

Objective Whether metformin and its adenosine 5'monophosphate-activated protein kinase (AMPK) activation protect from psoriasis risk is unconcluded. We investigated the effect of AMPK, a pharmacological target of metformin, on the risk of psoriasis and its comorbidities and mortality among participants in the UK Biobank (UKB).Methods To avoid immortal time biases in pharmacoepidemiologic studies, Mendelian randomization was used to infer the AMPK pathway-dependent effects. The cut-off age for distinguishing early-onset/late-onset psoriasis (EOP/LOP) was set at 60 years, based on the incident psoriasis peak in UKB. A genetic instrument comprising 44 single-nucleotide polymorphisms associated with glycated haemoglobin (HbA1c), serving as a proxy for AMPK genetic risk score (negatively associated with AMPK activation), was employed as previously reported in the literature. Log-binomial models were used to estimate the effect size of AMPK regarding relative risk (RR) and 95% CI.Results A total of 407 159 participants were analysed, including 9126 EOP and 3324 LOP. The AMPK genetic risk score was associated with a 12.4% increase in the risk of LOP in men (RR = 1.124, 95% CI: 1.022-1.236). This association was not significant for EOP or women. AMPK genetic risk score exhibited an elevated risk of ischemic heart disease (RR = 1.217, 95% CI 1.062-1.395) in male psoriasis patients.Conclusions AMPK activation may protect against LOPs and associated ischemic heart disease in men. A sex-specific, comorbidity-targeted intervention for psoriasis is needed.