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Carcinogenesis Advance Access originally published online on March 26, 2007
Carcinogenesis 2007 28(9):2036-2040; doi:10.1093/carcin/bgm074
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Role of angiotensinogen gene polymorphism on Helicobacter pylori infection-related gastric cancer risk in Japanese

Mitsushige Sugimoto*, Takahisa Furuta1, Naohito Shirai2, Chise Kodaira, Masafumi Nishino, Mutsuhiro Ikuma, Haruhiko Sugimura3 and Akira Hishida

First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
1 Center for Clinical Research, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan
2 Department of Gastroenterology, Enshu General Hospital, 1-1-1 Tyuou, Hamamatsu, Shizuoka 430-0929, Japan
3 First Department of Pathology, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan

* To whom correspondence should be addressed. Tel: +81 53 435 2261; Fax: +81 53 434 9447; Email: mitsu{at}hama-med.ac.jp


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Backgrounds and aims: The renin–angiotensin (RA) system including angiotensinogen (AGT), angiotensin I and angiotensin II influences the regulation of cell proliferation, angiogenesis and inflammation. AGT-20 A/C polymorphism is associated with the plasma AGT and angiotensin II levels. The aim of this study was to clarify the association of AGT-20 A/C polymorphism with susceptibility to gastric cancer and peptic ulcer in Japanese. Methods: We assessed the AGT-20 A/C polymorphism in Helicobacter pylori-positive patients with gastric cancer (n = 135), gastric ulcer (n = 148) and duodenal ulcer (n = 113) and controls (n = 292) consisting of H.pylori-positive gastritis alone (n = 160) and H.pylori-negative subjects (n = 132). Results: The age- and sex-adjusted odds ratios (ORs) of AGT-20 A/C and C/C genotypes relative to A/A genotype for gastric cancer risk were 1.695 [95% confidence interval (CI): 1.035–2.777] and 2.259 (95% CI: 0.351–14.533), respectively. The AGT-20 C allele increased the gastric cancer risk (OR: 1.685, 95% CI: 1.037–2.736), especially the intestinal type of gastric cancer (OR: 1.792, 95% CI: 1.040–3.089). However, there was no association between the AGT-20 polymorphism and susceptibility to peptic ulcer. Conclusions: The carriage of AGT-20 C allele was associated with an increased risk for H.pylori-related gastric cancer development in Japanese, indicating that the RA system plays an important role in the pathogenesis of gastric cancer.

Abbreviations: ACE, angiotensin I-converting enzyme; AGT, angiotensinogen; AT1R, angiotensin II type-1 receptor; CI, confidence interval; OR, odds ratio; PG, pepsinogen; RA, renin–angiotensin


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
In 1994, WHO/IARC designated Helicobacter pylori as a definite biological group 1 carcinogen of gastric cancer. In Japan, the cumulative incidence rate of gastric cancer was estimated to be 21.2% for 0- to 84-year-old males with H.pylori infection and 8.0% for 0- to 84-year-old females with H.pylori infection, under the condition that half of the populations was infected, and therefore, the H.pylori-infected subjects have a five-times higher risk of gastric cancer development in comparison with those without infection (1). Recently, Uemura et al. (2) reported that during 7.8 years of the mean follow-up period, gastric cancer developed in 2.9% of patients with H.pylori infection, but in none of the uninfected patients. Moreover, eradication of H.pylori reduced the risk of gastric cancer development in the patients with peptic ulcer disease (3,4). Therefore, H.pylori infection is now considered associated with gastric carcinogenesis, and eradication of H.pylori is recommended for the prevention of gastric cancer development (2–4).

The pathogenesis and progression of gastric cancer consist of a variety of processes, including cell proliferation, cell differentiation, angiogenesis and degradation of the extracellular matrix. Recently, gastric carcinogenesis has been thought to be associated with the interaction of a variety of environmental life-style factors, bacterial factors and host genetic factors. In particular, the association of host genetics with carcinogenesis (e.g. polymorphisms or mutations of inflammation-related cytokines, cytochrome P450 enzymes, glutathione S-transferase, N-acetyltransferase, matrix metalloproteinase, p53 and k-ras) has been intensively investigated in relation to chronic H.pylori infection (5–11).

The renin–angiotensin (RA) system, consisting of angiotensinogen (AGT), angiotensin I, angiotensin II, renin, angiotensin I-converting enzyme (ACE) and chymase, plays a key role in blood pressure regulation. Recently, there has been increasing evidence that angiotensin II is involved in the regulation of cell proliferation, angiogenesis, inflammation and tissue remodeling, via the angiotensin II type-1 receptors (AT1Rs) (12–15). A recent epidemiological study demonstrated that in a 9-year follow-up of a southern California community, systolic blood pressure was a significant predictor of subsequent cancer mortality (16), and that ACE inhibitors and AT1R blocker have inhibitory effects on tumor progression, vascularization and metastasis (17). Therefore, the angiotensin II/AT1R pathway might be related to cancer biology, and recently, been focused on as the candidate target of chemopreventive therapy for several neoplastic lesions (17,18).

AGT, mainly produced in the liver, is the substrate of renin. The reaction between renin and AGT is the initial and rate-limiting step of this enzymatic cascade that generates the decapeptide angiotensin I, which is converted to angiotensin II by ACE and chymase. The human AGT gene consists of five exons and four introns located in chromosome 1q42–43. A nucleotide substitution in the 5' upstream core promoter region of the AGT affects the basal transcriptional rate of the gene. AGT has three polymorphisms (e.g. ACE-20 A/C, –18 C/T and –6 G/A) (19,20). In particular, AGT-20 polymorphism leads to different AGT transcription in vitro (20). The plasma AGT level is a critical factor in the determination of the plasma angiotensin II level, and therefore, the AGT polymorphism has been shown to influence risks of hypertension and other cardiac diseases (21). Recently, it has been reported that women with the high-activity AGT allele/genotype are at a higher risk of the development of breast cancer compared with those with the low-producer allele/genotype (22). However, it has not fully been elucidated whether the AGT-20 polymorphism is associated with gastric cancer risk.

Although polymorphic effects of the RA system (e.g. CMA/B and ACE) on the development of gastric cancer have been reported (23–26), the relationship between AGT polymorphisms and gastric cancer risk is unclear. Moreover, there are a few reports about the association between RA system-related gene polymorphisms and peptic ulcer development (23). To further determine the possible role of the RA system in the development of gastric cancer and peptic ulcer in humans, we examined whether genetic polymorphisms in AGT-20 were associated with gastric cancer and peptic ulcer risk in Japanese patients with H.pylori infection.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
Subjects
A total of 688 Japanese patients who agreed to participate in the present study underwent gastroduodenoscopy at the University Hospital of Hamamatsu University School of Medicine from January 2001 to June 2006. Of 688 subjects, 556 infected with H.pylori infection on the basis of serological testing (HM-CAP kit, Enteric Product, NY), rapid urease test (Helico Check, Otsuka Co., Tokushima, Japan) and/or culture and 132 subjects without H.pylori infection on the above three tests were enrolled in this study. The 556 H.pylori-positive subjects consisted of the gastric cancer group (n = 135), gastric ulcer (n = 148), duodenal ulcer (n = 113) and gastritis alone (n = 160) (Table I). Each diagnosis was proven histopathologically and endoscopically. The gastric cancer group was further pathologically classified into the two subgroups, the intestinal type group and the diffuse-type group, according to the Lauren classification (Table I) (27).


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  		Table 1. Characteristics and frequencies of AGT-20 A/C polymorphisms in the study subjects

 
The protocol was approved in advance by the Human Institutional Review Board of Hamamatsu University School of Medicine. Written informed consent was obtained from each subject.

Genotyping of AGT-20
DNA was extracted from leukocytes of each subject, using a commercially available kit (IsoQuick, ORCA Research, Bothell, WA). AGT-20 polymorphism was determined as described by Ishigami et al. (21). Amplification primers for the 265 bp fragment were 5'-AGA GGT CCC AGC GTG AGT GTC-3' (nucleotide: –166 to –144) and 5'-AGC CCA CAG CTC AGT TAC ATC-3' (nucleotides: 81–101). Polymerase chain reaction conditions were as follows: 94°C for 5 min, and then 35 cycles of 94°C for 30 s, 64°C for 30 s, 72°C for 1 min and finally 72°C for 7 min. The polymerase chain reaction products were digested with EcoO109I (Takara Bio, Shiga, Japan) at 37°C for 3 h. Fragments were separated by electrophoresis on 3% agarose gels and stained with ethidium bromide. The C allele was designated if two bands of 127 and 137 bp were obtained and the A allele was designated if a single band of 265 bp was obtained. The genotypes were designated as follows: A/A, one band of 265 bp; A/C, three bands of 128, 137 and 265 bp and C/C, two single bands of 127 and 138 bp.

Assay of serum pepsinogen levels
Gastric atrophy and inflammation are important abnormalities associated with development of gastric ulcer and gastric cancer. Severe corpus inflammation and atrophy are associated with a decrease in the pepsinogen (PG) I level and the PG I:PG II ratio, and both have been used as surrogate markers of gastric atrophy and inflammation (28,29). Thus, we measured serum levels of PG I and PG II levels by radioimmunoassay (Abotto Japan, Tokyo, Japan) in both patients with H.pylori infection and H.pylori infection-negative control subjects, and the PG I:PG II ratio was calculated for the serological assessment of gastric atrophy in patients with H.pylori infection.

Data analysis
Differences in the AGT-20 genotype/allele frequencies between the control and H.pylori infection-related disease groups were determined by the Fisher's exact probability test. Differences in serum levels of PG I and PG I:PG II ratios between different genotype groups were assessed by one-way analysis of variance. The effects of genotypes/alleles of AGT-20 polymorphisms on the risk of gastric cancer development were expressed as odds ratios (ORs) with 95% confidence intervals (CIs) adjusted by age and sex. Hardy–Weinberg equilibrium was assessed using the Markov chain Monte–Carlo approximation of the Fisher's exact test. All P values were two sided, and P values <0.05 were considered statistically significant.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Characteristics of enrolled subjects
The mean age of subjects with gastric cancer was significantly higher than those of any other groups (P < 0.001, Table 1). Then, the ORs of development of gastric cancers and peptic ulcers were adjusted by sex and age afterward as noted in the above statistics section.

AGT-20 polymorphism and the development of gastric cancer
Hardy–Weinberg equilibrium of allele frequencies at individual loci was assessed by comparing the observed and expected genotype frequencies using the chi-squared test. The genotype frequencies of the AGT-20 polymorphisms in the H.pylori-negative control group did not deviate significantly from those expected under the Hardy–Weinberg equilibrium (Table 1).

In H.pylori-negative subjects and the H.pylori-positive gastritis alone group, the numbers of the AGT-20 A/A, A/C and C/C genotypes were 88/42/2 in subjects without H.pylori infection and 110/50/0 in patients with gastritis alone, respectively, and there were no significant differences in the genotype frequencies of AGT-20 polymorphisms between the two subgroups. Therefore, we combined patients with H.pylori-negative group and H.pylori-positive gastritis alone group and used them as the control group for the gastric cancer and peptic ulcer cases in the present study.

The frequencies of the AGT-20 A/A, A/C and C/C genotypes were 67.8, 31.5 and 0.7% in the control group, whereas those in the gastric cancer group were 54.8, 42.2 and 3.0%, respectively (Table 1). The adjusted ORs for gastric cancer risk in patients with A/C genotype of the AGT-20 significantly increased (adjusted OR: 1.695, 95% CI: 1.035–2.777) in comparison with those with the A/A genotype (Table 2). The adjusted OR of the carriage of the C allele was 1.685 (95% CI: 1.037–2.736), which was higher than non-C allele carriers (Table 2). When the gastric cancer group was classified according to the intestinal type and diffuse type, the adjusted OR of C allele carrier for intestinal type was 1.792 (95% CI: 1.040–3.087) (Table 3), whereas the adjusted OR of C allele carrier for diffuse type was 1.370 (95% CI: 0.655–2.863).


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  		Table 2. Influence of AGT-20 genotypes on gastric cancer, gastric ulcer and duodenal ulcer risks

 


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  		Table 3. Influences of the AGT-20 genotype status on the development of two different histological types of gastric cancer

 
AGT-20 polymorphism and the development of peptic ulcers
The frequencies of the AGT-20 A/A, A/C and C/C genotypes in the gastric ulcer and duodenal ulcer group were 66.2, 31.8 and 2.0%, and 64.6, 33.6 and 1.8%, respectively (Table 1). AGT-20 polymorphisms were not associated with the risks of the peptic ulcer development (Table 2).

Characteristics of the patients with/without H.pylori infection by PG assay in relation to AGT-20 polymorphisms
The mean serum PG I levels in control subjects, H.pylori-infected patients and patients with gastric cancer with the AGT-20 A/A genotype were 57.5 ± 2.2 ng/ml, 75.4 ± 3.1 ng/ml and 47.6 ± 9.2 ng/ml, respectively. Those in the group with AGT-20 A/C and C/C genotypes were 56.1 ± 2.7 ng/ml, 102.9 ± 17.7 ng/ml and 38.1 ± 5.9 ng/ml, respectively. The mean serum PG I level in H.pylori-infected patients with AGT-20 A/A genotype was significantly lower than those of patients with AGT-20 A/C or C/C genotypes (P = 0.0498) (Figure 1A).


Figure 1
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  		Fig. 1. Mean serum PG I levels (A) and PG I:PG II ratios (B) in AGT-20 A/C polymorphisms of Helicobacter pylori infection-negative control subjects, H.pylori-infected patients (gastritis alone and peptic ulcer) and patients with gastric cancer. The mean serum PG I level in H.pylori-infected patients with AGT-20 A/A genotype was significantly lower than that of patients with AGT-20 A/C or C/C genotypes (A). The mean serum PG I:PG II ratio in each group did not depend on different AGT-20 genotypes (B).

 
There were no significant differences in the mean serum PG I:PG II ratios between the AGT-20 A/A genotype group and the non-A/A genotype group in each of subgroups of control subjects, H.pylori-infected patients and gastric cancer patients (Figure 1B).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The present study was designed to test the hypothesis that polymorphisms of enzymes involved in the RA system, such as AGT, are associated with gastric carcinogenesis and peptic ulcer development. We demonstrated a significant association of AGT-20 A/C polymorphism with susceptibility to gastric cancer, not peptic ulcer, in Japanese patients with H.pylori infection. The C allele carriages of AGT-20 have the significantly increased risk of gastric cancer development.

The plasma angiotensin II levels and the mRNA and protein level of angiotensin II are associated with production of AGT, the activity of ACE and chymase and the number of AT1Rs (30–32). Although the carcinogenic effect of AGT remains controversial, angiotensin II–AT1R signaling pathways are generally thought to be associated with the cell proliferation, angiogenesis and inflammation (12–15,33). Several possible roles of angiotensin II–AT1R signaling pathways in the gastric cancer development have been considered as follows: First, the AT1R induces cell proliferation in cancer cells through various intracellular protein cascades associated with growth factor stimulation, of which epidermal growth factor receptor-related kinase and protein kinase C are major mediators in cells (34,35). Second, the angiotensin II–AT1R signaling regulates the expression of insulin-like growth factor I receptors via the Akt/phosphatidylinositol-3 pathway (18). The IGF system is directly involved in carcinogenesis (36). Recently, Yasumura et al. (18) reported that combination therapy with cyclooxygenase-2 inhibitor at a low dose and an ACE inhibitor or AT1R blocker could reduce tumor growth more effectively than cyclooxygenase-2 inhibitor, ACE inhibitor or AT1R blocker alone. Third, the activation of AT1Rs enhances the transcription of several pro-inflammatory cytokines (e.g. IL-1 and TNF-alpha) and chemokines involving nuclear factor kappa B and activator protein-1 (12). Fourth, the AT1R induces vascular endothelial growth factor (VEGF), VEGF-2 receptor and angiopoietin-II, resulting in angiogenesis in cancer tissues (37,38).

Recent studies have demonstrated the local over-expression of several components of the RA system in various cancer cells and tissues (e.g. lung, pancreas, breast, prostate, skin and cervix carcinoma), suggesting that local over-expression of the RA system is associated with carcinogenesis (24,39,40). Of H.pylori infection-related disorders, the presence and expressions of angiotensin II, chymase and ACE are significantly higher in H.pylori-associated chronic gastritis and gastric cancer cells than in the normal gastric mucosa without H.pylori infection (24,40–42). Therefore, the RA system is assumed to be associated with the pathogenesis of H.pylori-related disorders and gastric carcinogenesis.

Of AGT polymorphism, AGT 235 M/T variant is in strong linkage disequilibrium with both AGT-6 G/A, +68 T/C and –532 C/T polymorphism and also in weak linkage disequilibrium with AGT-20 A/C polymorphism (43, 44). A cis-acting DNA element located between the TATA box and transcription initiation site is critical in transcriptional activity in the human AGT (45), where the AGT-20 A/C polymorphism is located. In vitro studies have demonstrated that reporter constructs containing the AGT-20 C allele increased basal promoter activity in comparison with AGT-20 A allele in transiently transfected HepG2 cells (20,45). Thus, we assume that the AGT-20 C allele works as the high-producer allele of AGT in vivo, which is consistent with our study result that the AGT-20 C allele carriage significantly increased the risk of gastric cancer development compared with carriage of the A allele. Therefore, other AGT polymorphism (e.g. AGT-6 G/A) as observed in AGT-20 polymorphism might also influence gastric carcinogenesis by affecting plasma AGT levels. In addition, because recent reports have demonstrated that RA system-related gene polymorphisms (e.g. CMA/B and ACE I/D) have a strong association with risk of gastric cancer development (23–26), suggesting that an increase of local angiotensin-II levels depend on not only AGT-20 polymorphism but also other RA system-related gene polymorphisms (e.g. CMA/B and ACE I/D). Moreover, the combination analysis of AGT-20 C allele carrier and CMA/B A allele carrier for gastric cancer development increased (detailed data not shown, OR: 4.70 95% CI: 2.14–10.33). Therefore, we considered that the risk of gastric cancer development might increase in the patients with high-producer alleles of RA system-related genes (i.e. CMA/B, ACE I/D and AGT-20 A/C), and that any components of RA system might play additive interaction to gastric carcinogenesis.

The serum PG I level and the PG I:PG II ratio are decreased with the progression of atrophic gastritis, which is considered to be one of the major risk factors for gastric cancer (28,29). In this study, the mean serum PG I level in H.pylori-infected patients with AGT-20 A/A genotype was significantly lower than that of patients with AGT-20 A/C or C/C genotypes. We previously reported that the serum PG I:PG II ratio in the CMA/B A allele carriage group was significantly lower than that in the non-carriage group, suggesting that the high-producer allele carriage of a major component of RA system resulted in a higher risk for the development of intestinal type of gastric cancer (23). However, further studies are required for the elucidation of the role of RA system on the progression of gastritis in relation to H.pylori infection.

In conclusion, we demonstrated that the AGT-20 A/C polymorphism in the RA system was associated with an increased risk of the development of gastric cancer. The possible association of ACE I/D and CMA/B A/G polymorphisms in this process was reported previously (23). Therefore, we assumed that the RA system definitely plays an important role in gastric cancer development. Whether the genotyping test of AGT-20 A/C polymorphism is useful for the screening of individuals with higher risk of gastric cancer and whether ACE inhibitors or ATR1 antagonists are effective for the chemoprevention of gastric cancer remain to be determined.


   Acknowledgments
 
This work was supported in part by a Grant-in-Aid from YOKOYAMA Foundation for Clinical Pharmacology, and from the 21st century COE program Medical Photonics (Hamamatsu University School of Medicine).

Conflict of Interest Statement: None declared.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 

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Received January 10, 2007; revised February 26, 2007; accepted March 15, 2007.


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