title: Autophagy-related IRGM polymorphism is associated with mortality of patients with severe sepsis.
abstract: OBJECTIVE
  Autophagy is the regulated catabolic process for recycling damaged or unnecessary organelles, which plays crucial roles in cell survival during nutrient deficiency, and innate immune defense against pathogenic microorganisms. Autophagy has been also reported to be involved in various conditions including inflammatory diseases. IRGM (human immunity-related GTPase) has an important function in eliminating Mycobacterium tuberculosis from host cells via autophagy. We examined the association between genetic polymorphism and clinical course/outcome in severely septic patients.
  
  
  METHODS
  The study included 125 patients with severe sepsis/septic shock (SS) and 104 non-sepsis patients who were admitted to the intensive care unit (ICU) of Chiba University Hospital between October 2001 and September 2008 (discovery cohort) and 268 SS patients and 454 non-sepsis patients who were admitted to ICUs of five Japanese institutions including Chiba University Hospital between October 2008 and September 2012 (multi-center validation cohort). Three hundred forty seven healthy volunteers who consented to this study were also included. Genotyping was performed for a single-nucleotide polymorphism (SNP) within the coding region of IRGM, IRGM(+313) (rs10065172). Lipopolysaccharide challenge of whole blood from randomly selected healthy volunteers (n = 70) was performed for comparison of IRGM mRNA expression among different genotypes.
  
  
  RESULTS
  No significant difference in genotypic distributions (CC/CT/TT) at the IRGM(+313) locus was observed among the three subject groups (SS, non-sepsis, and healthy volunteers) in either cohort. When mortality were compared, no significant difference was observed in the non-sepsis group, while TT homozygotes exhibited a significantly higher mortality than the CC+CT genotype category in the SS group for both cohorts (P = 0.043, 0.037). Lipopolysaccharide challenge to whole blood showed a significant suppression of IRGM mRNA expression in TT compared with the CC+CT genotype category (P = 0.019).
  
  
  CONCLUSIONS
  The data suggest that the IRGM(+313), an autophagy-related polymorphic locus, influences outcome in severely septic patients, with the possible involvement of autophagy in sepsis exacerbation.
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-ku, Chiba City, Chiba, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-ku, Chiba City, Chiba, Japan.
authors.forename: Eizo
authors.initials: E
authors.lastname: Watanabe
authors.affiliation: Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume City, Fukuoka, Japan.
authors.forename: Teruo
authors.initials: T
authors.lastname: Sakamoto
authors.affiliation: Department of Emergency and Critical Care Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume City, Fukuoka, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Takasu
authors.affiliation: Division of Critical Care and Emergency Medicine, Tokyo Medical University Hachioji Medical Center, 1163 Tate-machi, Hachioji City, Tokyo, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Ikeda
authors.affiliation: Division of Critical Care and Emergency Medicine, Tokyo Medical University Hachioji Medical Center, 1163 Tate-machi, Hachioji City, Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Ikeda
authors.affiliation: Department of Emergency, Disaster and Critical Care Medicine, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya City, Hyogo, Japan.
authors.forename: Joji
authors.initials: J
authors.lastname: Kotani
authors.affiliation: Department of Emergency and Critical Care Medicine, Kimitsu Chuo Hospital, 1010 Sakurai, Kisarazu City, Chiba, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Kitamura
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-ku, Chiba City, Chiba, Japan.
authors.forename: Tomohito
authors.initials: T
authors.lastname: Sadahiro
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-ku, Chiba City, Chiba, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Tateishi
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-ku, Chiba City, Chiba, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Shinozaki
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chu-ku, Chiba City, Chiba, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Oda
mesh_terms: D000368:Aged; D001343:Autophagy; D002470:Cell Survival; D015331:Cohort Studies; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate; D007249:Inflammation / Q000382:microbiology; D007564:Japan; D008070:Lipopolysaccharides / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D009169:Mycobacterium tuberculosis; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D018805:Sepsis / Q000235:genetics* / Q000382:microbiology / Q000401:mortality*; D016896:Treatment Outcome
chemical_list: D008070:Lipopolysaccharides; D019204:GTP-Binding Proteins; C513539:IRGM protein, human