Blood neutrophil transcriptome in PiMM and PiZZ patients with chronic obstructive pulmonary disease (COPD)

Relative to normal PiMM, individuals with PiZZ (Glu342Lys) genotype of α1-antitrypsin (AAT) are at higher risk for developing early-onset, neutrophilic inflammation-driven COPD. There is a growing database on neutrophil (NEU) transcriptome in health and disease, yet similar analysis in blood NEU from PiMM and PiZZ COPD patients is not available. NEU were isolated by gradient centrifugation from 6 PiMM and 10 PiZZ (4 with and 6 without IV AAT) age-matched, non-smoking, stable patients. Neutrophil RNA was isolated and 200ng of it was used for sequencing. Principal component analysis performed with DESeq2 was used to normalize the read counts of 500 genes/isoforms with the highest biological variance. The differentially expressed gene (DEG) analysis was performed following gender correction. DEGs were defined as those with an adjusted p<0.05. We found 21 significant DEGs between PiMM and IV AAT PiZZ; only two significantly lower expressed genes were identified in PiZZ NEU from patients on IV AAT compared to PiMM: ATP2C2 (ATPase transporting Ca2+ and Mn2+ into the Golgi lumen) and FAM27E3 (Family with sequence similarity 27 member E3). Neutrophils PiZZ on- v.s. non-IV AAT showed higher expression of DMBT1, encoding a protein involved in immune defense and epithelial differentiation, and lower expression of ZNF682 and TMEM218. Blood NEU transcriptome was almost identical between stable PiMM and PiZZ patients, independently of patient’s augmentation status. Further research is needed to characterize blood Neu transcriptome in the context of COPD exacerbation. NSC2018/29/B/NZ5/02346