title: Common variants of NFE2L2 gene predisposes to acute respiratory distress syndrome in patients with severe sepsis.
abstract: BACKGROUND
  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.
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. m.acostaherrera@gmail.com.|Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario 145, 38010, Santa Cruz de Tenerife, Spain. m.acostaherrera@gmail.com.|Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n - 4th floor, south wing, 35019, Las Palmas de Gran Canaria, Spain. m.acostaherrera@gmail.com.
authors.forename: Marialbert
authors.initials: M
authors.lastname: Acosta-Herrera
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. mdelpino@ull.edu.es.|Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario 145, 38010, Santa Cruz de Tenerife, Spain. mdelpino@ull.edu.es.
authors.forename: Maria
authors.initials: M
authors.lastname: Pino-Yanes
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jblancov@saludcastillayleon.es.|Intensive Care Unit, Hospital Universitario Río Hortega, Valladolid, Spain. jblancov@saludcastillayleon.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Blanco
authors.affiliation: Intensive Care Unit, Hospital Clínico Universitario de Salamanca, Salamanca, Spain. jcballes@ono.com.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ballesteros
authors.affiliation: Intensive Care Unit, Hospital General Universitario de Ciudad Real, Ciudad Real, Spain. alfonsoa@sescam.jccm.es.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Ambrós
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. acm4580@yahoo.es.|Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario 145, 38010, Santa Cruz de Tenerife, Spain. acm4580@yahoo.es.
authors.forename: Almudena
authors.initials: A
authors.lastname: Corrales
authors.affiliation: Intensive Care Unit, Hospital Clínico de Valladolid, Valladolid, Spain. fgandia@saludcastillayleon.es.
authors.forename: Francisco
authors.initials: F
authors.lastname: Gandía
authors.affiliation: Intensive Care Unit, Fundació ALTHAIA, Manresa, Spain. csubira@althaia.cat.
authors.forename: Carlés
authors.initials: C
authors.lastname: Subirá
authors.affiliation: Department Anesthesia, Hospital Universitario Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain. daviddomgar@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Domínguez
authors.affiliation: Department Anesthesiology, Hospital Clínico Universitario, Santiago de Compostela, Spain. mariauror@gmail.com.
authors.forename: Aurora
authors.initials: A
authors.lastname: Baluja
authors.affiliation: Intensive Care Unit, Hospital Virgen de La Luz, Cuenca, Spain. jmaelizalde@gmail.com.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Añón
authors.affiliation: Department of Anesthesiology, Hospital Clinic de Barcelona, Barcelona, Spain. radalia@gmail.com.
authors.forename: Ramón
authors.initials: R
authors.lastname: Adalia
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. cuidadospreventivos@hotmail.com.|Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario 145, 38010, Santa Cruz de Tenerife, Spain. cuidadospreventivos@hotmail.com.
authors.forename: Lina
authors.initials: L
authors.lastname: Pérez-Méndez
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. cflores@ull.edu.es.|Research Unit, Hospital Universitario Nuestra Señora de Candelaria, Carretera del Rosario 145, 38010, Santa Cruz de Tenerife, Spain. cflores@ull.edu.es.|Applied Genomics Group, Laboratory of Genetics, Instituto Universitario de Enfermedades Tropicales y Salud Pública de Canarias, Universidad de La Laguna, Tenerife, Spain. cflores@ull.edu.es.
authors.forename: Carlos
authors.initials: C
authors.lastname: Flores
authors.affiliation: CIBER de Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain. jesus.villar54@gmail.com.|Multidisciplinary Organ Dysfunction Evaluation Research Network, Research Unit, Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n - 4th floor, south wing, 35019, Las Palmas de Gran Canaria, Spain. jesus.villar54@gmail.com.|Keenan Research Center for Biomedical Science, St. Michael's Hospital, Toronto, ON, Canada. jesus.villar54@gmail.com.
authors.forename: Jesus
authors.initials: J
authors.lastname: Villar
mesh_terms: D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012128:Respiratory Distress Syndrome / Q000175:diagnosis / Q000235:genetics*; D018805:Sepsis / Q000175:diagnosis / Q000235:genetics*
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human