Polymorphisms in von Willebrand factor gene promoter influence the glucocorticoid-induced increase in von Willebrand factor: the lesson learned from Cushing syndrome

Cushing syndrome (CS) features high-glucocorticoid secretion and an associated hypercoagulable state often involving an increase in von Willebrand factor (VWF). To identify any influence of VWF promoter on glucocorticoid haemostatic effects, four polymorphic positions (-3267, -2708, -2659 and -2525) segregating as haplotypes 1 (GCAG) or 2 (CTGA) were analysed in 50 CS patients with high VWF (group I) and normal VWF (group II) levels, divided by ABO group. Genotype distribution differed significantly between the two groups: in group I, 25·8% had genotype 1/1, 22·6% had 2/2 and 38·7% had 1/2; in group II, 0% had genotype 1/1, 57·9% had 2/2 and 31·6% had 1/2 ( P  = 0·03). Patients' genotypes also differed from those of controls ( P  = 0·003 for group I, P  = 0·03 for group II). Haplotype 1 was prevalent in group I, haplotype 2 in group II ( P  = 0·002), both with frequencies differing from controls ( P  < 0·001 and P  = 0·009). By odds ratio analysis, genotype 1/1 carried a 12 times greater risk of high-VWF levels than genotype 2/2, and haplotype 1 carried a five times greater risk than haplotype 2. Our findings suggest that VWF promoter haplotypes influence the corticosteroid-mediated increase in VWF.