Genetic polymorphisms impact the risk of acute rejection in pediatric heart transplantation: a multi-institutional study.
OBJECTIVE
The objective of this study was to determine the association between the genetic polymorphisms of proinflammatory and regulatory cytokines and long-term rates of repeat and late acute rejection episodes in pediatric heart transplant (PHTx) recipients.


METHODS
Three hundred twenty-three PHTx recipients: 205 White non-Hispanic, 43 Black non-Hispanic, and 75 Hispanic were analyzed for time to first repeat and late acute rejection episodes by race, age at transplantation, and gene polymorphism (interleukin [IL]-6, -174 G/C, IL-10, -1082 G/A, -819 C/T, 592 C/A; vascular endothelial growth factor (VEGF) -2578 C/A, -460 C/T, +405 C/G; tumor necrosis factor alpha (TNF-alpha)-308 G/A).


RESULTS
Recipient black race and older age at transplant were risk factors for both repeat and late rejections, though black race was more significantly related to late rejection (P=0.006). Individually, TNF-alpha high, IL-6 high, VEGF high, and IL-10 low phenotypes did not impact the risk of repeat or late rejection. However, the combination VEGF high/IL-6 high and IL-10 low was associated with increased estimated risk of late rejection (P=0.0004) and only marginally with repeat rejection (P=0.051). In a multivariate analysis, adjusting for age and race, VEGF high/IL-6 high and IL-10 low still remained an independent risk factor for late acute rejection (RR=1.91, P<0.001).


CONCLUSIONS
This is the largest multicenter study to document the impact of genetic polymorphism combinations on PHTx recipients' outcome. The high proinflammatory (VEGF high/IL-6 high) and lower regulatory (IL-10 low) cytokine gene polymorphism profile exhibited increased risk for late rejection, irrespective of age and race/ethnicity.
Girnita
Diana M
DM
Department of Pathology, Thomas E Starzl Transplant Institute, University of Pittsburgh, PA, USA.
Brooks
Maria M
MM
Webber
Steven A
SA
Burckart
Gilbert J
GJ
Ferrell
Robert
R
Zdanowicz
Gina
G
DeCroo
Susan
S
Smith
Louise
L
Chinnock
Richard
R
Canter
Charles
C
Addonizio
Linda
L
Bernstein
Daniel
D
Kirklin
James K
JK
Ranganathan
Sarangarajan
S
Naftel
David
D
Girnita
Alin L
AL
Zeevi
Adriana
A
D000208:Acute Disease; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D005006:Ethnicity; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006084:Graft Rejection / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D016027:Heart Transplantation / Q000473:pathology*; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic; D011379:Prognosis; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D014481:United States / Q000453:epidemiology
D016207:Cytokines; D004247:DNA