Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation.

TitleOxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation.
Publication TypeJournal Article
Year of Publication2015
AuthorsCantu E, Shah RJ, Lin W, Daye ZJ, Diamond JM, Suzuki Y, Ellis JH, Borders CF, Andah GA, Beduhn B, Meyer NJ, Rushefski M, Aplenc R, Feng R, Christie JD
Corporate AuthorsLung Transplant Outcomes Group Investigators
JournalJ Thorac Cardiovasc Surg
Volume149
Issue2
Pagination596-602
Date Published02/2015
ISSN1097-685X
KeywordsAdult, Epistasis, Genetic, Female, Genetic Variation, Genotype, Glutathione Peroxidase, Humans, Lung Transplantation, Male, Membrane Proteins, Middle Aged, NADPH Oxidase, NF-E2-Related Factor 2, Oxidative Stress, Polymorphism, Single Nucleotide, Primary Graft Dysfunction, Risk, Tissue Donors
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.

DOI10.1016/j.jtcvs.2014.09.077
Alternate JournalJ. Thorac. Cardiovasc. Surg.
PubMed ID25439478
PubMed Central IDPMC4346512
Grant ListHL081619 / HL / NHLBI NIH HHS / United States
HL087115 / HL / NHLBI NIH HHS / United States
HL090021 / HL / NHLBI NIH HHS / United States
HL096845 / HL / NHLBI NIH HHS / United States
HL114626 / HL / NHLBI NIH HHS / United States
HL115354 / HL / NHLBI NIH HHS / United States
HL116656 / HL / NHLBI NIH HHS / United States
K23 HL116656 / HL / NHLBI NIH HHS / United States
K23 HL121406 / HL / NHLBI NIH HHS / United States
K24 HL115354 / HL / NHLBI NIH HHS / United States
R01 GM088566 / GM / NIGMS NIH HHS / United States
R01 HL081619 / HL / NHLBI NIH HHS / United States
R01 HL087115 / HL / NHLBI NIH HHS / United States
R01 HL096845 / HL / NHLBI NIH HHS / United States
R01 HL114626 / HL / NHLBI NIH HHS / United States
R0IGM088566 / / PHS HHS / United States