title: Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP in Post-Lung Transplant Primary Graft Dysfunction Risk.
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.
authors.affiliation: Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: E
authors.initials: E
authors.lastname: Cantu
authors.affiliation: Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: J M
authors.initials: JM
authors.lastname: Diamond
authors.affiliation: Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: J
authors.initials: J
authors.lastname: Ellis
authors.affiliation: Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: J
authors.initials: J
authors.lastname: Tiwari
authors.affiliation: Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: B
authors.initials: B
authors.lastname: Beduhn
authors.affiliation: Division of Cardiovascular Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: J R
authors.initials: JR
authors.lastname: Nellen
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: R
authors.initials: R
authors.lastname: Shah
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: N J
authors.initials: NJ
authors.lastname: Meyer
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York, New York.
authors.forename: D J
authors.initials: DJ
authors.lastname: Lederer
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA.|Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA.|Penn Cardiovascular Institute, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: S M
authors.initials: SM
authors.lastname: Kawut
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University, Durham, NC.
authors.forename: S M
authors.initials: SM
authors.lastname: Palmer
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University, Durham, NC.
authors.forename: L D
authors.initials: LD
authors.lastname: Snyder
authors.affiliation: Division of Cardiothoracic Surgery, Duke University, Durham, NC.
authors.forename: M G
authors.initials: MG
authors.lastname: Hartwig
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, University of Michigan, Ann Arbor, MI.
authors.forename: V N
authors.initials: VN
authors.lastname: Lama
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Chicago, Chicago, IL.
authors.forename: S
authors.initials: S
authors.lastname: Bhorade
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care, University of Pittsburgh, Pittsburgh, PA.
authors.forename: M
authors.initials: M
authors.lastname: Crespo
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA.|Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: E
authors.initials: E
authors.lastname: Demissie
authors.affiliation: Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, AL.
authors.forename: K
authors.initials: K
authors.lastname: Wille
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Johns Hopkins University Hospital, Baltimore, MD.
authors.forename: J
authors.initials: J
authors.lastname: Orens
authors.affiliation: Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Johns Hopkins University Hospital, Baltimore, MD.
authors.forename: P D
authors.initials: PD
authors.lastname: Shah
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Palo Alto, CA.
authors.forename: A
authors.initials: A
authors.lastname: Weinacker
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Stanford University, Palo Alto, CA.
authors.forename: D
authors.initials: D
authors.lastname: Weill
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: D
authors.initials: D
authors.lastname: Wilkes
authors.affiliation: Division of Pulmonary, Allergy, Critical Care, and Occupational Medicine, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: D
authors.initials: D
authors.lastname: Roe
authors.affiliation: Departments of Medicine and Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN.
authors.forename: L B
authors.initials: LB
authors.lastname: Ware
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: F
authors.initials: F
authors.lastname: Wang
authors.affiliation: Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: R
authors.initials: R
authors.lastname: Feng
authors.affiliation: Pulmonary, Allergy, and Critical Care Division, University of Pennsylvania School of Medicine, Philadelphia, PA.|Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine, Philadelphia, PA.
authors.forename: J D
authors.initials: JD
authors.lastname: Christie
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000032:analysis*; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D016040:Lung Transplantation / Q000009:adverse effects*; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood; D055031:Primary Graft Dysfunction / Q000097:blood / Q000175:diagnosis* / Q000209:etiology; D011379:Prognosis; D011446:Prospective Studies; D040641:Quantitative Trait Loci
chemical_list: D015415:Biomarkers; D047908:Intracellular Signaling Peptides and Proteins; D017395:Plasminogen Activator Inhibitor 1; C051321:SERPINE1 protein, human; C410602:TOLLIP protein, human
keywords: dysfunction; immune; inflammatory; ischemia reperfusion injury (IRI); lung (allograft) function; lung disease; lung transplantation; pulmonology; science; translational research