Abstract Rationale Idiopathic Pulmonary Fibrosis (IPF) is a chronic, irreversible interstitial lung disease. Although metabolic dysregulation is a prominent feature, the causal effect of lipid traits on IPF remains unclear. This study aimed to explore the relationship between lipid levels and severity of IPF and evaluate the potential of lipid-lowering drug targets in IPF. Method We retrospectively reviewed diagnosed IPF patients at the First Affiliated Hospital of Zhengzhou University. Clinical outcomes, lipid profiles, and lung function tests were analysed in IPF patients and propensity score-matched healthy controls. Based on the GAP model, the severity of IPF is classified into stages I, II, and III. Genome-wide association study data on IPF, lipid metabolism, blood cells, and variants of genes encoding potential lipid-lowering drug targets were obtained for Mendelian randomisation (MR) and mediation analyses. Results 187 IPF patients and 90 healthy volunteers were included. There were 105 IPF cases in stage I (56.14%), 66 cases in stage II (35.29%), and 16 cases in stage III (8.55%). Multivariate logistic regression analysis identified that the total cholesterol (TC) level, FEV1%, lymphocyte% %, basophil%, and KL-6 were independently associated with IPF severity. A significant negative correlation between TC and GAP index was observed (r = -0.169, P 0.05). The high-density lipoproteins (HDL) was positively correlated with DLCO % (r = 0.204, P 0.01), the parameter of small airway, including MEF50% (r = 0.154, P 0.05), MEF25% (r = 0.199, P 0.01), MEF75-25% (r = 0.197, P 0.05). Compared with the healthy control, stage I of IPF patients have an apparent higher level of TC, LDL, triglyceride (TG), and a lower level of HDL, and reduced the FEV% and FVC%. In MR analysis, decreased apolipoprotein B was associated with an increased risk of IPF (OR: 0.83, 95% CI: 0.69 to 0.99, P 0.05). Elevated BMI was associated with a higher risk of IPF (OR: 1.42, 95% CI: 1.17 to 1.71, P 0.0001). Genetic mimicry of HMGCR inhibition was associated with a reduced risk of IPF (OR: 2.07, P 0.001) and DLCO% (OR: 1.16, P 0.001). Conclusions Our results support the crucial role of lipid and metabolism-related traits in the severity of IPF. HDL may be closely related to the small airway dysfunction in IPF. HMGCR contributes to the development of IPF by regulating apolipoprotein B. These findings provide evidence for lipid-related mechanisms and a promising lipid-lowering drug target for IPF. This abstract is funded by: None
Lin et al. (Fri,) studied this question.