Donor and recipient-transforming growth factor-beta 1 polymorphism and cardiac transplant-related coronary artery disease.
BACKGROUND
Transforming growth factor-beta1 (TGF-beta1) 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-beta1 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.
Densem
C G
CG
Cardiothoracic Transplant Unit, Wythenshawe Hospital, Manchester, UK. cameron.d@virgin.net
Hutchinson
I V
IV
Yonan
N
N
Brooks
N H
NH
D017023:Coronary Angiography; D003324:Coronary Artery Disease / Q000000981:diagnostic imaging / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D005838:Genotype; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007165:Immunosuppression Therapy; D019990:Perioperative Care; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors; D014019:Tissue Donors; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1; D006113:United Kingdom / Q000453:epidemiology
C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1