Cushings syndrome (CS) is associated with hypercoagulable state, mainly dependent on corticosteroid-induced increase of von Willebrand factor (VWF) levels, even though this does not affects all patients. In normals plasma VWF levels are genetically determined by ABO blood groups and polymorphisms G/C −1793, C/T −1234, A/G −1185, G/A −1050 of VWF promoter. These SNPs segregate as haplotype 1 (G/C/A/G) and haplotype 2 (C/T/G/A) with genotype 1/1 (GG/CC/AA/GG) associated with higher VWF:Ag levels than genotype 2/2 (CC/TT/GG/AA), and intermediate VWF values in heterozygote subjects (genotype 1/2). In this study we aim to investigate the relationship between SNPs of VWF promoter and VWF levels in CS patients, in order to evaluate whether glucocorticoid effects may be influenced by VWF promoter genotypes.
50 patients with Cushings syndrome and 200 normal subjects were analyzed.
Patients were divided by ABO blood group into groups A (increased VWF) and B (normal VWF). While a significant difference in VWF levels was observed between the two groups (P<0.001), cortisol values were similar (P=0.44). A direct correlation between cortisol and plasma VWF levels was observed in group A (P< 0.001), while no correlation was found in group B (P>0.1).Genotype distribution differed significantly between the two groups being 25.8% genotype 1/1, 22.6% type 2/2 and 38.7% type 1/2 in group A, as opposed to 0% type 1/1, 57.9% type 2/2 and 31.6% type 1/2 in group B (P=0.03) and their genotypes also differed from the controls (P=0.003 for group A, P=0.03 for group B). Our findings suggest that corticosteroid-mediated increases of VWF, and its associated prothrombotic state, are dependent on peculiar haplotypes of VWF gene promoter. CS patients presenting genotype 1/1 have a higher risk of developing thrombosis than patients with genotype 2/2.