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

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

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. We performed a case-control study including 321 patients fulfilling international criteria for severe sepsis and ARDS admitted to a Spanish network of post-surgical and critical care units, and 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 regressions. 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 (OR) of 1.93 per T allele (95%CI: 1.17-3.18, p = 0.0089). 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.