Polymorphism of the transforming growth factor-beta 1 gene correlates with the development of coronary vasculopathy following cardiac transplantation.
BACKGROUND
Expression of transforming growth factor-beta1 (TGF-beta1) 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-beta1 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).


METHODS
Using sequence-specific primers to the TGF-beta1 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.


RESULTS
C 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.


CONCLUSIONS
This study demonstrates a correlation between a high-producing TGF-beta1 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.
Densem
C G
CG
Cardiothoracic Transplant Unit, Wythenshawe Hospital, Manchester, UK.
Hutchinson
I V
IV
Cooper
A
A
Yonan
N
N
Brooks
N H
NH
D000328:Adult; D000483:Alleles; D017023:Coronary Angiography; D003327:Coronary Disease / Q000000981:diagnostic imaging / Q000209:etiology* / Q000235:genetics; D004247:DNA / Q000032:analysis; D017931:DNA Primers / Q000737:chemistry; D005819:Genetic Markers; D005838:Genotype; D016027:Heart Transplantation / Q000009:adverse effects* / Q000000981:diagnostic imaging; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011379:Prognosis; D012189:Retrospective Studies; D016212:Transforming Growth Factor beta / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D005819:Genetic Markers; D016212:Transforming Growth Factor beta; D004247:DNA