Association of lipid-lowering drugs with venous thromboembolism outcomes: a phenome-wide association study and a drug-target Mendelian randomization study.

Abstract

Common anticoagulants can lead to potentially fatal internal bleeding, which restricts their extensive use in the prevention of Venous thromboembolism (VTE). We aimed to use a PheWAS and MR analysis to find novel therapeutic targets for VTE events(containing pulmonary embolism (PE) and deep vein thrombosis (DVT)) and offer new opportunities to develop safer and more effective preventative medications. The present study utilized a PheWAS analysis to examine 2005 health-related phenotypes from the MRC-IEU consortium on VTE risk genetic variants to pinpoint possible treatment targets. Subsequently, through Summary-data-based MR (SMR) and inverse-variance-weighted MR (IVW-MR) analysis, we assessed the associations between lipid-lowering drug targets (including HMGCR inhibitor, PCSK9 inhibitor, and NPC1L1 inhibitor) and VTE events. We utilized two types of genetic instruments to represent the exposure to lipid-lowering drugs: eQTLs of drug target genes and genetic variants within or near drug target genes associated with LDL cholesterol from genome-wide association studies. PheWAS analysis identified 13 cholesterol-related traits significantly associated with VTE risk, indicating lipid-lowering drugs might be targets of VTE outcomes. SMR analysis showed that higher NPC1L1 gene expression in the blood was a risk factor for PE (OR = 1.107, 95%CI = 1.026-1.195; p = 0.009). Additionally, an IVW-MR association was found between LDL mediated by NPC1L1 and blood clot in the lung (OR = 4.091, 95% CI = 1.375-12.173; p = 0.011). This study suggested a potential causal relationship between NPC1L1 inhibition and the reduced risk of PE.