The influence of promoter polymorphism of nuclear factor-erythroid 2-related factor 2 gene on the aberrant DNA methylation in gastric epithelium.
Aberrant promoter methylation is an important mechanism for gene silencing. Inflammation-related reactive oxygens contribute to this CpG island methylation. The nuclear factor-erythroid 2-related factor 2 gene (Nrf2) is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene and the CpG island methylation in non-cancerous gastric mucosa. The study was performed in 85 subjects (46 without gastric malignancies, non-GC group, and 39 with gastric cancer, GC group). The promoter methylation status of p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by methylation-specific-polymerase chain reaction. The Nrf2 gene genotypes were determined by the PCR-SSCP method. In the 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16, none for p21. The frequency of the methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95% CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was much higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95% CI, 1.26-8.59; p=0.015, and OR, 0.38; 95% CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95% CI, 1.14-7.36; p=0.026, and OR, 0.33; 95% CI, 0.13-0.88; p=0.027, respectively). Our results suggested that the promoter polymorphisms of Nrf2 gene may affect the methylation status of tumor-related genes, especially the p14 gene, under the influence of H. pylori-induced gastric inflammation.
Arisawa
Tomiyasu
T
Department of Gatroenterology, Fujita Health University, School of Medicine, Toyoake 470-1192, Japan. tarisawa@fujita-hu.ac.jp
Tahara
Tomomitsu
T
Shibata
Tomoyuki
T
Nagasaka
Mitsuo
M
Nakamura
Masakatsu
M
Kamiya
Yoshio
Y
Fujita
Hiroshi
H
Yoshioka
Daisuke
D
Arima
Yuko
Y
Okubo
Masaaki
M
Hirata
Ichiro
I
Nakano
Hiroshi
H
D000368:Aged; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000502:physiology*; D005756:Gastritis / Q000235:genetics / Q000382:microbiology; D016481:Helicobacter Infections / Q000150:complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D050983:NF-E2 Transcription Factor / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic / Q000235:genetics; D013274:Stomach Neoplasms / Q000235:genetics*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
D050983:NF-E2 Transcription Factor; D025803:Tumor Suppressor Protein p14ARF