| Title: | Multiomics Mendelian randomization identifies serpin family G member 1 as a chronic obstructive pulmonary disease modulator |
| Journal: | Signal Transduction and Targeted Therapy |
| Published: | 21 Jan 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41559025/ |
| DOI: | https://doi.org/10.1038/s41392-025-02547-7 |
Publication 18601
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Abstract
Chronic obstructive pulmonary disease (COPD), the third leading cause of death worldwide, lacks effective disease-modifying therapies, partly because of complex gene-environment interactions and extensive missing heritability. Here, we applied a multiomics Mendelian randomization (MR) framework - integrating proteome- and transcriptome-wide association analyses (pQTLs/eQTLs) with genome-wide association summary statistics, sensitivity analyses, and colocalization - to assign evidence levels to genes and prioritize those with higher causal likelihoods across diverse cohorts. We identified serpin family G member 1 (SERPING1) as a robust causal candidate, with consistent pQTL associations with COPD (β = -0.038 to -0.006) and with lung function measures, including FEV₁ (β = 0.008 to 0.015) and FEV₁/FVC% (β = 0.014 to 0.026). Longitudinal analyses in the UK Biobank (n = 46,369) and ECOPD cohort (n = 576) revealed that higher circulating SERPING1 protein levels were causally linked to slower FEV₁ decline during early follow-up (UKB: adjusted difference = -22.1 mL/year per standardized unit; ECOPD: -0.73 mL/year per ng/mL), accompanied by marked expression differences between European (higher) and Asian (lower) smokers and COPD patients. In a murine model exposed to cigarette smoke, AAV-mediated SERPING1 overexpression improved lung function, reduced alveolar destruction, and upregulated the expression of fibroblast elastic fiber-related genes. Collectively, these findings identify SERPING1 as a complement pathway regulator that may function both as a short-term biomarker of lung function decline and as a population specific, disease-modifying therapeutic target for COPD.</p>
13 Keywords
- Animals
- Complement C1 Inhibitor Protein
- Female
- Genome-Wide Association Study
- Humans
- Male
- Mendelian Randomization Analysis
- Mice
- Middle Aged
- Multiomics
- Pulmonary Disease, Chronic Obstructive
- Quantitative Trait Loci
- Serpins
18 Authors
- Erkang Yi
- Jieda Cui
- Hairong Wang
- Fan Wu
- Qiyang Hong
- Qingyang Li
- Chengshu Xie
- Huahua Xu
- Yu Liu
- Xinru Ran
- Xiaohui Wu
- Qi Wan
- Gaoying Tang
- Leqing Zhu
- Junling Pang
- Yumin Zhou
- Erping Long
- Pixin Ran
1 Application
| Application ID | Title |
|---|---|
| 150455 | Dissecting the genetic underpinnings of comorbidities via functional genomics |
Enabling scientific discoveries that improve human health