Plasma proteins and different onset subtype of COPD: Proteome-wide Mendelian randomization study and co-localization analyses

Several studies have reported a strong association between plasma proteins and chronic obstructive pulmonary disease (COPD). However, the directionality and causality of the association and whether proteins effected COPD remain unclear. Therefore, we used Proteome-wide Mendelian randomization (MR) study and co-localization analyses to estimate the casual relationship between them. Summary-level data of 2923 plasma protein levels were extracted from a large-scale protein quantitative trait loci study including 54,219 individuals by the UK Biobank Pharma Proteomics Project. The outcome data for COPD and its subtypes were sourced from the FinnGen study. MR analysis was conducted to estimate the associations between protein and COPD and its subtypes risk. Additionally, phenome-wide MR analysis, and candidate drug prediction were employed to identify potential causal circulating proteins and novel drug targets. STROBE MR guidelines are followed for the study. We assessed the effect of 1929 plasma proteins on COPD. We found that Seven proteins, 4 proteins, and 3 proteins were associated with overall COPD, early-onset COPD, and later-onset COPD risk, respectively. MHC class I polypeptide-related sequence B_A (MICB_MICA) and tyrosine-protein kinase receptor tie-1 (TIE-1) would increase 8% and 27% COPD risk (MICB_MICA: odds ratios [OR], 1.08; 95% CI, 1.05-1.10; PFDR = 2.53 × 10-5; TIE-1: OR, 1.27; 95% CI, 1.13-1.43; PFDR = .012). There was negative association of Septin-8 and Butyrophilin subfamily 1 member A1 (BTN1A1) with overall COPD risk (Septin-8: OR, 0.68; 95% CI, 0.57-0.79; PFDR = 8.00 × 10-4 BTN1A1: OR, 0.82; 95% CI, 0.75-0.90; PFDR = .010). There was a protective effect of BTN1A1 on early COPD incidence (OR, 0.72; 95% CI, 0.63-0.83; PFDR = .002). However, there was no evidence indicating a shared causal variant between the other proteins and COPD and its subtypes in these regions (all posterior probability.H4 < .8). The study revealed the causal relationship between several plasma proteins and COPD and its subtypes, providing new theoretical support for understanding COPD.