title: Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium.
abstract: BACKGROUND
  Aberrant methylation patterns in CpG island are known to be influential in gene silencing. Histamine plays important physiological roles in the upper gastrointestinal tract and acts via the H2 receptor. We report an investigation into the effect of HRH2 promoter polymorphism (rs2607474 G > A) on the methylation of DAPK and CDH1.
  
  
  METHODS
  Non cancerous gastric mucosa samples were obtained from 115 subjects with gastric cancer (GC) and 412 non-cancer subjects (non-GC). Methylation status of genes was determined by MSP. The genotyping of rs2607474 was performed by PCR-SSCP.
  
  
  RESULTS
  Methylation of DAPK and CDH1 was observed in 296 and 246 subjects, respectively. The frequency of CDH1 methylation in the subjects with GC was significantly lower in cancer lesion than in non cancerous mucosa, whereas that of DAPK methylation was not different. The allelic distribution of rs2607474 was 401GG, 119GA and 7AA. The GG homozygote was associated with a significantly increased risk for methylation of both DAPK and CDH1 (p < 0.0001 and p = 0.0009, respectively). In the non-GC subjects or more than 60 years of age, GG homozygote was more closely associated with both DAPK and CDH1 methylation. However, this genotype did not show an increased risk for the development of methylation of both genes in patients with GC. In H. pylori negative subjects, GG homozygote showed an increased risk for the methylation of both DAPK and CDH1 (p = 0.0074 and p = 0.0016, respectively), whereas this genotype was associated with an increased risk for the development of DAPK methylation in H. pylori positive subjects (p = 0.0018). In addition, in subjects older than 60 years of age, atrophy and metaplasia scores were significantly higher in the GG homozygote (p = 0.011 and p = 0.039, respectively) and a significant correlation was observed between age and atrophy or metaplasia.
  
  
  CONCLUSIONS
  Our results suggest that rs2607474 GG homozygote confers a significantly increased risk for age- and inflammation-related DAPK and CDH1 methylation.
authors.affiliation: Department of Gastroenterology, Kanazawa Medical University, 1-1, Daigaku, Uchinada-machi, Ishikawa, 920-0293, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Nomura
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Tahara
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Shiroeda
authors.forename: Takahiro
authors.initials: T
authors.lastname: Minato
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Matsue
authors.forename: Ranji
authors.initials: R
authors.lastname: Hayashi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Matsunaga
authors.forename: Toshimi
authors.initials: T
authors.lastname: Otsuka
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Nakamura
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Toshikuni
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Shibata
authors.forename: Tomiyasu
authors.initials: T
authors.lastname: Arisawa
mesh_terms: D000368:Aged; D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D015820:Cadherins / Q000235:genetics*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics*; D016022:Case-Control Studies; D019175:DNA Methylation / Q000235:genetics*; D064550:Death-Associated Protein Kinases; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011970:Receptors, Histamine H2 / Q000235:genetics*; D012307:Risk Factors; D013270:Stomach / Q000473:pathology; D013274:Stomach Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D051017:Apoptosis Regulatory Proteins; C513384:CDH1 protein, human; D015820:Cadherins; D011970:Receptors, Histamine H2; D064550:Death-Associated Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases