Protein Quantitative Trait Loci Analysis Identifies Genetic Variation in the Innate Immune Regulator TOLLIP

Abstract

Summary We previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in PGD. We hypothesized plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A 2-stage cohort study was performed. In stage 1, we 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. 297 enrollees were evaluated in Stage 1. 6 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% CI: 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.

Peripheral Blood Gene Expression Changes Associated With Primary Graft Dysfunction After Lung Transplantation

“…Likewise, mirroring our blood findings, Nod-like receptor (NLR), toll-like receptor (TLR), and myeloid differentiation primary response gene 88 (MyD88) pathways were among the most highly ranked gene sets in patients with PGD in an analysis of BAL fluid gene expression in a nested population from this CTOT 03 study 7 . Recipient genetic variation in toll-interacting protein ( TOLLIP ), a regulator of innate inflammatory TLR signaling cascades, is also significantly associated with risk for PGD after lung transplantation 21 . Taken together, the pathways identified in our current and previous studies indicate that inflammasome and innate immune activity are upregulated both locally in the allograft and systemically in the recipient in patients with PGD, thus providing further evidence that innate immune and inflammasome signaling pathways are novel targets for future PGD preventative and therapeutic interventions.…”

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation

“…32 Notably, those findings from experimental models of lung IRI are consistent with recent human genomic studies of PGD. 11,23 …”

“…8 Janeway and Medzhitov showed that DAMPs, along with pathogen-associated molecule patterns (PAMPs), are recognized by pattern recognition receptors (PRRs) that, when engaged, stimulate inflammatory gene expression. 9 Later reports showed DAMP accumulation and the involvement of PRR signaling pathways in PGD patients, but precisely how they contribute to this type of acute lung injury remains an active area of investigation, 3,10,11 as lung IRI also may be influenced by PAMPs derived from the gut microbiota. 12 In addition, the recent availability of multicenter-derived lung transplant recipient outcome data in conjunction with transcriptome and genomic analysis and new experimental approaches has identified additional mechanisms that could promote PGD.…”

Cell-free hemoglobin promotes primary graft dysfunction through oxidative lung endothelial injury

“…A variety of clinical risk factors for PGD have been identified with contributions from the donor (3)(4)(5)(6)(7), the recipient (3)(4)(5)(7)(8)(9)(10), and operative variables (4,5,8,11). In addition, a number of biomarkers have been associated with increased risk of PGD, including markers of innate and adaptive immune activation, epithelial and endothelial injury, coagulation, vascular permeability, and lipid peroxidation (2,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27). Despite identification of these clinical and biomarker predictors of PGD, the mechanisms leading to PGD are not well understood, and there are no specific therapeutic interventions for PGD.…”