A novel polymorphism of the gene encoding furin, a TGF-β1 activator, and the influence on cardiac allograft vasculopathy formation

• Published in: Transplant immunology 2004-11, Vol.13 (3), p.185-190
• Main Authors: Densem, C.G., Mutlak, A.-S.M., Pravica, V., Brooks, N.H., Yonan, N., Hutchinson, I.V.
• Format: Article
• Language: English
• Subjects: Cardiac transplantation; Furin; Transforming growth factor β1; Vasculopathy
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2004.04.005

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-β1 (TGF-β1) gene strongly influences CV development. Furin is a proprotein convertase enzyme important in TGF-β1 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-β1 polymorphism, was subsequently related to the development of CV. Methods and 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-β1 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-β1 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.