title: A novel polymorphism of the gene encoding furin, a TGF-beta1 activator, and the influence on cardiac allograft vasculopathy formation.
abstract: BACKGROUND
  Coronary vasculopathy (CV) is an important determinant of survival following cardiac transplantation. We have previously shown that G915C polymorphism of the Transforming Growth Factor-beta1 (TGF-beta1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-beta1 activation. We investigated for polymorphism within the promoter region of the gene for furin (fur). Allelic variation of the fur gene, in conjunction with TGF-beta1 polymorphism, was subsequently related to the development of CV.
  
  
  RESULTS
  The fur gene promoter region (position -1199 to +39) was analysed by SSCP and sequencing. A C/T single nucleotide substitution polymorphism at position -231* was identified. Using PCR the fur and TGFB1 genotypes were identified in 115 cardiac transplant recipients. CV was diagnosed at routine surveillance post-transplant coronary angiography. Fur polymorphism had no influence on vasculopathy development; median time to diagnosis, *C/C homozygotes, 2.27 years (2.10-4.32), *C/T heterozygotes 2.97 years (2.09-4.24), *T/T homozygotes 2.65 years (2.33-4.08), (P=0.95). Allelic variation did not influence Kaplan Meier actuarial analysis of disease onset (P=0.54). Ninety-three percent of recipients were high TGF-beta1 producers. We used fur polymorphism to substratify patients with the +915*G/G TGFB1 (high producing) allele. Fur polymorphism did not influence CV development within this TGF-beta1 high producer cohort, when analysed by time to first diagnosis and Kaplan Meier testing.
  
  
  CONCLUSIONS
  We have described a novel polymorphism at position -231* in the gene encoding furin. The fur -231* single nucleotide polymorphism in isolation, or in conjunction with TGFB1 polymorphism, is not useful as a genetic risk marker for cardiac transplant associated coronary vasculopathy.
authors.affiliation: Cardiothoracic Transplant Unit, Wythenshawe Hospital, Manchester, UK. cameron.d@virgin.net
authors.forename: C G
authors.initials: CG
authors.lastname: Densem
authors.forename: A-S M
authors.initials: AS
authors.lastname: Mutlak
authors.forename: V
authors.initials: V
authors.lastname: Pravica
authors.forename: N H
authors.initials: NH
authors.lastname: Brooks
authors.forename: N
authors.initials: N
authors.lastname: Yonan
authors.forename: I V
authors.initials: IV
authors.lastname: Hutchinson
mesh_terms: D000328:Adult; D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics; D005260:Female; D045683:Furin / Q000235:genetics*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D014184:Transplantation, Homologous; D006113:United Kingdom
chemical_list: C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D045683:Furin