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

Abstract

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. 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.

Methods: We 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.

Results: After multiple testing adjustments, our analysis revealed 10 non-coding SNPs in tight linkage disequilibrium (0.75 ≤ r (2) ≤ 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).

Conclusions: Our 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.

Fig. 1

Regional plot of association results. Upper panel: The y-axis represents the − log₁₀-transformed p values for association tests. The x-axis represents the approximate location of the 40 single-nucleotide polymorphisms (SNPs) tested for association relative to the gene. Red circles depict associated SNPs after multiple comparison adjustments. Lower panel: This linkage disequilibrium (LD) plot is based on pairwise r ² values among SNPs from the European population of the 1000 Genomes Project. Each diamond of the LD plot represents an r ² value between two SNPs, schematically symbolized by a color gradient ranging from black (r ² = 1, corresponding to complete LD) to gray (1 < r ² < 0, moderate LD) and white (r ² = 0, absence of LD)