title: Extremely high interleukin-6 blood levels and outcome in the critically ill are associated with tumor necrosis factor- and interleukin-1-related gene polymorphisms.
abstract: OBJECTIVE
  To determine the allelic frequencies of interleukin (IL)-6-, IL-1-, and tumor necrosis factor-alpha (TNF)-related gene polymorphisms in critically ill patients with extremely high IL-6 blood level and to examine the genetic effects on their clinical courses.
  
  
  METHODS
  Population-based association study.
  
  
  METHODS
  A general intensive care unit in a university teaching hospital.
  
  
  METHODS
  A total of 150 consecutive critically ill patients recruited at admission to the intensive care unit, regardless of diagnosis, and 150 healthy volunteers.
  
  
  RESULTS
  IL-6 blood levels were measured daily with chemiluminescence immunoassay. The IL-6 peak levels were significantly correlated with simultaneously measured TNF (r = .659, p < .0001) and IL-1beta levels (r = .518, p < .0001), respectively. Single nucleotide polymorphism at position -174 and -596 sites of the IL-6 (IL6-174*G/C and IL6-596*G/A), -308 site of the TNF (TNF-308*G/A), and -511 site of the IL-1beta (IL1B-511*C/T) were identified with real-time polymerase chain reaction assay using specific fluorescence-labeled probe. Within the IL-1 receptor antagonist intron 2, a various number of tandem repeat polymorphisms (IL1RN*1-5) were identified after polymerase chain reaction with gel electrophoresis. Allelic frequencies of patients with IL-6 peak levels of > or =10,000 pg/mL (group A) were compared with those of patients with IL-6 peak levels of <10,000 pg/mL (group B). Neither IL6-174*C nor IL6-596*A were recognized in all the subjects; however, group A showed a higher frequency of TNF-308*A (p = .054), IL1B-511*T (p = .013), and non-IL1RN*1 (p = .008) allele compared with group B. TNF-308*A, IL1RN*2 or IL1RN*3 allele carriers of group A showed sustained high IL-6 levels, despite countermeasures against hypercytokinemia, and their survival rate was lower than that of the noncarriers of those high-risk alleles (p = .025).
  
  
  CONCLUSIONS
  TNF-308*A, IL1RN*2, and IL1RN*3 alleles were associated with the prevalence of the extremely high IL-6 blood level in the critically ill, their uncontrollable blood IL-6 kinetics, and outcome.
authors.affiliation: Department of Emergency and Critical Care Medicine, Graduate School of Medicine, Chiba University, Japan.
authors.forename: Eizo
authors.initials: E
authors.lastname: Watanabe
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hirasawa
authors.forename: Shigeto
authors.initials: S
authors.lastname: Oda
authors.forename: Kenichi
authors.initials: K
authors.lastname: Matsuda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Hatano
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tokuhisa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016638:Critical Illness / Q000401:mortality*; D005260:Female; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D017052:Hospital Mortality; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000097:blood / Q000235:genetics*; D015850:Interleukin-6 / Q000097:blood* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000276:immunology / Q000401:mortality; D017063:Outcome Assessment, Health Care; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D012795:Sialoglycoproteins / Q000097:blood / Q000235:genetics; D015996:Survival Rate; D018746:Systemic Inflammatory Response Syndrome / Q000097:blood / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism
chemical_list: C507763:IL1RN protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha