Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP
Year: 2015
Type: article
Study design: Observational Study
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.
DOI: 10.1111/ajt.13525
Authors: 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. Orens, P.D. Shah, A. Weinacker, D. Weill, D. Wilkes, D. Roe, L.B. Ware, F. Wang, R. Feng, J.D. Christie
Institutions: University of Pennsylvania, Columbia University, Duke University, University of Michigan, University of Chicago, University of Pittsburgh, University of Alabama at Birmingham, UAB Medicine, Johns Hopkins University, Johns Hopkins Hospital, Stanford University, Indiana University Indianapolis, Indiana University School of Medicine, Vanderbilt University
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,300
Awards: G1492157730, G1716080238, G1790595161, G1824412847, G1928704240, G207824585, G2119626930, G2120629349, G2237247269, G2451029711, Role of anti-Col (V) immunity in primary graft dysfunction, G2803751606, G3089758050, G3723776939, Long Pentraxin-3 genomics and outcomes after lung transplantation, G508706923, G543669872, G5538590106, G5894413795, Genetics of primary graft dysfunction, Mentored Patient-Oriented Research in Pulmonary Arterial Hypertension, G6608807841, G772516870, Mentored Patient Oriented Research in Lung Transplantation, G9000006503, G9000007332, G9000116104, G9000125658, G9000196175, G9000224224, G9000247242, G9000352518, G92921375, G934033823, G941931125, G990528317
OpenAlex ID: W2191756586