title: Association of genetic polymorphisms and risk of late post-transplantation infection in pediatric heart recipients.
abstract: 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.
authors.affiliation: Department of Pediatrics, Division Cardiology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Erin L
authors.initials: EL
authors.lastname: Ohmann
authors.forename: Maria M
authors.initials: MM
authors.lastname: Brooks
authors.forename: Steven A
authors.initials: SA
authors.lastname: Webber
authors.forename: Diana M
authors.initials: DM
authors.lastname: Girnita
authors.forename: Robert E
authors.initials: RE
authors.lastname: Ferrell
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Burckart
authors.forename: Richard
authors.initials: R
authors.lastname: Chinnock
authors.forename: Charles
authors.initials: C
authors.lastname: Canter
authors.forename: Linda
authors.initials: L
authors.lastname: Addonizio
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
authors.forename: James K
authors.initials: JK
authors.lastname: Kirklin
authors.forename: David C
authors.initials: DC
authors.lastname: Naftel
authors.forename: Adriana
authors.initials: A
authors.lastname: Zeevi
mesh_terms: 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*
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1