Common variants of NFE2L2 gene predisposes to acute respiratory distress syndrome in patients with severe sepsis.

Marialbert Acosta-Herrera,Maria Pino-Yanes,Ramón Adalia,Almudena Corrales,Carlés Subirá,Lina Pérez-Méndez,For The Grecia And Gen-Sep Networks ,David Domínguez,Aurora Baluja,Carlos Flores,Francisco Gandía,Juan Carlos Ballesteros,Jesus Villar,Jesús Blanco,Alfonso Ambrós,José Manuel Añón

doi:10.1186/s13054-015-0981-y

Abstract

IntroductionThe purpose of this study was to investigate whether common variants across the nuclear factor erythroid 2-like 2 (NFE2L2) gene contribute to the development of the acute respiratory distress syndrome (ARDS) in patients with severe sepsis. NFE2L2 is involved in the response to oxidative stress, and it has been shown to be associated with the development of ARDS in trauma patients.MethodsWe performed a case–control study of 321 patients fulfilling international criteria for severe sepsis and ARDS who were admitted to a Spanish network of post-surgical and critical care units, as well as 871 population-based controls. Six tagging single-nucleotide polymorphisms (SNPs) of NFE2L2 were genotyped, and, after further imputation of additional 34 SNPs, association testing with ARDS susceptibility was conducted using logistic regression analysis.ResultsAfter multiple testing adjustments, our analysis revealed 10 non-coding SNPs in tight linkage disequilibrium (0.75 ≤ r2 ≤ 1) that were associated with ARDS susceptibility as a single association signal. One of those SNPs (rs672961) was previously associated with trauma-induced ARDS and modified the promoter activity of the NFE2L2 gene, showing an odds ratio of 1.93 per T allele (95 % confidence interval, 1.17–3.18; p = 0.0089).ConclusionsOur findings support the involvement of NFE2L2 gene variants in ARDS susceptibility and reinforce further exploration of the role of oxidant stress response as a risk factor for ARDS in critically ill patients.

Highlights

The purpose of this study was to investigate whether common variants across the nuclear factor erythroid 2-like 2 (NFE2L2) gene contribute to the development of the acute respiratory distress syndrome (ARDS) in patients with severe sepsis
Given that chromatin modifications on histone marks are critically involved in the regulation of gene expression and that these regions tend to collocate with DNase-sensitive sites in transcriptional start sites [31], this evidence highlights the key role of rs6721961 in the regulation of NFE2L2 expression
Research in this field will eventually translate into potentially useful information by identifying new pathways and novel therapeutic approaches, and by developing predisposition biomarkers to stratify at-risk patients, facilitating personalized patient assessment and better patient management

Summary

Introduction

The purpose of this study was to investigate whether common variants across the nuclear factor erythroid 2-like 2 (NFE2L2) gene contribute to the development of the acute respiratory distress syndrome (ARDS) in patients with severe sepsis. The nuclear factor erythroid 2-like 2, known as NRF2 or NFE2L2, plays a central role in the antioxidant mechanisms against ROS. In previous positional cloning studies in experimental animals, researchers have identified NFE2L2 as a candidate gene for hyperoxia-induced lung injury susceptibility [7, 8]. These results were validated in humans, in whom common single-nucleotide polymorphisms (SNPs) were identified by resequencing analysis and candidate SNP functionality was proven in cell lines. The association of common variants with ARDS susceptibility and mortality has been reported recently [9,10,11]

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