Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium

Tomoe Nomura, Tomomitsu Tahara, Hisakazu Shiroeda, Takahiro Minato, Yasuhiro Matsue, Ranji Hayashi, Kazuhiro Matsunaga, Toshimi Otsuka, Masakatsu Nakamura, Nobuyuki Toshikuni, Tomoyuki Shibata, Tomiyasu Arisawa

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article number1
JournalBMC Gastroenterology
Volume13
Issue number1
DOIs
Publication statusPublished - 02-01-2013

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DNA Methylation
Methylation
Stomach
Epithelium
Homozygote
Stomach Neoplasms
Pylorus
Metaplasia
Atrophy
Genotype
Single-Stranded Conformational Polymorphism
Neoplasms
Histamine H2 Receptors
CpG Islands
Upper Gastrointestinal Tract
Gene Silencing
Gastric Mucosa
Histamine
Genes
Mucous Membrane

All Science Journal Classification (ASJC) codes

  • Gastroenterology

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Nomura, Tomoe ; Tahara, Tomomitsu ; Shiroeda, Hisakazu ; Minato, Takahiro ; Matsue, Yasuhiro ; Hayashi, Ranji ; Matsunaga, Kazuhiro ; Otsuka, Toshimi ; Nakamura, Masakatsu ; Toshikuni, Nobuyuki ; Shibata, Tomoyuki ; Arisawa, Tomiyasu. / Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium. In: BMC Gastroenterology. 2013 ; Vol. 13, No. 1.
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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.",
author = "Tomoe Nomura and Tomomitsu Tahara and Hisakazu Shiroeda and Takahiro Minato and Yasuhiro Matsue and Ranji Hayashi and Kazuhiro Matsunaga and Toshimi Otsuka and Masakatsu Nakamura and Nobuyuki Toshikuni and Tomoyuki Shibata and Tomiyasu Arisawa",
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Nomura, T, Tahara, T, Shiroeda, H, Minato, T, Matsue, Y, Hayashi, R, Matsunaga, K, Otsuka, T, Nakamura, M, Toshikuni, N, Shibata, T & Arisawa, T 2013, 'Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium', BMC Gastroenterology, vol. 13, no. 1, 1. https://doi.org/10.1186/1471-230X-13-1

Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium. / Nomura, Tomoe; Tahara, Tomomitsu; Shiroeda, Hisakazu; Minato, Takahiro; Matsue, Yasuhiro; Hayashi, Ranji; Matsunaga, Kazuhiro; Otsuka, Toshimi; Nakamura, Masakatsu; Toshikuni, Nobuyuki; Shibata, Tomoyuki; Arisawa, Tomiyasu.

In: BMC Gastroenterology, Vol. 13, No. 1, 1, 02.01.2013.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Influence of HRH2 promoter polymorphism on aberrant DNA methylation of DAPK and CDH1 in the gastric epithelium

AU - Nomura, Tomoe

AU - Tahara, Tomomitsu

AU - Shiroeda, Hisakazu

AU - Minato, Takahiro

AU - Matsue, Yasuhiro

AU - Hayashi, Ranji

AU - Matsunaga, Kazuhiro

AU - Otsuka, Toshimi

AU - Nakamura, Masakatsu

AU - Toshikuni, Nobuyuki

AU - Shibata, Tomoyuki

AU - Arisawa, Tomiyasu

PY - 2013/1/2

Y1 - 2013/1/2

N2 - 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.

AB - 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.

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