Mendelian randomisation study finds no genetic link between CETP-mediated LDL-C and pulmonary vascular disease, unlike NPC1L1 and PCSK9 (Pulm Circ 2025)

The therapeutic value of lipid-lowering drugs in pulmonary vascular disease remains uncertain due to insufficient studies and evidence. This study aims to investigate the causal effects of lipid-lowering drugs (specifically, inhibitors of APOB, CETP, HMGCR, NPC1L1, and PCSK9) on pulmonary vascular diseases using a Mendelian randomization (MR) approach. We utilized summary-level statistics from genome-wide association studies (GWAS) to simulate the exposure to low-density lipoprotein cholesterol (LDL-C) and its outcomes on pulmonary arterial hypertension (PAH), pulmonary embolism (PE), and pulmonary heart disease (PHD). Single-nucleotide polymorphisms (SNPs) within or near drug target-associated LDL-C loci were selected as proxies for the lipid-lowering drugs. Data from the FinnGen cohort and UK Biobank (UKB) were incorporated to enhance the robustness and generalizability of the findings. The inverse variance weighted (IVW) and MR-Egger methods were employed to estimate MR effects. Our MR analysis indicated that LDL-C mediated by NPC1L1 (odds ratio [OR] = 104.76, 95% confidence interval [CI] = 2.01-5457.01, p = 0.021) and PCSK9 (OR = 10.20, 95% CI = 3.58-29.10, p < 0.001) was associated with an increased risk of PAH. In contrast, LDL-C mediated by APOB was associated with a decreased risk of PE (FinnGen: OR = 0.74, 95% CI = 0.60-0.91, p = 0.005; UKB: OR = 0.998, 95% CI = 0.996-1.000, p = 0.031) and PHD (FinnGen: OR = 0.73, 95% CI = 0.59-0.91, p = 0.004). However, LDL-C mediated by CETP and HMGCR did not show significant associations with the risks of PAH, PE, or PHD. This MR study revealed the causal effects of NPC1L1 and PCSK9 inhibitors on increased PAH risk, while APOB inhibitors appear to reduce the risks of PE and PHD. These findings enhance our understanding of the potential roles of lipid-lowering drugs in pulmonary vascular disease.