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. 2015 Feb;149(2):596-602.
doi: 10.1016/j.jtcvs.2014.09.077. Epub 2014 Sep 28.

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

Edward Cantu  1 , Rupal J Shah  2 , Wei Lin  3 , Zhongyin J Daye  3 , Joshua M Diamond  2 , Yoshikazu Suzuki  4 , John H Ellis  4 , Catherine F Borders  4 , Gerald A Andah  4 , Ben Beduhn  4 , Nuala J Meyer  2 , Melanie Ruschefski  2 , Richard Aplenc  5 , Rui Feng  3 , Jason D Christie  2 ; Lung Transplant Outcomes Group Investigators
Collaborators, Affiliations

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

Edward Cantu et al. J Thorac Cardiovasc Surg. 2015 Feb.

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.

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Conflict of interest statement

Competing interests

The author(s) declare that they have no competing interests.

Figures

FIGURE 1
FIGURE 1
Enrollment Design
FIGURE 2
FIGURE 2
SNPset Block interaction Individual SNPs are represented by a rectangle. Blocks are delineated by dotted lines. The highest intensities are evident in donor NOX3 block 3 with recipient NFE2L2 block 1 and in donor NOX3 block 3 with recipient NFE2L2 blocks 1 and 2. SNP, single nucleotide polymorphism.
See this image and copyright information in PMC

Comment in

References

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