Donor and recipient-transforming growth factor-beta 1 polymorphism and cardiac transplant-related coronary artery disease

Abstract

Background: Transforming growth factor-β1 (TGF-β1) has been implicated in the pathogenesis of coronary vasculopathy following cardiac transplantation. The TGFB1 gene contains polymorphisms at positions +915* (Arg25Pro) and +869* (Leu10Pro) which may influence TGF-β1 expression. We investigated the relationship between the development of coronary vasculopathy and the prevalence of these alleles in a cardiac transplant population. Methods: Vasculopathy was diagnosed at routine surveillance post-transplant coronary angiography. Using sequence-specific polymerase chain reaction we identified the TGFB1 +915* and +869* genotypes in 147 cardiac transplant recipients and 134 cardiac donors. Results TGFB1 +915*C allele carriers (low producers) made up 10.5% of the recipient population but were significantly less likely to develop coronary vasculopathy ( P=0.03). Median time to diagnosis was 6.0 years (3.9–8.72) in +915*C allele carriers compared to 2.75 years (2.10–4.22) in *G/G homozygotes ( p=0.002). Pre- and 1 year post-transplant clinical variables were equivalent between the two groups. Multivariate analysis identified the recipient +915*G/G genotype (hazard ratio 2.96 (95% CI, 1.09–9.98); p=0.039), donor age (hazard ratio 1.05 (95% CI, 1.02–1.09); p=0.008) and number of acute rejection episodes of ISHLT grade 3 or greater in the first year (hazard ratio 1.12 (95% CI, 1.01–1.23); p=0.03) as significant predictors of vasculopathy. The recipient TGFB1 +869*, and both alleles in the donor, had no influence on vasculopathy development. Conclusions Recipient TGFB1 +915* genotype influences the development of cardiac transplant-related coronary vasculopathy. This gives an important insight to the pathophysiology of the disease. On the contrary, donor TGFB1 +915* and TGFB1 +869* polymorphisms do not appear to be important and cannot be used as genetic risk factors.