Background We tested the hypotheses that fibrinogen and α₁-antitrypsin are observationally and genetically associated with exacerbations in COPD.

Methods We studied 13 591 individuals with COPD from the Copenhagen General Population Study (2003–2013), of whom 6857 were genotyped for FGB -455 (rs1800790, G>A) and FGB -448 (rs4220, G>A) and had plasma fibrinogen measured. Furthermore, 13 405 individuals were genotyped for the SERPINA1 S-allele (rs17580) and the Z-allele (rs28929474) and had measurements of plasma α₁-antitrypsin. Exacerbations were defined as hospital admissions or treatments with systemic corticosteroids. We studied observational associations between plasma measurements and exacerbations in Cox regression analyses, associations between genotypes and exacerbations in logistic regression analyses and associations between genetically determined plasma levels and exacerbations in instrumental variable analyses.

Results Elevated fibrinogen and α₁-antitrypsin levels were associated with increased risk of exacerbations in COPD, HR=1.14 (1.07 to 1.22, p<0.001) and 1.18 (1.11 to 1.25, p<0.001), respectively, per SD increase. Presence of the Z-allele was associated with increased odds of exacerbations, OR=1.25 (1.05 to 1.48, p=0.01), as was α₁-antitrypsin level genetically lowered by the Z-allele, OR=1.07 (1.02 to 1.13, p=0.004), per SD decrease. Fibrinogen elevating genotypes, FGB -455 (AA) and FGB -448 (AA), were not associated with exacerbations, OR=0.96 (0.73 to 1.25, p=0.77) and OR=1.01 (0.75 to 1.33, p=0.90), respectively, and neither was genetically elevated fibrinogen level, OR=1.11 (0.76 to 1.63, p=0.58) per SD increase.

Conclusions Fibrinogen and α₁-antitrypsin were observationally associated with increased risk of exacerbations. However, genetically, fibrinogen per se was not associated with exacerbations, while lowered α₁-antitrypsin was associated with increased odds of exacerbations.