Statin-Associated Hepatotoxicity Linked to CASP8 Polymorphisms: Mechanistic Insights from Proteomic Analysis

Purpose: Statins are widely used for cardiovascular diseases, but statin-associated hepatotoxicity remains a concern. Apoptotic caspases, including caspase-8 (CASP8) and caspase-3 (CASP3), are crucial in hepatotoxicity and may affect statin-associated hepatotoxicity. We examined how these gene variants affect hepatotoxicity risk and protein expression in statin users. Materials and Methods: We retrospectively analyzed prospectively collected samples from 851 South Korean statin users to assess associations between CASP8 and CASP3 polymorphisms and hepatotoxicity, defined as grade II or higher according to the Common Terminology Criteria for Adverse Events. Nine single nucleotide polymorphisms were genotyped using a TaqMan assay. Multivariable logistic regression included clinical variables alone (Model 1) or combined with genetic variants (Model 2). To evaluate functional relevance, we examined 8995 participants from the UK Biobank, assessing associations between genetic variants and protein expression levels using the Olink proteomics platform. Results: Among 851 patients, 66 experienced hepatotoxicity. In Model 1, lipophilic statins, atrial fibrillation, and diabetes mellitus were significantly associated with hepatotoxicity. In Model 2, three CASP8 polymorphisms—rs1045487 (GG genotype), rs3769825 (G allele carriers), and rs6745051 (CC genotype)—were independently associated with increased risk, with adjusted odds ratios of 1.93 [95% confidence interval (CI): 1.04–3.60], 2.38 (95% CI: 1.33–4.24), and 3.00 (95% CI: 1.31–6.84), respectively. Incorporating genetic data improved the model’s predictive performance (area under the receiver operating characteristic curve: 0.720 vs. 0.622). In the UK Biobank, risk-associated CASP8 variants showed suggestive trends toward elevated CASP8 protein expression, directionally consistent with the primary findings. Conclusion: CASP8 gene polymorphisms are associated with an increased risk of hepatotoxicity in statin users.