Moll Matthew, Hobbs Brian D, Pratte Katherine A, Zhang Chengyue, Ghosh Auyon J, Bowler Russell P, Lomas David A, Silverman Edwin K, DeMeo Dawn L
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115.
medRxiv. 2025 Jan 13:2025.01.11.25320392. doi: 10.1101/2025.01.11.25320392.
Individuals homozygous for the Alpha-1 Antitrypsin (AAT) Z allele (Pi*ZZ) exhibit heterogeneity in COPD risk. COPD occurrence in non-smokers with AAT deficiency (AATD) suggests inflammatory processes may contribute to COPD risk independently of smoking. We hypothesized that inflammatory protein biomarkers in non-AATD COPD are associated with moderate-to-severe COPD in AATD individuals, after accounting for clinical factors.
Participants from the COPDGene (PiMM) and AAT Genetic Modifier Study (PiZZ) were included. Proteins associated with FEV/FVC were identified, adjusting for confounders and familial relatedness. Lung-specific protein-protein interaction (PPI) networks were constructed. Proteins associated with AAT augmentation therapy were identified, and drug repurposing analyses performed. A protein risk score (protRS) was developed in COPDGene and validated in AAT GMS using AUC analysis. Machine learning ranked proteomic predictors, adjusting for age, sex, and smoking history.
Among 4,446 PiMM and 352 PiZZ individuals, sixteen blood proteins were associated with airflow obstruction, fourteen of which were highly expressed in lung. PPI networks implicated regulation of immune system function, cytokine and interleukin signaling, and matrix metalloproteinases. Eleven proteins, including IL4R, were linked to augmentation therapy. Drug repurposing identified antibiotics, thyroid medications, hormone therapies, and antihistamines as potential AATD treatments. Adding protRS improved COPD prediction in AAT GMS (AUC 0.86 vs. 0.80, p = 0.0001). AGER was the top-ranked protein predictor of COPD.
Sixteen proteins are associated with COPD and inflammatory processes that predict airflow obstruction in AATD after accounting for age and smoking. Immune activation and inflammation are modulators of COPD risk in AATD.
α1抗胰蛋白酶（AAT）Z等位基因（Pi*ZZ）纯合个体在慢性阻塞性肺疾病（COPD）风险方面存在异质性。AAT缺乏症（AATD）的非吸烟者发生COPD表明炎症过程可能独立于吸烟而导致COPD风险增加。我们假设，在考虑临床因素后，非AATD型COPD中的炎症蛋白生物标志物与AATD个体的中重度COPD相关。
纳入慢性阻塞性肺疾病基因研究（PiMM）和AAT基因修饰研究（PiZZ）的参与者。确定与FEV/FVC相关的蛋白质，并对混杂因素和家族相关性进行校正。构建肺特异性蛋白质-蛋白质相互作用（PPI）网络。确定与AAT增强疗法相关的蛋白质，并进行药物重新利用分析。在慢性阻塞性肺疾病基因研究中开发蛋白质风险评分（protRS），并在AAT基因修饰研究中使用AUC分析进行验证。机器学习对蛋白质组学预测因子进行排序，并对年龄、性别和吸烟史进行校正。
在4446名PiMM个体和352名PiZZ个体中，16种血液蛋白与气流阻塞相关，其中14种在肺中高表达。PPI网络涉及免疫系统功能调节、细胞因子和白细胞介素信号传导以及基质金属蛋白酶。包括IL4R在内的11种蛋白质与增强疗法有关。药物重新利用确定抗生素、甲状腺药物、激素疗法和抗组胺药为潜在的AATD治疗药物。添加protRS可改善AAT基因修饰研究中COPD的预测（AUC为0.86对0.80，p = 0.0001）。AGER是COPD的排名最高的蛋白质预测因子。
16种蛋白质与COPD和炎症过程相关，这些炎症过程在考虑年龄和吸烟因素后可预测AATD中的气流阻塞。免疫激活和炎症是AATD中COPD风险的调节因素。
