Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiency
Abstract Rationale 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 that inflammatory processes may contribute to COPD risk independently of smoking. We hypothesized that i...
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| Format: | Article |
| Language: | English |
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BMC
2025-07-01
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| Series: | Respiratory Research |
| Online Access: | https://doi.org/10.1186/s12931-025-03320-8 |
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| author | Matthew Moll Brian D. Hobbs Katherine A. Pratte Chengyue Zhang Auyon J. Ghosh Russell P. Bowler David A. Lomas Edwin K. Silverman Dawn L. DeMeo |
| author_facet | Matthew Moll Brian D. Hobbs Katherine A. Pratte Chengyue Zhang Auyon J. Ghosh Russell P. Bowler David A. Lomas Edwin K. Silverman Dawn L. DeMeo |
| author_sort | Matthew Moll |
| collection | DOAJ |
| description | Abstract Rationale 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 that 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. Methods Participants from the COPDGene (Pi*MM) and AAT Genetic Modifiers Study (Pi*ZZ) were included. Proteins associated with FEV1/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 AUROC analysis. Machine learning ranked proteomic predictors, adjusting for age, sex, and smoking history. Results Among 4,446 Pi*MM and 352 Pi*ZZ 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 adjunctive AATD treatments. Adding protRS improved COPD prediction in AAT GMS (AUROC 0.86 vs. 0.80, p = 0.0001). AGER was the top-ranked protein predictor of COPD. Conclusions 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. |
| format | Article |
| id | doaj-art-ec210e9fe1ee49bd8df683a7a40260ec |
| institution | Kabale University |
| issn | 1465-993X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj-art-ec210e9fe1ee49bd8df683a7a40260ec2025-08-20T04:02:55ZengBMCRespiratory Research1465-993X2025-07-0126111110.1186/s12931-025-03320-8Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiencyMatthew Moll0Brian D. Hobbs1Katherine A. Pratte2Chengyue Zhang3Auyon J. Ghosh4Russell P. Bowler5David A. Lomas6Edwin K. Silverman7Dawn L. DeMeo8Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s HospitalRegeneron PharmaceuticalDepartment of Biostatistics, National Jewish HealthChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s HospitalDivision of Pulmonary and Critical Care Medicine, SUNY Upstate Medical CenterDepartment of Genomic Medicine, Cleveland Clinic Lerner College of MedicineDivision of Medicine, UCL Respiratory, Rayne Institute, University College LondonChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s HospitalChanning Division of Network Medicine, Department of Medicine, Brigham and Women’s HospitalAbstract Rationale 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 that 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. Methods Participants from the COPDGene (Pi*MM) and AAT Genetic Modifiers Study (Pi*ZZ) were included. Proteins associated with FEV1/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 AUROC analysis. Machine learning ranked proteomic predictors, adjusting for age, sex, and smoking history. Results Among 4,446 Pi*MM and 352 Pi*ZZ 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 adjunctive AATD treatments. Adding protRS improved COPD prediction in AAT GMS (AUROC 0.86 vs. 0.80, p = 0.0001). AGER was the top-ranked protein predictor of COPD. Conclusions 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.https://doi.org/10.1186/s12931-025-03320-8 |
| spellingShingle | Matthew Moll Brian D. Hobbs Katherine A. Pratte Chengyue Zhang Auyon J. Ghosh Russell P. Bowler David A. Lomas Edwin K. Silverman Dawn L. DeMeo Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiency Respiratory Research |
| title | Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiency |
| title_full | Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiency |
| title_fullStr | Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiency |
| title_full_unstemmed | Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiency |
| title_short | Assessing inflammatory protein biomarkers in COPD subjects with and without alpha-1 antitrypsin deficiency |
| title_sort | assessing inflammatory protein biomarkers in copd subjects with and without alpha 1 antitrypsin deficiency |
| url | https://doi.org/10.1186/s12931-025-03320-8 |
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