Abstract Background Alpha-1-antitrypsin deficiency (AATD), a rare genetic condition and known risk factor for emphysema, can present with unexplained phenotypic heterogeneity, including small airway disease and bronchiectasis. Although the genotype predicts the emphysema risk, with severely deficient (PiZZ) being at higher risk than mildly deficient (PiMZ) genotype, other clinical endotypes do not correlate with the genotype. Furthermore, AATD with bronchiectasis is often associated with recurrent or incomplete clearance of pathogens, such as Pseudomonas and Non-tuberculous Mycobacteria (NTM). We hypothesize that analysis of the plasma proteome will identify unique and shared biomarkers of NTM-associated bronchiectasis in AATD and non-AATD individuals. Methods Using the SomaScan V7.0 platform, we analyzed the serum of 60 individuals with positive NTM sputum samples from National Jewish Health with known AAT genotype, spirometry, CT scan (Table 1). Bronchiectasis was defined as clinically significant if they met these criteria: CT scan findings plus productive cough and/or use of airway clearance methods. We assessed the severity of airway injury using the bronchiectasis score developed by COPDGene investigators, where higher scores indicate increased severity. Using multivariable linear regression and Metascape pathway enrichment analysis we tested the association between 6,596 individual proteins and bronchiectasis score or forced vital capacity (FVC) in AATD and non-AATD individuals. Findings In AATD with NTM (AATD-NTM) vs. non-AATD with NTM (non-AATD-NTM), 702 proteins were differentially expressed, three (HN1L, RM33, and sPLA2-XII) at FDR≤0.05 significance. In AATD-NTM 310 proteins were associated with FVC and 132 proteins with total bronchiectasis score, of which 13 and 18, respectively were shared with non-AATD-NTM. Interestingly, we identified five shared proteins (CETP, IZUMO4, NPTX1, TIAM1, PLA1A) associated with both lower FVC and higher bronchiectasis score in AATD-NTM. Enrichment analysis of top 130 and 224 proteins associated with bronchiectasis score in AATD-NTMand non-AATD-NTM showed apoptosis and integrin signaling, respectively as the top enriched pathways. To test functional protein-protein interactions we used Cytoscape; relevant interacting protein networks were cell-cell crosstalk in response to pathogens, pathogen opsonization by the complement cascade, pathogen recognition and endocytosis were the relevant networks in AATD-NTM vs. cytoplasmatic and mitochondrial signaling in cell fate, necroptosis, apoptosis and canonical NF-kB signaling in non-AATD-NTM. Conclusion Plasma proteomics can identify both shared and unique biomarkers between AATD-NTM and non-AATD-NTM individuals and discover a “systemic signature” associated with FVC and bronchiectasis independent of AATD genotype. Funding: Alpha-1 Foundation and National Jewish Health This abstract is funded by: Alpha-1 Foundation
Serban et al. (Fri,) studied this question.
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