Lipid-lowering drugs and risk of psoriasis: a mendelian randomisation study

Importance: Lipid pathways have been implicated in the pathogenesis of psoriasis, and some lipid lowering drugs, such as statins, are hypothesised to have disease modifying properties. However, large population level studies are scarce, and causal interpretation of results from traditional observational designs is limited by confounding.

Objective: To investigate the causal association between genetically proxied lipid‐lowering drugs and psoriasis risk.

Design: 2-sample mendelian randomization study performed from August to October 2022.

Setting: Population level genome-wide association studies of psoriasis in the UK Biobank and FinnGen studies, and of low-density lipoprotein (LDL) by the Global Lipids Genetics Consortium. The inverse variance weighted method was used with pleiotropy robust methods and colocalization as sensitivity analyses.

Participants: Genetic association data were obtained from up to 1.3 million individuals of European ancestry.

Exposures: Genetically proxied inhibition of HMGCR (HMG-CoA reductase, targeted by statins), NPC1L1 (Niemann-Pick C1-Like 1, targeted by ezetimibe) and PCSK9 (proprotein convertase subtilisin/kexin type 9 targeted by, e.g., alirocumab), using LDL as the biomarker.

Main outcomes and measures: Risk of psoriasis.

Results: Data from 12,116 psoriasis cases and ~1.3 million individuals with LDL measurement were analysed. Genetically proxied PCSK9 inhibition was associated with reduced risk of psoriasis (OR 0.69 per standard deviation reduction in LDL; 95%CI 0.55, 0.88; p=0.003), which was replicated in FinnGen (OR 0.71; 95%CI 0.57, 0.88; p=0.002). Sensitivity analyses did not provide statistical evidence of bias from pleiotropy or genetic confounding. No robust association was found for HMGCR or NPC1L1 inhibition.

Conclusions and Relevance: This study provides genetic evidence that PCSK9 is implicated in psoriasis pathogenesis, and that its inhibition may reduce psoriasis risk. These findings pave the way for future studies that may allow personalised selection of lipid lowering drugs in those at risk of psoriasis.