ARDS is a lung condition characterized by impaired gas exchange with systemic release of inflammatory mediators, causing inflammation, hypoxemia and multiple organ failure. Disease susceptibility and progression are poorly understood and there are few effective therapeutic options. Existing biomarkers have limited effectiveness as diagnostic and therapeutic targets. Whole-exome sequencing is an effective tool in detection of disease-causing genetic variants in complex genetic conditions such as acute respiratory distress syndrome (ARDS). To identify disease-causing variants in ARDS patients, whole-exome sequencing was performed on 96 patient DNA samples from the National Heart, Lung and Blood Institute's ARDS Network (ARDSnet). By comparing these exome data with 625 participants of the 1000 Genomes Project, we have tentatively identified a number of single nucleotide polymorphisms (SNP) which are potentially associated with ARDS. In this study, we validated three SNPs (rs78142040, rs9605146, and rs3848719) in an additional 117 ARDS patients using TaqMan SNP genotyping assays (Life Technologies) to substantiate their associations with the susceptibility, severity and outcome of ARDS. rs78142040 (C>T) occurs within a histone mark in intron 6 of the Arylsulfatase D gene. rs9605146 (G>A)(also known as rs114989947) causes a coding change (proline to leucine) with a deleterious effect in the XK, Kell blood group complex subunit-related family, member 3 gene. rs3848719 (G>A) is a synonymous SNP in exon 5 of gene Zinc-Finger/Leucine-Zipper Co-Transducer NIF1. rs78142040 and rs9605146 are significantly associated with susceptibility to ARDS[minor allele frequency (MAF): 0.219 versus 0.003 (control), p 1A—10-4) in our cases. These 3 SNPs have not been previously associated with ARDS and represent potential new genetic biomarkers for ARDS. More validations in larger patient populations and further exploration of underlying molecular mechanisms are warranted

Introduction: Angiopoietin-like protein 4 (ANGPTL4) is a dual-function protein: an inhibitor of lipoprotein and hepatic lipases with angiogenic properties. Its E40K mutation is associated with an i...

Restricted accessAbstractFirst published March 2006Novel Role of Pre-B-Cell Colony-Enhancing Factor in Pulmonary Endothelial Barrier RegulationL.Q. Zhang, J. Cepeda, […], J.G.N. Garcia, and S.Q. Ye+1-1View all authors and affiliationsVolume 54, Issue 2_supplhttps://doi.org/10.1177/108155890605402s49

Rationale Our prior genomic and genetic studies identified pre-B-cell colony-enhancing factor (PBEF) as a potential novel biomarker in acute lung injury (ALI) (Ye et al, 2005). To elucidate the molecular mechanism underlying PBEF in the pathogenesis of ALI, we assessed the role of PBEF in in vitro vascular barrier regulation using confluent human pulmonary artery endothelial cell (HPAEC) or microvascular cells (HMVEC-L) monolayers since increased vascular permeability is a cardinal feature of ALI. Methods Inhibition of PBEF expression was achieved by the PBEF siRNAs. Overexpression of the PBEF gene was accomplished by adeno-PBEF. Endothelial cells (EC) were transfected with PBEF siRNA or infected with adeno-PBEF for 48 hours before treated with thrombin (0.1 U/mL) or S1P (1 mm) for various time. Parameters to evaluate endothelial cell barrier functions include transendothelial electric resistance (TER), actin staining, myosin light chain phosphorylation, calcium influx. Results Reductions in PBEF protein expression (> 70%) by siRNA significantly attenuated EC barrier dysfunction induced by the potent edemagenic agent, thrombin reflected by reductions in TER (60 to 70% reduction). Furthermore, PBEF siRNA blunted thrombin-mediated increases in increases in Ca2+ entry, polymerized actin formation, and myosin light chain phosphorylation, events critical to the thrombin-mediated permeability response. Overexpression of PBEF by adeno-PBEF vector significantly increases EC permeability reflected by decreased TER in HMVEC-L by ≈30%, indicating that overexpression of PBEF results in dysfunction. Conclusions These in vitro observations strongly support that PBEF is critically involved in the endothelial cell barrier regulation. It encourages us to further explore the mechanistic insight into PBEF in the murine model of ALI. Funded by NHLBI SCCOR-Molecular Approaches to Ventilator-Associated Lung Injury (U01HL 073994).

An increased expression of E‐selectin has been observed in the arterial endothelium interacting with lymphocytes and macrophages in human atherosclerotic lesions. We examined whether a polymorphism in the E‐selectin gene, due to a G to T mutation (G98T) in the untranslated region of exon 2, was associated with premature coronary artery disease (CAD). Other lipid and nonlipid risk factors including a Ser to Arg (S128R) substitution in the E‐selectin gene were also assessed. In patients with premature CAD (men ≤45 years old and women ≤55 years old, N=51) who underwent an elective diagnostic coronary arteriography, the frequency of the mutation was significantly higher than in controls (N=50, 0.22 vs. 0.10, p=0.024). After controlling for other CAD risk factors (plasma total cholesterol, triglyceride, LDL‐apolipoprotein B, cigarette smoking and the S128R mutation) by multiple logistic analysis, the G98T mutation in the E‐selectin gene was still a significant predictor of premature CAD [p=0.022, odds ratio (95%, CI)=3.58 (1.20–10.67)].