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Genetically Supported Lipoprotein Lipase as a Promising Drug Target for Preventing Non-Alcoholic Fatty Liver Disease
35 Pages Posted: 18 Oct 2022
More...Abstract
Background: Dyslipidemia is one of the major contributors to non-alcoholic fatty liver disease (NAFLD), but it is still unclear whether lipid-lowering drugs are capable of preventing NAFLD. This genetics-based study aimed to evaluate the potential effect of existing lipid-lowering drug targets on NAFLD to prioritize candidate therapeutics advancing to clinical trials.
Methods: Drug-target Mendelian randomisation analyses were performed to assess the associations of genetic proxies for the effects of nine lipid-lowering drug classes (low-density lipoprotein cholesterol-lowering variants in HMGCR, NPC1L1, PCSK9, APOB, ABCG5/ABCG8, and LDLR genes and triglyceride-lowering variants in ANGPTL3, APOC3 and lipoprotein lipase [LPL] genes) with NAFLD risk. Drug targets that reached significance for NAFLD risk were further tested using gene expression in the blood. Genetic associations with liver function traits (liver fat percent and liver enzymes), metabolic disorder (type 2 diabetes [T2D]), and cardiovascular disease (coronary artery disease [CAD]) were explored.
Findings: The genetic mimicry of LPL enhancement was associated with lower NAFLD risk in the discovery dataset (odds ratio [OR], 0.60; 95% CI, 0.50–0.72, P = 2.07 × 10−8) and lower NAFLD risk in the replication dataset (OR, 0.57; 95% CI, 0.39–0.82, P = 2.88 × 10−3). A significant association was observed for LPL expression in the blood. Moreover, the genetic mimicry of LPL enhancement was associated with lower liver fat percent, improved liver enzymes, and lower risk of T2D and CAD.
Interpretation: Genetically supported LPL can be prioritized as a promising drug target for the prevention of NAFLD.
Funding: Capital’s Funds for Health Improvement and Research (2022-4-4037).
Declaration of Interest: Nothing to disclosure
Keywords: Drug-target Mendelian Randomisation, LPL, Lipid-lowering Drugs, Genome-wide Association Studies, Genetic Variants.
Suggested Citation: Suggested Citation