Microsatellite (GT) n is part of the von Willebrand factor (VWF) promoter region that influences the glucocorticoid-induced increase in VWF in Cushing's syndrome

Abstract

Introduction The cortisol-induced increase in von Willebrand factor (VWF) in Cushing's syndrome (CS) seems to depend on single nucleotide polymorphisms (SNPs) of the VWF promoter, haplotype 1 (-3268G/-2709C/-2661A/-2527G) being the susceptible pattern. Materials and Methods This study focused on a new variable region of the VWF promoter, the -2144(GT) n locus, to establish whether different GT-repeat lengths are also involved in modulating the cortisol-induced increase in VWF. Sixty-nine CS patients were investigated, divided into groups A (high VWF) and B (normal VWF). Results Analysing the (GT) n locus revealed a similar allele distribution in CS patients and normal subjects, (GT) n variants ranging from 15 to 24 repeats and (GT) 19 and (GT) 21 being the two most represented. However, when groups A and B were analysed separately, a different allele distribution was observed: short GT-repeats (15-19, GT S) were more frequent in group A, long GT-repeats (20-24, GT L) in group B (p = 0.01). About genotype distributions, (GT) S/(GT) S was higher in group A and rare in group B (22.5% and 3.4%, respectively), whereas (GT) L/(GT) L was higher in group B than in group A (55.2%, 27.5%) (p = 0.021). Odds-ratio analysis revealed a risk of a cortisol-dependent increase in VWF three times higher for alleles (GT) S than for (GT) L, and 13-fold for genotype (GT) S/(GT) S respect to (GT) L/(GT) L. Conclusions In conclusion, not only the SNPs haplotypes in the VWF gene promoter, but also the variable-length (GT) n locus predict the risk of developing high VWF levels under conditions of glucocorticoid excess; the combination of (GT) S and haplotype 1 represents the susceptible pattern.