title: New insight into the hypercoagulability of Cushing's syndrome.
abstract: BACKGROUND
  Hypercoagulability and a tendency for thromboembolic complications are reported in Cushing's syndrome (CS). The hypercoagulability is due mainly to the cortisol-induced increase in von Willebrand factor (VWF) and factor VIII. This is not a constant feature of CS, however; it depends on particular single nucleotide polymorphism (SNP) haplotypes in the VWF gene promoter: haplotype 1 (-3268G/-2709C/-2661A/-2527G) confers a greater risk of VWF upregulation by cortisol than haplotype 2 (-3268C/ -2709T/-2661G/-2527A). In healthy individuals these SNPs are in linkage disequilibrium with the -2144 (GT)(n) of the VWF promoter: haplotype 1 mainly segregates with short GT repeats (15-19, GTs), haplotype 2 with long repeats (GT ≥ 20, GT(L)).
  
  
  METHODS
  We analyzed the (GT)(n) locus, the SNP haplotypes and their association with VWF levels in 80 CS patients in order to precisely define the cortisol-sensitive VWF promoter pattern. CS patients were divided into groups A (increased VWF) and B (normal VWF).
  
  
  RESULTS
  Haplotype 1 and (GT)(S) were more frequent in group A patients, and conferred a 9- and 7.5-fold risk of developing high VWF levels, respectively. Haplotype 2 and (GT)(L) were more represented in group B. There was also an unexpected higher prevalence of recombinant SNP haplotypes in CS patients (6.2%) than in normals (0.9%), p = 0.002.
  
  
  CONCLUSIONS
  Our results indicate that the cortisol-induced increase in VWF may be predicted by VWF promoter polymorphisms, haplotype 1 and (GT)(S) being the sensitive pattern. These represent new markers for defining the prothrombotic risk of CS. The clinical significance, if any, of the increased recombination rate in SNP haplotypes in the VWF promoter warrants further study.
authors.affiliation: Department of Cardiologic, Thoracic and Vascular Sciences, Second Chair of Internal Medicine, University of Padua Medical School, Padua, Italy.
authors.forename: Viviana
authors.initials: V
authors.lastname: Daidone
authors.forename: Marco
authors.initials: M
authors.lastname: Boscaro
authors.forename: Elena
authors.initials: E
authors.lastname: Pontara
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Cattini
authors.forename: Gianluca
authors.initials: G
authors.lastname: Occhi
authors.forename: Carla
authors.initials: C
authors.lastname: Scaroni
authors.forename: Franco
authors.initials: F
authors.lastname: Mantero
authors.forename: Alessandra
authors.initials: A
authors.lastname: Casonato
mesh_terms: D000328:Adult; D003480:Cushing Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000652:urine; D005260:Female; D006239:Haplotypes; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics; D019851:Thrombophilia / Q000235:genetics* / Q000378:metabolism*; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor; D006854:Hydrocortisone