Multi-omics integration identifies associations between large high-density lipoprotein and lung function, asthma, and COPD: evidence from genetic and population-based analyses

BACKGROUND: Metabolomic signatures of lung function and chronic inflammatory respiratory diseases have been associated with potential early disease processes. We aimed to investigate the genetic correlations and causal relationships of plasma metabolites with lung function and chronic respiratory inflammatory diseases. METHODS: Leveraging large-scale genome-wide association study (GWAS) summary-level data and individual-level data from UK Biobank, we applied linkage disequilibrium score regression (LDSC) for genetic correlation analysis, Mendelian randomization (MR) for causal inference, cross-trait meta-analysis for identifying shared genetic loci, and transcriptome-wide association studies (TWAS) for gene-level association analysis to examine the genetic and observational associations, causal relationships and shared genes of metabolites with lung function, asthma, and chronic obstructive pulmonary disease (COPD). RESULTS: High-density lipoprotein (HDL) profiles consistently showed significant genetic correlations with lung function measurements, asthma, and COPD, especially large HDL profiles (L-HDL- [cholesterol, cholesteryl esters, total lipids, particles, and phospholipid]). The genetic correlations (rg) of large HDL profiles with forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) ranged from 0.12 to 0.20, and with asthma and COPD ranged from − 0.27 to -0.10 (P < 0.05/249). In MR analysis, genetically elevated large HDL profile levels (per unit) showed a significant association with increased FEV1 (mL, β coefficient ranged from 11.81 to 14.64, P < 0.05/6) and decreased risks of asthma and COPD (odds ratio ranged from 0.94 to 0.95, P < 0.05/6). Six shared genes at chr17q12 were identified in priority metabolites with lung function, asthma, and COPD. CONCLUSIONS: Our findings revealed significant associations of HDL profiles with lung function, asthma, and COPD, and provided evidence supporting potential causal relationships of HDL size and large HDL profiles in explaining these associations.