A novel polymorphism of the gene encoding furin, a TGF-beta1 activator, and the influence on cardiac allograft vasculopathy formation.
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.
Densem
C G
CG
Cardiothoracic Transplant Unit, Wythenshawe Hospital, Manchester, UK. cameron.d@virgin.net
Mutlak
A-S M
AS
Pravica
V
V
Brooks
N H
NH
Yonan
N
N
Hutchinson
I V
IV
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
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D045683:Furin