Multiomics Mendelian randomization identifies serpin family G member 1 as a chronic obstructive pulmonary disease modulator.

Summary

Using multi-omics MR across cohorts and translational validation, SERPING1 emerged as a causal COPD modulator. Higher circulating SERPING1 predicted slower early FEV1 decline and AAV-driven overexpression in smoke-exposed mice improved lung function and alveolar integrity, positioning SERPING1 as both biomarker and therapeutic target.

Key Findings

• SERPING1 pQTLs associate with COPD risk and improved lung function metrics (FEV1, FEV1/FVC).
• Higher circulating SERPING1 causally linked to slower early FEV1 decline in UK Biobank (−22.1 mL/year per SD) and ECOPD (−0.73 mL/year per ng/mL).
• AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated elastic fiber–related genes in smoke-exposed mice.
• Population differences observed: higher SERPING1 expression in European vs Asian smokers/COPD patients.

Clinical Implications

SERPING1 could be used to risk-stratify COPD patients for rapid lung function decline and represents a tractable complement-pathway target, opening avenues for host-directed therapy and potential population-tailored interventions.

Limitations

• Causal inference via MR assumes no horizontal pleiotropy; residual confounding cannot be fully excluded.
• Population differences and translational gaps from mouse models may limit generalizability and clinical extrapolation.

Future Directions

Prospective validation of SERPING1 as a predictive biomarker for lung function decline, mechanistic dissection of complement signaling in COPD endotypes, and early-phase trials of SERPING1/complement modulation stratified by ancestry.