Demonstration of potential link between Helicobacter pylori related promoter CpG island methylation and telomere shortening in human gastric mucosa.
Telomere length shortening in Helicobacter pylori (H. pylori) infected gastric mucosa constitutes the earliest steps toward neoplastic transformation. In addition to this genotoxic changes, epigenetic changes such as promoter CpG island (PCGI) methylation are frequently occurred in H. pylori infected gastric mucosa. The aim of this study was to investigate a potential link between H. pylori related PCGI methylation and telomere length shortening in the human gastric mucosa.



Telomere length was measured in non-neoplastic gastric mucosa from 106 cancer-free subjects. To identify H. pylori related PCGI methylation, bisulfite pyrosequencing was used to quantify the methylation of 49 PCGIs from 47 genes and LINE1 repetitive elementResults: We identified five PCGIs (IGF2, SLC16A12, SOX11, P2RX7 and MYOD1), which the methylation is closely associated with H. pylori infection. Hypermethylation of all these PCGIs was associated with development of pathological state from normal to mild, active, and atrophic gastritis (P<0.001) and lower pepsinogen I/II ratio (P<0.05), an indicator for gastric mucosal atrophy. Telomere shortening was significantly associated with mean Z score methylation of five PCGIs (R=-0.39, P<0.0001) and four of these locus (IGF2: R=-0.35, P=0.0003, SLC16A12: R=-0.35, P=0.0002, P2RX7: R=-0.29, P=0.003, and MYOD1: R=-0.33, P=0.0005). Multivariate analysis revealed that telomere shortening held an increased risk for hypermethylation (odds ratio: 1.71, 95% confidence interval: 1.11-2.63, P=0.016).



Potential link between H. pylori related PCGI methylation and telomere shortening emphasize the importance of genotoxic-epigenetic interaction in the pathological state of H. pylori infected gastric mucosa.
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Tomomitsu
T
Tahara
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Tomoyuki
T
Shibata
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Masaaki
M
Okubo
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Tomohiko
T
Kawamura
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Noriyuki
N
Horiguchi
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Takamitsu
T
Ishizuka
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Naoko
N
Nakano
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Mitsuo
M
Nagasaka
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Yoshihito
Y
Nakagawa
Department of Gastroenterology, Fujita Health University School of Medicine, Toyoake, Japan.
Naoki
N
Ohmiya
D000368:Aged; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology; D020022:Genetic Predisposition to Disease / Q000235:genetics; D016481:Helicobacter Infections / Q000235:genetics* / Q000382:microbiology; D016480:Helicobacter pylori / Q000302:isolation & purification* / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D017422:Sequence Analysis, DNA / Q000379:methods; D013272:Stomach Diseases / Q000235:genetics / Q000382:microbiology; D059506:Telomere Shortening / Q000235:genetics*
DNA methylation; H. pylori; gastric mucosa; gastritis; telomere length