Background: Corticosteroid Binding Globulin (CBG) binds >85% of plasma cortisol and controls the circulating free cortisol pool. Proteolytic cleavage by neutrophil elastase is proposed to reduce CBG binding affinity and increase free cortisol availability to inflamed tissues. The CORtisol NETwork (CORNET) consortium found that genetic variation at a locus spanning SERPINA1 (encoding alpha-1 antitrypsin, A1AT, the endogenous inhibitor of neutrophil elastase) and SERPINA6 (CBG) contributes to morning total plasma cortisol variation. We hypothesised that A1AT deficiency increases CBG cleavage and hence free plasma cortisol. We tested this in recall-by-genotype studies of people who are heterozygous for inactivating mutations in SERPINA1.
Methods: 16 healthy carriers of either of the two most common A1AT-deficiency single nucleotide polymorphisms (rs17580 & rs28929474) and 16 age-, gender- and BMI-matched controls were recruited from the Generation Scotland Biobank. Plasma free cortisol was measured by isotopic dilution and ultrafiltration, total CBG by ELISA in plasma, and A1AT by ELISA in serum.
Results: Serum A1AT was confirmed lower in those with heterozygous mutations vs. wild type controls (411.3 +/− 27.44 vs. 565.1 +/− 23.38 mg/dl, P=0.0002). No significant differences in total CBG were observed. However, plasma free cortisol fraction was higher in those carrying A1AT mutations (16.13 +/− 0.2 vs. 13.88 +/− 0.04 %, P<0.0001).
Conclusion: Alpha-1 antitrypsin mutation heterozygosity, common in the general population, is associated with higher free cortisol fraction, consistent with enhanced cleavage of CBG. This may influence tissue actions of glucocorticoids and provides a paradigm in which to dissect the pathophysiological importance of CBG cleavage.