title: Association of common genetic variation in the protein C pathway genes with clinical outcomes in acute respiratory distress syndrome.
abstract: BACKGROUND
  Altered plasma levels of protein C, thrombomodulin, and the endothelial protein C receptor are associated with poor clinical outcomes in patients with acute respiratory distress syndrome (ARDS). We hypothesized that common variants in these genes would be associated with mortality as well as ventilator-free and organ failure-free days in patients with ARDS.
  
  
  METHODS
  We genotyped linkage disequilibrium-based tag single-nucleotide polymorphisms in the ProteinC, Thrombomodulin and Endothelial Protein C Reptor Genes among 320 self-identified white patients of European ancestry from the ARDS Network Fluid and Catheter Treatment Trial. We then tested their association with mortality as well as ventilator-free and organ-failure free days.
  
  
  RESULTS
  The GG genotype of rs1042580 (p = 0.02) and CC genotype of rs3716123 (p = 0.002), both in the thrombomodulin gene, and GC/CC genotypes of rs9574 (p = 0.04) in the endothelial protein C receptor gene were independently associated with increased mortality. An additive effect on mortality (p < 0.001), ventilator-free days (p = 0.01), and organ failure-free days was observed with combinations of these high-risk genotypes. This association was independent of age, severity of illness, presence or absence of sepsis, and treatment allocation.
  
  
  CONCLUSIONS
  Genetic variants in thrombomodulin and endothelial protein C receptor genes are additively associated with mortality in ARDS. These findings suggest that genetic differences may be at least partially responsible for the observed associations between dysregulated coagulation and poor outcomes in ARDS.
authors.affiliation: Departments of Pediatrics, University of California, Box 0106, , 550, 16th Street, San Francisco, CA, 94143, USA. saprua@peds.ucsf.edu.|David Geffen School of Medicine, Department of Pediatrics, University of California, 10833 Le Conte Avenue, 12-488 MDCC, Los Angeles, 90095, CA, USA. saprua@peds.ucsf.edu.
authors.forename: Anil
authors.initials: A
authors.lastname: Sapru
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Kathleen D
authors.initials: KD
authors.lastname: Liu
authors.affiliation: Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Wiemels
authors.affiliation: Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: Helen
authors.initials: H
authors.lastname: Hansen
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.|Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Pawlikowska
authors.affiliation: Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.
authors.forename: Annie
authors.initials: A
authors.lastname: Poon
authors.affiliation: Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Jorgenson
authors.affiliation: Institute for Human Genetics, University of California, San Francisco, CA, USA.
authors.forename: John S
authors.initials: JS
authors.lastname: Witte
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.
authors.forename: Carolyn S
authors.initials: CS
authors.lastname: Calfee
authors.affiliation: Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: Lorraine B
authors.initials: LB
authors.lastname: Ware
authors.affiliation: Department of Medicine, University of California, San Francisco, CA, USA.|Cardiovascular Research Institute, University of California, San Francisco, CA, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Matthay
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D001777:Blood Coagulation / Q000235:genetics / Q000276:immunology; D000074283:Endothelial Protein C Receptor; D005260:Female; D014644:Genetic Variation / Q000276:immunology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011486:Protein C / Q000235:genetics* / Q000276:immunology; D011956:Receptors, Cell Surface / Q000378:metabolism; D012128:Respiratory Distress Syndrome / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics; D018180:Thrombomodulin / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D015703:Antigens, CD; D000074283:Endothelial Protein C Receptor; C478370:PROCR protein, human; D011486:Protein C; D011956:Receptors, Cell Surface; D018180:Thrombomodulin