title: The -144C/A polymorphism in the promoter of HSP90beta is associated with multiple organ dysfunction scores.
abstract: BACKGROUND
  Variations in genetic background are the leading cause of differential susceptibility to traumatic infection. Heat shock protein 90 (HSP90), a broadly distributed and conserved molecule, regulates inflammation under stressful and traumatic conditions. However, the relationships between HSP90 genetic polymorphisms, post-traumatic inflammatory responses and organ function remain unknown.
  
  
  METHODS
  A total of 286 healthy volunteers and patients with severe trauma took part in a single nucleotide polymorphism (SNP)-based analysis of the HSP90beta gene and a clinical association analysis. HSP90beta and TNF-alpha levels were determined using quantitative PCR and western blot. The transcriptional activity of the HSP90beta promoter was assayed using the Dual-Luciferase Reporter Assay System.
  
  
  RESULTS
  The minor allele frequencies for the SNP located at -144 bp relative to the HSP90beta transcriptional start site were 28.47% and 28.52% in the normal and trauma populations, respectively; no significant differences were found between these two distributions. However, the results showed that a promoter containing the -144A allele had a higher transcriptional activity than did a promoter containing the wild-type -144C allele. Furthermore, the -144A promoter induced high expression of HSP90beta and low expression of the inflammatory factor TNF-alpha in a lipopolysaccharide-induced inflammatory model. A clinical association analysis showed that the multiple organ dysfunction scores for -144AA genotype carriers were significantly lower than those of -144CC carriers following trauma. No significant correlations were found between the presence of the two alleles and the incidence of sepsis.
  
  
  CONCLUSIONS
  These results indicate that differences in expression caused by the -144 polymorphism in the HSP90beta promoter are associated with cellular inflammatory responses and the severity of organ injury. These findings will aid in risk assessment and early prevention of complications for patients with severe trauma.
authors.affiliation: The Molecular Biology Center, State Key Laboratory of Trauma, Burn and Combined Injury, Research Institute of Surgery and Daping Hospital, Third Military Medical University, Chongqing, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhao
authors.forename: Liju
authors.initials: L
authors.lastname: Tao
authors.forename: Dongpo
authors.initials: D
authors.lastname: Jiang
authors.forename: Xingyun
authors.initials: X
authors.lastname: Chen
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Yalei
authors.initials: Y
authors.lastname: Ning
authors.forename: Renping
authors.initials: R
authors.lastname: Xiong
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Yizhi
authors.initials: Y
authors.lastname: Peng
authors.forename: Yuan-Guo
authors.initials: YG
authors.lastname: Zhou
mesh_terms: D000328:Adult; D000368:Aged; D044466:Asian People / Q000208:ethnology; D016022:Case-Control Studies; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D005787:Gene Frequency / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000235:genetics*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000097:blood / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014947:Wounds and Injuries / Q000235:genetics; D055815:Young Adult
chemical_list: D018841:HSP90 Heat-Shock Proteins; C493165:HSP90AB1 protein, human; D014409:Tumor Necrosis Factor-alpha