Genetic polymorphism in platelet-derived growth factor and vascular endothelial growth factor are significantly associated with cardiac allograft vasculopathy.
BACKGROUND
The role of cytokine gene polymorphism and its association with acute heart allograft rejection and cardiac allograft vasculopathy (CAV) is controversial. The role of growth factor gene polymorphism has never been investigated in heart allograft recipients.


METHODS
Seventy heart transplant recipients were studied. Mean age at transplant was 50.4 +/- 12.4 years (73% white, 91% male). Patients were followed for an average of 28 +/- 12 months. Cellular rejection episodes were determined based on criteria established by the International Society of Heart and Lung Transplantation. Angiography and intravascular ultrasound (IVUS) were performed annually. Cytokine and growth factor polymorphism data were analyzed using the single-nucleotide polymorphism polymerase chain reaction (SNP PCR) approach.


RESULTS
Patients who developed early CAV, documented by angiography, had increased frequency of the interferon-gamma high-producer phenotype, increased frequency of PDGF-286 AA, and decreased frequency of PDGF-1135 CC (p < 0.03, p < 0.03 and p = 0.01, respectively). Platelet-derived growth factor (PDGF) associations with early CAV were substantiated when vasculopathy was determined by IVUS. Additional associations were identified with vascular endothelial growth factor (VEGF) polymorphisms-1154 GG and -2578 AC (p < 0.03 and p = 0.01, respectively). Some of these associations translated to decreased patient survival, as indicated by Kaplan-Meier analysis. No significant association was identified between cytokine gene polymorphism (tumor necrosis factor-alpha, transforming growth factor-beta, interferon-gamma, interleukin-6 and interleukin-10) and acute cellular rejection episodes.


CONCLUSIONS
These data suggest an association between PDGF and VEGF polymorphism and CAV. It is essential, however, due to the redundancy of the immune system and other confounding factors, that future studies be centrally conducted and include multiple programs, large cohorts of patients and properly chosen controls. Only then will we be able to identify the true association between cytokine and growth factor polymorphism and heart transplant outcome.
Tambur
Anat R
AR
Division of Organ Transplantation, Department of Surgery, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611-3008, USA. a-tambur@northwestern.edu
Pamboukian
Salpy
S
Costanzo
Maria-Rosa
MR
Heroux
Alain
A
D000368:Aged; D017023:Coronary Angiography; D003327:Coronary Disease / Q000235:genetics* / Q000276:immunology / Q000401:mortality; D005260:Female; D016027:Heart Transplantation / Q000276:immunology* / Q000401:mortality; D006789:Host vs Graft Reaction; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000235:genetics; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D018084:Ultrasonography, Interventional; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics*
D015850:Interleukin-6; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D007371:Interferon-gamma