Lipid-lowering drugs and essential hemorrhagic thrombocythemia’s risk: A drug-target Mendelian randomization study

Lipid-lowering drugs are currently widely used by clinicians in clinical practice; numerous related studies have confirmed the pivotal role of the lipid pathway in regulating platelet function. Lipid-lowering drugs, represented by statins, have been found to have an improving effect on platelet-related diseases. However, there is a lack of large-scale population studies at present, and the causal explanation of traditional observational design studies is easily limited by confounding variables. The impact of lipid-lowering drugs on the risk of essential hemorrhagic thrombocythemia is not clearly understood. Our study sought to investigate the causal association between essential hemorrhagic thrombocythemia and lipid-lowering drugs through a drug-target Mendelian randomization (MR) analysis. We utilized the data from the Global Lipid Genetics Consortium to identify instrumental variables for 3 types of lipid-lowering drugs (3-hydroxy-3-methylglutaryl-CoA reductase inhibitors, proprotein convertase subtilisin/kexin type 9 PCSK9 inhibitors, and NPC1-like intracellular cholesterol transporter 1 NPC1L1 inhibitors). We obtained the genome-wide association study data for essential hemorrhagic thrombocythemia from the FinnGen study. We employed the MR method based on aggregated data and the inverse variance weighted method for the analysis. Sensitivity analyses were conducted using the conventional MR method. By analyzing data from 1171 patients with essential hemorrhagic thrombocythemia and about 1.3 million individuals with low-density lipoprotein (LDL) testing, PCSK9 inhibition was associated with a significantly increased risk of essential hemorrhagic thrombocythemia (odds ratio OR, LDL ratio of 1.87 for every 1 standard deviation increased; 95% confidence interval CI = 1.2–2.91; P = .02). NPC1L1 inhibition was associated with a reduced risk of essential hemorrhagic thrombocythemia (OR, LDL 0.19 for every 1 standard deviation reduction; 95% CI = 0.05–0.73; P = .03). No association was found between 3-hydroxy-3-methylglutaryl-CoA reductase inhibition and essential hemorrhagic thrombocythemia (OR = 0.76, 95% CI = 0.34–1.69, P = .51). The results of this MR study suggest that NPC1L1 inhibition is causally associated with a reduction in primary hemorrhagic thrombocythemia, whereas PCSK9 inhibition was positively correlated with the occurrence of the disease, which provided a new clue for the future treatment of essential hemorrhagic thrombocythemia.