title: Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation.
abstract: OBJECTIVE
  Oxidant stress pathway activation during ischemia reperfusion injury may contribute to the development of primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidant stress gene variation in recipients and donors is associated with PGD.
  
  
  METHODS
  Donors and recipients from the Lung Transplant Outcomes Group (LTOG) cohort were genotyped using the Illumina IBC chip filtered for oxidant stress pathway genes. Single nucleotide polymorphisms (SNPs) grouped into SNP sets based on haplotype blocks within 49 oxidant stress genes selected from gene ontology pathways and literature review were tested for PGD association using a sequencing kernel association test. Analyses were adjusted for clinical confounding variables and population stratification.
  
  
  RESULTS
  Three hundred ninety-two donors and 1038 recipients met genetic quality control standards. Thirty percent of patients developed grade 3 PGD within 72 hours. Donor NADPH oxidase 3 (NOX3) was associated with PGD (P = .01) with 5 individual significant loci (P values between .006 and .03). In recipients, variation in glutathione peroxidase (GPX1) and NRF-2 (NFE2L2) was significantly associated with PGD (P = .01 for both). The GPX1 association included 3 individual loci (P values between .006 and .049) and the NFE2L2 association included 2 loci (P = .03 and .05). Significant epistatic effects influencing PGD susceptibility were evident between 3 different donor blocks of NOX3 and recipient NFE2L2 (P = .026, P = .017, and P = .031).
  
  
  CONCLUSIONS
  Our study has prioritized GPX1, NOX3, and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases the risk of PGD.
authors.affiliation: Cardiovascular Surgery Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa. Electronic address: edward.cantu@uphs.upenn.edu.
authors.forename: Edward
authors.initials: E
authors.lastname: Cantu
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Rupal J
authors.initials: RJ
authors.lastname: Shah
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Zhongyin J
authors.initials: ZJ
authors.lastname: Daye
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Diamond
authors.affiliation: Cardiovascular Surgery Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Cardiovascular Surgery Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
authors.forename: John H
authors.initials: JH
authors.lastname: Ellis
authors.affiliation: Cardiovascular Surgery Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
authors.forename: Catherine F
authors.initials: CF
authors.lastname: Borders
authors.affiliation: Cardiovascular Surgery Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
authors.forename: Gerald A
authors.initials: GA
authors.lastname: Andah
authors.affiliation: Cardiovascular Surgery Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa.
authors.forename: Ben
authors.initials: B
authors.lastname: Beduhn
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Melanie
authors.initials: M
authors.lastname: Ruschefski
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa; Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pa.
authors.forename: Richard
authors.initials: R
authors.lastname: Aplenc
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pa; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Division of Oncology, Philadelphia, Pa.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
mesh_terms: D000328:Adult; D004843:Epistasis, Genetic; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D005979:Glutathione Peroxidase / Q000235:genetics*; D006801:Humans; D016040:Lung Transplantation; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D019255:NADPH Oxidases / Q000235:genetics*; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D055031:Primary Graft Dysfunction / Q000235:genetics*; D012306:Risk; D014019:Tissue Donors; D000094765:Glutathione Peroxidase GPX1
chemical_list: D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D005979:Glutathione Peroxidase; D019255:NADPH Oxidases; C431570:Nox3 protein, human; D000094765:Glutathione Peroxidase GPX1; C000722067:GPX1 protein, human