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 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 Modifier 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 AUC 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 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. 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.

DLD has received grant support from Bayer. EKS received grant support from Bayer and Northpond Laboratories. BDH received grant support from Bayer and is currently employed by Regeneron. MM received consulting fees from Sitka, TheaHealth, 2ndMD, TriNetX, Axon Advisors, Verona Pharma, Dialectica, Sanofi.

This study was funded by the Alpha-1 Foundation.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Mass General Brigham Institutional Review Board.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors. COPDGene data are available through dbGaP.