Polymorphism of the transforming growth factor-beta 1 gene correlates withthe development of coronary vasculopathy following cardiac transplantation

Background: Expression of transforming growth factor-beta 1 (TGF-beta 1) is central to vascular repair due to its effects on smooth muscle cell, monoc yte/macrophage, leucocyte, and extracellular matrix accumulation and prolif eration. Genetic polymorphism at position +915 of the TGF-beta 1 gene deter mines the degree of cytokine production in response to injury. We investiga ted this allelic variation on the development of cardiac transplant-related coronary vasculopathy (CV). Methods: Using sequence-specific primers to the TGF-beta 1 gene region of i nterest, a polymerase chain reaction (PCR) and gel electrophoresis identifi ed the genotype in 129 cardiac transplant recipients. An association was so ught between the presence of a high- (GG) or low/intermediate-producing (CC /GC) genotype and the development of coronary vasculopathy diagnosed by cor onary angiography. Results: C allele carriers made up 10.9% of the recipient population but we re significantly less likely to develop coronary vasculopathy (p = 0.0361). Mean time to diagnosis was 1240.5 days in G homozygotes relative to 2266.5 days in C allele carriers (p = 0.002). Pre- and 1-year posttransplant clin ical variables were equivalent between the 2 groups. Multivariate analysis identified the GG genotype (p = 0.042, hazard ratio 3.01, [95% CI, 1.056-10 .99]), donor age (p = 0.002 hazard ratio 1.063, [95% CI, 1.029-1.097]), and number of acute-rejection episodes of grade 3 or greater in the first year (p = 0.029, hazard ratio 1.11, [95% CI, 1.05-1.26]) as significant predict ors of vasculopathy. Conclusions: This study demonstrates a correlation between a high-producing TGF-beta 1 genotype and an earlier onset of cardiac-transplant coronary va sculopathy. This gives an important insight into the pathophysiology of car diac transplant vasculopathy and suggests new treatment options.