title: A functional synonymous coding variant in the IL1RN gene is associated with survival in septic shock.
abstract: BACKGROUND
  Death from infection is a highly heritable trait, yet there are few genetic variants with known mechanism influencing survival during septic shock.
  
  
  OBJECTIVE
  We hypothesized that a synonymous coding variant in the IL-1 receptor antagonist gene (IL1RN), rs315952, previously associated with reduced risk for acute respiratory distress syndrome, would be functional and associate with improved survival in septic shock.
  
  
  METHODS
  We used a human endotoxin (LPS) model of evoked inflammatory stress to measure plasma IL-1 receptor antagonist (IL1RA) following low-dose Food and Drug Administration-grade LPS injection (1 ng/kg) in 294 human volunteers. RNA sequencing of adipose tissue pre- and post-LPS was used to test for allelic imbalance at rs315952. In the Vasopressin and Septic Shock Trial cohort, we performed a genetic association study for survival, mortality, and organ failure-free days.
  
  
  RESULTS
  Adipose tissue displayed significant allelic imbalance favoring the rs315952C allele in subjects of European ancestry. Consistent with this, carriers of rs315952C had slightly higher plasma IL1RA at baseline (0.039) and higher evoked IL1RA post-LPS (0.011). In the Vasopressin and Septic Shock Trial cohort, rs315952C associated with improved survival (P = 0.028), decreased adjusted 90-day mortality (P = 0.044), and faster resolution of shock (P = 0.029).
  
  
  CONCLUSIONS
  In European ancestry subjects, the IL1RN variant rs315952C is preferentially transcribed and associated with increased evoked plasma IL1RA and with improved survival from septic shock. It may be that genetically determined IL1RA levels influence survival from septic shock.
authors.affiliation: 1 Center for Translational Lung Biology, Pulmonary, Allergy, and Critical Care Division.
authors.forename: Nuala J
authors.initials: NJ
authors.lastname: Meyer
authors.forename: Jane F
authors.initials: JF
authors.lastname: Ferguson
authors.forename: Rui
authors.initials: R
authors.lastname: Feng
authors.forename: Fan
authors.initials: F
authors.lastname: Wang
authors.forename: Parth N
authors.initials: PN
authors.lastname: Patel
authors.forename: Mingyao
authors.initials: M
authors.lastname: Li
authors.forename: Chenyi
authors.initials: C
authors.lastname: Xue
authors.forename: Liming
authors.initials: L
authors.lastname: Qu
authors.forename: Yichuan
authors.initials: Y
authors.lastname: Liu
authors.forename: John H
authors.initials: JH
authors.lastname: Boyd
authors.forename: James A
authors.initials: JA
authors.lastname: Russell
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.forename: Keith R
authors.initials: KR
authors.lastname: Walley
authors.forename: Muredach P
authors.initials: MP
authors.lastname: Reilly
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D022981:Allelic Imbalance; D044383:Black People; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics* / Q000378:metabolism; D008297:Male; D017423:Sequence Analysis, RNA; D012772:Shock, Septic / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D015996:Survival Rate; D044465:White People / Q000235:genetics*
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein
keywords: RNA-seq; functional genetic variant; polymorphism; septic shock
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