Association of genetic polymorphisms and risk of late post-transplantation infection in pediatric heart recipients.
BACKGROUND
Late infections are common causes of morbidity and mortality after pediatric heart transplantation. In this multicenter study from 6 centers, we investigated the association between genetic polymorphisms (GPs) in immune response genes and late post-transplantation infections in 524 patients.


METHODS
Late infection was defined as a clinical infectious process occurring >60 days after transplantation and requiring hospitalization, intravenous antimicrobial therapy, or a life-threatening infection requiring oral therapy. All patients provided a blood sample for GP analyses of 18 GPs in cytokine, growth factor, and effector molecule genes by single specific primer-polymerase chain reaction and/or sequencing. Significant associations in univariable analyses were tested in multivariable Cox regression models.


RESULTS
Late infection was common, with 48.7% of patients experiencing ≥ 1 late infection, 25.2% had ≥ 1 late bacterial infection, and 30.5% had ≥ 1 late viral infection. Older age at transplantation was a protective factor for late infection, both bacterial and viral (hazard ratio [HR] 0.89-0.92 per 1-year age increase, p < 0.001). Adjusting for age, race, and transplant etiology, late bacterial infection was associated with HMOX1 A+326G AG and GG genotypes (HR, 2.41, 95% confidence interval [CI] 1.35-4.30; p = 0.003) and GZMB A-295G AA genotype (HR, 1.47; 95% CI; 1.03-2.1; p = 0.036). Late viral infection was associated with FAS A-670G GG genotype (HR, 1.42; 95% CI, 1.00-2.00; p = 0.050) in the adjusted model and with CTLA4 A+49G AA and AG genotypes (HR, 1.49; 95% CI, 1.02-2.19; p = 0.041) in univariable analysis.


CONCLUSIONS
We found an association between late bacterial infection and GP of HMOX1, which may control macrophage activation. A weaker association was also found between late viral infection and GP of CTLA4, a regulator of T-cell activation. This represents progress toward understanding the clinical and genetic risk factors of outcomes after transplantation.
Ohmann
Erin L
EL
Department of Pediatrics, Division Cardiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Brooks
Maria M
MM
Webber
Steven A
SA
Girnita
Diana M
DM
Ferrell
Robert E
RE
Burckart
Gilbert J
GJ
Chinnock
Richard
R
Canter
Charles
C
Addonizio
Linda
L
Bernstein
Daniel
D
Kirklin
James K
JK
Naftel
David C
DC
Zeevi
Adriana
A
D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics; D001424:Bacterial Infections / Q000235:genetics*; D060908:CTLA-4 Antigen; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016027:Heart Transplantation / Q000276:immunology*; D051547:Heme Oxygenase-1 / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D011110:Polymorphism, Genetic / Q000276:immunology*; D012307:Risk Factors; D014777:Virus Diseases / Q000235:genetics*
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1