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 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 392 donors and 1038 recipients met genetic quality control standards. 30% of subjects developed grade 3 PGD within 72 hours. Donor NADPH Oxidase 3 (NOX3) was associated with PGD (p=0.01) with 5 individual significant loci (p-values between 0.006 and 0.03). In recipients, variation in glutathione peroxidase (GPX1) and NRF-2 (NFE2L2) was significantly associated with PGD (p=0.01 for both). The GPX1 association included 3 individual loci (p-values between 0.006 and 0.049) and the NFE2L2 association included 2 loci (p=0.03 and 0.05). Significant epistatic effects influencing PGD susceptibility were evident between three different donor blocks of NOX3 and recipient NFE2L2 (p=0.026, p=0.017 and p=0.031). Conclusions Our study prioritizes GPX1, NOX3, and NFE2L2 genes for future research in PGD pathogenesis, and highlights a donor-recipient interaction of NOX3 and NFE2L2 that increases PGD risk.

The Perioperative Lung Transplant Virome: Torque Teno Viruses Are Elevated in Donor Lungs and Show Divergent Dynamics in Primary Graft Dysfunction

“…Activated immune cells and reactive oxygen species generated during ischemia-reperfusion are thought to injure lung endothelium and epithelium (3). Host genetic variation in genes involved in oxidant stress responses and innate immunity correlate with risk of PGD (13, 14). PGD has also been associated with inflammasome activation, pattern recognition receptor signaling, and complement activation within the allograft (15–17).…”

One step closer to the elimination of primary graft dysfunction

“…As supported by the findings in the study published by Cantu and colleagues 1 in this issue of the Journal , as many as 30%of patients will have development of grade 3 PGD, defined by a PaO2 to inspired oxygen fraction ratio less than 200 along with diffuse allograft infiltrates on chest radiography. Implicated in PGD is ischemia–reperfusion injury, which our laboratory has studied and published on extensively, as well as activation of the oxidant stress pathway.…”

“…Cantu and colleagues 1 completed a large, multicenter prospective cohort study of lung transplant donors and recipients selected from the Lung Transplant Outcomes Group. DNA samples from 1038 lung transplant recipients and 392 lung donors were analyzed for the presence of 49 oxidant stress genes with single-nucleotide polymorphism set analysis.…”

Onset of Inflammation With Ischemia: Implications for Donor Lung Preservation and Transplant Survival

“…Of note, these inflammatory signals may or may not translate into clinical symptoms of PGD because posttransplant outcome depends on factors associated with both the donor lung and the recipient. As we showed previously, both donor lung oxidant stress and recipient antioxidant status are pivotal in determining injury outcome and PGD . Recipient antioxidant status as well as the inconsistency in the definition of PGD may also account for the contrasting conclusions (from clinical trials) regarding the correlation between ischemia time and PGD.…”