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

Edward Cantu, Rupal J. Shah, Wei Lin, Zhongyin J Daye, Joshua M. Diamond, Yoshikazu Suzuki, John H. Ellis, Catherine F. Borders, Gerald A. Andah, Ben Beduhn, Nuala J. Meyer, Melanie Ruschefski, Richard Aplenc, Rui Feng, Jason D. Christie

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)596-602.e3
JournalJournal of Thoracic and Cardiovascular Surgery
Volume149
Issue number2
DOIs
StatePublished - Feb 1 2015
Externally publishedYes

Fingerprint

Primary Graft Dysfunction
Lung Transplantation
Oxidants
Tissue Donors
NADPH Oxidase
Genes
Single Nucleotide Polymorphism
Gene Ontology
Confounding Factors (Epidemiology)
Reperfusion Injury
Quality Control
Haplotypes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Surgery
  • Pulmonary and Respiratory Medicine

Cite this

Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation. / Cantu, Edward; Shah, Rupal J.; Lin, Wei; Daye, Zhongyin J; Diamond, Joshua M.; Suzuki, Yoshikazu; Ellis, John H.; Borders, Catherine F.; Andah, Gerald A.; Beduhn, Ben; Meyer, Nuala J.; Ruschefski, Melanie; Aplenc, Richard; Feng, Rui; Christie, Jason D.

In: Journal of Thoracic and Cardiovascular Surgery, Vol. 149, No. 2, 01.02.2015, p. 596-602.e3.

Research output: Contribution to journalArticle

Cantu, E, Shah, RJ, Lin, W, Daye, ZJ, Diamond, JM, Suzuki, Y, Ellis, JH, Borders, CF, Andah, GA, Beduhn, B, Meyer, NJ, Ruschefski, M, Aplenc, R, Feng, R & Christie, JD 2015, 'Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation', Journal of Thoracic and Cardiovascular Surgery, vol. 149, no. 2, pp. 596-602.e3. https://doi.org/10.1016/j.jtcvs.2014.09.077
Cantu, Edward ; Shah, Rupal J. ; Lin, Wei ; Daye, Zhongyin J ; Diamond, Joshua M. ; Suzuki, Yoshikazu ; Ellis, John H. ; Borders, Catherine F. ; Andah, Gerald A. ; Beduhn, Ben ; Meyer, Nuala J. ; Ruschefski, Melanie ; Aplenc, Richard ; Feng, Rui ; Christie, Jason D. / Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation. In: Journal of Thoracic and Cardiovascular Surgery. 2015 ; Vol. 149, No. 2. pp. 596-602.e3.
@article{ed61d88e8b9a462580b14a9aff8593e8,
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.",
author = "Edward Cantu and Shah, {Rupal J.} and Wei Lin and Daye, {Zhongyin J} and Diamond, {Joshua M.} and Yoshikazu Suzuki and Ellis, {John H.} and Borders, {Catherine F.} and Andah, {Gerald A.} and Ben Beduhn and Meyer, {Nuala J.} and Melanie Ruschefski and Richard Aplenc and Rui Feng and Christie, {Jason D.}",
year = "2015",
month = "2",
day = "1",
doi = "10.1016/j.jtcvs.2014.09.077",
language = "English (US)",
volume = "149",
pages = "596--602.e3",
journal = "Journal of Thoracic and Cardiovascular Surgery",
issn = "0022-5223",
publisher = "Mosby Inc.",
number = "2",

}

TY - JOUR

T1 - Oxidant stress regulatory genetic variation in recipients and donors contributes to risk of primary graft dysfunction after lung transplantation

AU - Cantu, Edward

AU - Shah, Rupal J.

AU - Lin, Wei

AU - Daye, Zhongyin J

AU - Diamond, Joshua M.

AU - Suzuki, Yoshikazu

AU - Ellis, John H.

AU - Borders, Catherine F.

AU - Andah, Gerald A.

AU - Beduhn, Ben

AU - Meyer, Nuala J.

AU - Ruschefski, Melanie

AU - Aplenc, Richard

AU - Feng, Rui

AU - Christie, Jason D.

PY - 2015/2/1

Y1 - 2015/2/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84923614930&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84923614930&partnerID=8YFLogxK

U2 - 10.1016/j.jtcvs.2014.09.077

DO - 10.1016/j.jtcvs.2014.09.077

M3 - Article

C2 - 25439478

AN - SCOPUS:84923614930

VL - 149

SP - 596-602.e3

JO - Journal of Thoracic and Cardiovascular Surgery

JF - Journal of Thoracic and Cardiovascular Surgery

SN - 0022-5223

IS - 2

ER -