New target-HMGCR inhibitors for the treatment of primary sclerosing cholangitis: A drug Mendelian randomization study.

Background: No intervention definitively extends transplant-free survival in primary sclerosing cholangitis (PSC). Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), may enhance PSC prognosis, but their efficacy is debated.

Methods: We analyzed HMGCR single-nucleotide polymorphisms from published genome-wide association studies using Mendelian randomization to assess the causal relationship between HMGCR and PSC risk. Effects of HMGCR were compared with proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors, common lipid-lowering drugs, using coronary heart disease risk as a positive control. The inverse-variance weighted (IVW) method was the primary analysis, complemented by the weighted median method. Heterogeneity analysis, examination of horizontal pleiotropy, and leave-one-out sensitivity analysis were conducted for result robustness.

Results: Genetically predicted HMGCR exhibited a pronounced detrimental effect on PSC in both the IVW method (odds ratio [OR] [95%] = 2.43 [1.23-4.78], P = 0.010) and the weighted median method (OR [95%] = 2.36 [1.02-5.45], P = 0.044). However, PCSK9 did not reach statistical significance. Moreover, all analyses passed through heterogeneity analysis, horizontal pleiotropy analysis, and leave-one-out sensitivity analysis.

Conclusion: This study has confirmed a causal relationship between HMGCR and PSC risk, suggesting statins targeting HMGCR could enhance PSC patient outcomes.