Genetic Inhibition of PCSK9 and Liver Function

Antoine Rimbert (1) , Sarra Smati (1) , Wieneke Dijk (1) , Cedric Le May (1) , Bertrand Cariou (1)

1 ITX - ITX - unité de recherche de l'institut du thorax

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with anti-PCSK9 monoclonal antibodies (alirocumab and evolocumab) or with small-interfering RNAs (inclisiran) lowers plasma low-density lipoprotein cholesterol (LDL-C) levels, a major risk factor for the development of atherosclerotic cardiovascular disease (ASCVD). 1,2 So far, the pharmacologic inhibition of PCSK9 presents with a favorable safety profile, but longer-term safety remains to be proven. Studies in preclinical models and in humans have suggested a potential link between PCSK9 deficiency and the risk of nonalcoholic fatty liver disease (NAFLD), 3,4 a spectrum of progressive liver diseases ranging from simple steatosis to fibrosis that can lead to cirrhosis and hepatocellular carcinoma. Notably, it has been shown that PCSK9 knockout mice are more prone to develop severe hepatic steatosis and fibrosis when receiving a high-fat diet. 3 This study aims to study the associations of the lifelong genetic inhibition of PCSK9 with plasma liver enzymes and NAFLD by using the loss-of-function variant PCSK9p.Arg46Leu as a genetic instrument. For comparison, we used 2 variants in PNPLA3 and TM6SF2, known to be involved in the pathogenesis of NAFLD. 5 Methods | Approval. Both the UK Biobank and the Electronic Medical Record and Genomics (eMERGE) cohort have obtained regulatory approvals, and all participants provided written informed consent. Because the data were publicly available, we did not obtain specific approval for this study. UK-Biobank Data Sets. Genetic associations with biologic traits (plasma circulating liver enzymes) in the UK-Biobank cohort were extracted from the second-round results (released August 1, 2018) by the Nealelab (see description in http://www. nealelab.is/uk-biobank/). These data were obtained from 361 194 participants (194 174 women and 167 020 men) of the UK-Biobank cohort (https://www.ukbiobank.ac.uk).

Domaines: Physiologie [q-bio.TO]; Hépatologie et Gastroentérologie; Endocrinologie et métabolisme; Cardiologie et système cardiovasculaire

Antoine Rimbert, Sarra Smati, Wieneke Dijk, Cedric Le May, Bertrand Cariou. Genetic Inhibition of PCSK9 and Liver Function. JAMA Cardiology, 2020, ⟨10.1001/jamacardio.2020.5341⟩. ⟨hal-03100949⟩