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

Abstract

Background: Expression of transforming growth factor–β1 (TGF-β1) is central to vascular repair due to its effects on smooth muscle cell, monocyte/macrophage, leucocyte, and extracellular matrix accumulation and proliferation. Genetic polymorphism at position +915 of the TGF-β1 gene determines the degree of cytokine production in response to injury. We investigated this allelic variation on the development of cardiac transplant–related coronary vasculopathy (CV). MethodsUsing sequence-specific primers to the TGF-β1 gene region of interest, a polymerase chain reaction (PCR) and gel electrophoresis identified the genotype in 129 cardiac transplant recipients. An association was sought between the presence of a high- (GG) or low/intermediate-producing (CC/GC) genotype and the development of coronary vasculopathy diagnosed by coronary angiography. ResultsC allele carriers made up 10.9% of the recipient population but were 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 clinical 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 predictors of vasculopathy. ConclusionsThis study demonstrates a correlation between a high-producing TGF-β1 genotype and an earlier onset of cardiac-transplant coronary vasculopathy. This gives an important insight into the pathophysiology of cardiac transplant vasculopathy and suggests new treatment options.