Lifelong Genetic Inhibition of PCSK9 and Hepatic Safety

Pharmacologic inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9), achieved through monoclonal antibodies or small interfering RNA, lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular risk by increasing hepatic LDL receptor availability.1 Such pharmacological strategies are rapidly spreading into clinical practice and are being enriched by new approaches based on gene editing.2,3 There are concerns that blocking PCSK9 production by the liver may lead to fatty liver disease.4 Randomized clinical trials with relatively short-term follow-up showed a favorable hepatic safety profile, but long-term, liver-related, adverse events remain uncertain.3 Human genetic studies of PCSK9 loss-of-function (LoF) variants provide a model to anticipate the hepatic consequences of intracellular PCSK9 inhibition, mimicking the lifelong phenotype observed in patients with autosomal dominant PCSK9-linked familial hypobetalipoproteinemia (FHBL). Most prior analyses relied on the R46L variant, which determines a only partial reduction of circulating PCSK9, rather than a marked impairment of hepatic PCSK9 production.5,6 Other studies examined low-cholesterol states mediated by distinct pathways, including apolipoprotein B (APOB) and angiopoietin-like 3 (ANGPTL3).7,8 However, those studies did not systematically evaluate the full spectrum of rare PCSK9 LoF variants, and evidence on incident liver outcomes remains scarce. Here, we investigated whether the full spectrum of rare PCSK9 LoF variants is associated with incident liver-related outcomes in the UK Biobank (UKBB), a question of increasing clinical relevance given the development of gene-silencing therapies and emerging gene-editing approaches targeting PCSK9.