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<p>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>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月21日

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  • 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

摘要

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.