Causal effects of lipid-lowering drugs on inflammatory skin diseases: Evidence from drug target Mendelian randomisation

Abstract

Clinical research has revealed that inflammatory skin diseases are associated with dyslipidaemia. Modulating lipids is also a rising potential treatment option. However, there is heterogeneity in the existing evidence and a lack of large-scale clinical trials. Observational research is prone to bias, making it difficult to determine causality. This study aimed to evaluate the causal association between lipid-lowering drugs and inflammatory skin diseases. A drug target Mendelian randomisation (MR) analysis was conducted. Genetic targets of lipid-lowering drugs, including proprotein convertase subtilis kexin 9 (PCSK9) and 3-hydroxy-3-methylglutaryl-assisted enzyme A reductase (HMGCR) inhibitor, were screened. Common inflammatory skin diseases, including psoriasis, allergic urticaria, rosacea, atopic dermatitis, systemic sclerosis and seborrhoeic dermatitis, were considered as outcomes. Gene-predicted inhibition of PCSK9 was causally associated with a decreased risk of psoriasis (OR_IVW [95%CI] = 0.600 [0.474–0.761], p = 2.48 × 10⁻⁵) and atopic dermatitis (OR_IVW [95%CI] = 0.781 [0.633–0.964], p = 2.17 × 10⁻²). Gene-predicted inhibition of HMGCR decreased the risk of seborrhoeic dermatitis (OR_IVW [95%CI] = 0.407 [0.168–0.984], p = 4.61 × 10⁻²) but increased the risk of allergic urticaria (OR_IVW [95%CI] = 3.421 [1.374–8.520], p = 8.24 × 10⁻³) and rosacea (OR_IVW [95%CI] = 3.132 [1.260–7.786], p = 1.40 × 10⁻²). Among all causal associations, only PCSK9 inhibition demonstrated a robust causal effect on psoriasis after a more rigorous Bonferroni test (p < 4.17 × 10⁻³, which is 0.05/12). Modulating lipids via PCSK9 inhibition may offer potential therapeutic targets for psoriasis and atopic dermatitis. Given the potential cutaneous side effects associated with HMGCR inhibitors, PCSK9 inhibitors could be considered viable alternatives in lipid-lowering medication.