Circulating lipids, lipoproteins, and the risk of idiopathic pulmonary fibrosis: a cohort study and genetic analysis.

Circulating lipids and lipoproteins have been implicated in lung health and disease, yet their associations with the risk of developing idiopathic pulmonary fibrosis (IPF) remain poorly characterized. We integrated a prospective cohort study of 479,738 United Kingdom Biobank participants (1,236 incident IPF cases during 10 years of follow-up) with two-sample Mendelian randomization (MR) using the largest available genome-wide association data (5,159 IPF cases and 27,459 controls). Circulating lipids and lipoproteins were quantified via NMR spectroscopy (138 biomarkers) and clinical biochemistry (6 biomarkers). Multivariable-adjusted Cox proportional hazards models estimated associations with incident IPF and MR using genetic variants as instruments was performed to assess potential causal relationships. After multiple-testing correction, 83 lipid biomarkers were significantly associated with incident IPF in the prospective analysis. Apolipoprotein B (ApoB)-containing lipoproteins, including LDL and VLDL, showed broadly inverse associations across lipid components and particle sizes. A size-dependent pattern was observed for HDL particles, with small HDL subfractions inversely associated with IPF risk, whereas very large HDL subfractions were positively associated. Inverse associations were also observed for apolipoprotein B, apolipoprotein A1 (ApoA-1), and broader lipid classes, including sphingomyelins. Triangulating evidence across approaches, MR analyses supported inverse associations of genetically predicted total cholesteryl esters and sphingomyelins with IPF risk. This study identifies circulating lipids and lipoproteins associated with IPF risk and highlights cholesterol and sphingolipid metabolism as potential contributors to IPF susceptibility. Further mechanistic studies and validation in independent cohorts are warranted.