SERPINA6 encodes corticosteroid-binding globulin (CBG), the major transport protein for glucocorticoids and progestins in vertebrate blood 1. CBG binds >85% of circulating glucocorticoids, serving as a crucial regulator of cortisol bioavailability and transport 2. The protein functions through a buffering mechanism where targeted proteolytic cleavage by neutrophil elastase reduces CBG binding affinity, potentially increasing 'free' glucocorticoid levels at inflammatory sites 2. Genetic variants in SERPINA6 significantly influence plasma cortisol levels and CBG concentrations, with genome-wide association studies identifying this locus as the primary genetic determinant of morning plasma cortisol variation 13. Expression quantitative trait analyses demonstrate that SERPINA6 variants affect hepatic CBG expression and have trans-effects on adipose tissue gene expression, suggesting altered cortisol delivery to peripheral tissues 3. SERPINA6 variants also influence diurnal and stress-induced cortisol patterns in children, with higher polygenic risk scores associated with elevated hypothalamic-pituitary-adrenal axis activity 4. Clinically, genetic variation in SERPINA6 contributes to cardiovascular disease risk through altered cortisol signaling pathways 3, and CBG deficiency is associated with increased mortality in septic shock 5.