Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk

E. Cantu*, Y. Suzuki, J. M. Diamond, J. Ellis, J. Tiwari, B. Beduhn, J. R. Nellen, R. Shah, N. J. Meyer, D. J. Lederer, S. M. Kawut, S. M. Palmer, L. D. Snyder, M. G. Hartwig, V. N. Lama, S. Bhorade, M. Crespo, E. Demissie, K. Wille, J. OrensP. D. Shah, A. Weinacker, D. Weill, D. Wilkes, D. Roe, L. B. Ware, F. Wang, R. Feng, J. D. Christie

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10-4 cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis. Plasma plasminogen activator inhibitor-1 quantitative trait analysis prioritizes genetic variations in TOLLIP for posttransplant primary graft dysfunction and supports a role for Toll-like receptors in primary graft dysfunction pathogenesis.

Original languageEnglish (US)
Pages (from-to)833-840
Number of pages8
JournalAmerican Journal of Transplantation
Volume16
Issue number3
DOIs
StatePublished - Mar 1 2016

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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