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

被引：21

作者：

Cantu, E. ^{[1
]}

Suzuki, Y. ^{[1
]}

Diamond, J. M. ^{[2
]}

Ellis, J. ^{[1
]}

Tiwari, J. ^{[1
]}

Beduhn, B. ^{[1
]}

Nellen, J. R. ^{[1
]}

Shah, R. ^{[2
]}

Meyer, N. J. ^{[2
]}

Lederer, D. J. ^{[3
]}

Kawut, S. M. ^{[2
,4
,5
]}

Palmer, S. M. ^{[6
]}

Snyder, L. D. ^{[6
]}

Hartwig, M. G. ^{[7
]}

Lama, V. N. ^{[8
]}

Bhorade, S. ^{[9
]}

Crespo, M. ^{[10
]}

Demissie, E. ^{[2
,4
]}

Wille, K. ^{[11
]}

Orens, J. ^{[12
]}

Shah, P. D. ^{[12
]}

Weinacker, A. ^{[13
]}

Weill, D. ^{[13
]}

Wilkes, D. ^{[14
]}

Roe, D. ^{[14
]}

Ware, L. B. ^{[15
,16
]}

Wang, F. ^{[4
]}

Feng, R. ^{[4
]}

Christie, J. D. ^{[2
,4
]}

机构：

[1] Univ Penn, Sch Med, Div Cardiovasc Surg, Philadelphia, PA 19104 USA

[2] Univ Penn, Sch Med, Pulm Allergy & Crit Care Div, Philadelphia, PA 19104 USA

[3] Columbia Univ, Coll Phys & Surg, Div Pulm Allergy & Crit Care Med, New York, NY 10027 USA

[4] Univ Penn, Sch Med, Ctr Clin Epidemiol & Biostat, Philadelphia, PA 19104 USA

[5] Univ Penn, Sch Med, Penn Cardiovasc Inst, Philadelphia, PA 19104 USA

[6] Duke Univ, Div Pulm Allergy & Crit Care Med, Durham, NC USA

[7] Duke Univ, Div Cardiothorac Surg, Durham, NC USA

[8] Univ Michigan, Div Pulm Allergy & Crit Care Med, Ann Arbor, MI 48109 USA

[9] Univ Chicago, Div Pulm & Crit Care Med, Chicago, IL 60637 USA

[10] Univ Pittsburgh, Div Pulm Allergy & Crit Care, Pittsburgh, PA USA

[11] Univ Alabama Birmingham, Div Pulm & Crit Care Med, Birmingham, AL USA

[12] Johns Hopkins Univ Hosp, Dept Med, Div Pulm Allergy & Crit Care Med, Baltimore, MD 21205 USA

[13] Stanford Univ, Div Pulm & Crit Care Med, Palo Alto, CA 94304 USA

[14] Indiana Univ, Sch Med, Div Pulm Allergy Crit Care & Occupat Med, Indianapolis, IN 46204 USA

[15] Vanderbilt Univ, Dept Pathol & Med, 221 Kirkland Hall, Nashville, TN 37235 USA

[16] Vanderbilt Univ, Dept Microbiol & Immunol, 221 Kirkland Hall, Nashville, TN 37235 USA

来源：

AMERICAN JOURNAL OF TRANSPLANTATION | 2016年 / 16卷 / 03期

基金：

美国国家卫生研究院;

关键词：

translational research; science; lung transplantation; pulmonology; ischemia reperfusion injury (IRI); lung (allograft) function; dysfunction; lung disease; immune; inflammatory; GENOME-WIDE ASSOCIATION; RESPIRATORY-DISTRESS-SYNDROME; EXPRESSION; SET; SUSCEPTIBILITY; POLYMORPHISMS; DEFINITION; OUTCOMES; INJURY; MOUSE;

D O I：

10.1111/ajt.13525

中图分类号：

R61 [外科手术学];

学科分类号：

摘要：

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 < 5x10(-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.

引用

页码：833 / 840

页数：8

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