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

Abstract Primary sclerosing cholangitis (PSC) lacks specific drugs. Statins, inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR), have shown potential for improving PSC prognosis, but their therapeutic efficacy remains controversial. We analyzed HMGCR single nucleotide polymorphisms (SNPs) from published genome-wide association studies using Mendelian randomization (MR) to assess the causal link 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. Genetically predicted HMGCR exhibited a pronounced detrimental effect on PSC in both the IVW method (OR [95%] = 2.43 [1.23 to 4.78], P = 0.010) and weighted median method (OR [95%] = 2.36 [1.02 to 5.45], P = 0.04). Conversely, PCSK9 did not reach statistical significance. Heterogeneity tests, horizontal multiple validity tests and sensitivity analyses all reflect the reliability of the results. This study establishes a causal relationship between HMGCR and PSC, providing robust evidence supporting the potential enhancement of prognosis in PSC patients through statin drugs targeting HMGCR.