title: Association of hepatocyte growth factor promoter polymorphism with severity of interstitial lung disease in Japanese patients with systemic sclerosis.
abstract: OBJECTIVE
  To examine associations of single-nucleotide polymorphisms (SNPs) within genes for hepatocyte growth factor (HGF) and its receptor c-met with disease susceptibility and organ involvement in Japanese patients with systemic sclerosis (SSc).
  
  
  METHODS
  Four SNPs (HGF -1652 C/T, +44222 C/T, and +63555 G/T, and c-met -980 T/A) were analyzed in 159 SSc patients and 103 healthy control subjects with the use of a polymerase chain reaction-based assay. The influence of the HGF -1652 SNP on transcription activity was evaluated with a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA).
  
  
  RESULTS
  There was no difference in the distribution of HGF/c-met SNPs between SSc patients and controls. HGF -1652 TT was found much more frequently in SSc patients with end-stage lung disease (ESLD) than in those without (41% versus 8%; P = 0.0004). This association was confirmed by a replication study involving a separate cohort of 155 SSc patients. Kaplan-Meyer analysis revealed that HGF -1652 TT carriers had a higher probability of developing ESLD than did CT or CC carriers. The HGF promoter carrying the HGF -1652 T allele had lower transcription activity than did the promoter carrying the C allele. EMSA showed the presence of a potential negative transcription regulator that binds specifically to the HGF promoter carrying a T allele at position -1652. Finally, TT carriers had a relative inability to increase circulating HGF levels even in the presence of advanced interstitial lung disease.
  
  
  CONCLUSIONS
  A SNP in the HGF promoter region may modulate the severity of interstitial lung disease by controlling the transcriptional efficiency of the HGF gene.
authors.affiliation: Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kana
authors.initials: K
authors.lastname: Hoshino
authors.forename: Takashi
authors.initials: T
authors.lastname: Satoh
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawaguchi
authors.forename: Masataka
authors.initials: M
authors.lastname: Kuwana
mesh_terms: D000328:Adult; D000483:Alleles; D044466:Asian People / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D017563:Lung Diseases, Interstitial / Q000150:complications / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012595:Scleroderma, Systemic / Q000150:complications / Q000235:genetics*; D012720:Severity of Illness Index
chemical_list: D017228:Hepatocyte Growth Factor