Abstract
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Current options such as glucocorticoids and bronchodilators improve symptoms but carry risks, including infection and immunosuppression. To guide safer, mechanism-based therapies and biomarker discovery, we genetically prioritize circulating proteins. METHODS: We used the integrated dataset from Sun et al., which combined seven large-scale plasma proteome GWAS covering 4,853 proteins measured on SOMAscan, Olink, and xMAP platforms, to evaluate the causal effects of circulating proteins on COPD through two-sample Mendelian randomization (MR). Only genome-wide significant cis-pQTLs (P < 5 × 10⁻⁸) with F > 10 were retained after LD clumping. Discovery analysis was performed with FinnGen R10 COPD GWAS (20,066 cases, 338,303 controls), and replication analyses with deCODE (35,559 individuals, 4,907 proteins) and the Million Veteran Program (103,054 cases, 315,450 controls). Results were meta-analyzed and validated using Bayesian colocalization, Steiger tests, proteome-wide association study (PWAS, ARIC cohort), and protein-protein interaction (PPI) analysis. RESULTS: Eleven proteins showed significant associations with COPD risk in the discovery stage (FDR < 0.05), including risk-enhancing MST1, TIE1, and PILRA, and protective ERAP2, PILRB, SERPING1, SNX1, IL17RD, STARD5, IL27RA, and TNFRSF6B. Replication confirmed consistent effects for five proteins, with IL17RD, IL27RA, and TIE1 remaining significant. Meta-analysis provided robust evidence for IL27RA (OR = 0.97, 95% CI: 0.95-0.98, P = 1.0×10-6) and TIE1 (OR = 1.14, 95% CI: 1.07-1.21, P = 4.8×10⁻⁵), while IL17RD was nominally significant. ERAP2 and SNX1 did not replicate. PWAS supported ERAP2, TIE1, IL27RA, and SMPD1, and PPI revealed functional interactions of IL27RA, MMP12, and TIE1 with known COPD drug targets. CONCLUSION: By integrating MR, replication, meta-analysis, PWAS, and PPI, our findings genetically nominate IL27RA, IL17RD, and TIE1 as putative candidates for therapeutic investigation and/or biomarker development in COPD. Further mechanistic and pharmacological studies are required before any treatment claims can be made.