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Carcinogenesis Advance Access originally published online on July 8, 2006
Carcinogenesis 2006 27(12):2491-2496; doi:10.1093/carcin/bgl121
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Myeloperoxidase G–463A polymorphism and the risk of gastric cancer: a case–control study

Huaijun Zhu1,{dagger}, Li Yang1,2,{dagger}, Bo Zhou1, Rongbin Yu3, Naping Tang1 and Bin Wang1,*

1 Key Laboratory of Reproductive Medicine, Department of Pharmacology, Nanjing Medical University 140 Hanzhong Road, Nanjing, 210029, China
2 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University China
3 Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University China

*To whom correspondence should be addressed. Tel: +0086 25 86862884; Fax: +0086 25 86862884; Email: binwang{at}njmu.edu.cn


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Statistics
 Results
 Discussion
 References
 
Several epidemiological studies have shown that the myeloperoxidase (MPO) G–463A polymorphism may influence the risk of many cancers, including lung, breast, bladder and laryngeal cancer. However, there is no study concerning the MPO polymorphism and gastric cancer risk. In this hospital-based, case–control study, we used polymerase chain reaction–restriction fragment length polymorphism protocols to examine the prevalence of MPO G–463A polymorphism in gastric cancer. A significantly different distribution of the MPO –463G/A genotype was demonstrated among the cases and controls ({chi}2 = 7.42, P = 0.03). Subjects with the variant genotypes (the sum of GA and AA) had a 44% reduced risk of gastric cancer relative to those with GG [adjusted odds ratio (OR) = 0.56; 95% CI: 0.32–0.97]. Stratified analyses revealed that the protective effect of A allele was significant in male (adjusted OR = 0.51; 95% CI: 0.26–0.98) or younger subjects (age <58 years) (adjusted OR = 0.42; 95% CI: 0.18–0.94), but not in female or older subjects. In addition, there was also a significantly reduced risk in subjects residing in rural areas (adjusted OR = 0.41; 95% CI: 0.18–0.95) but not in urban areas. The interaction between the MPO G–463A polymorphism and smoking status was not observed in this study. Tumor differentiation was also not found to be associated with the MPO genotype. In conclusion, our results showed that the MPO –463 G to A variant may be associated with the decreased risk of gastric cancer in Chinese population.

Abbreviations: GST, glutathione S-transferases; MPO, myeloperoxidase


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Statistics
 Results
 Discussion
 References
 
Reported by International Agency for Research on Cancer in 2005 (Global Cancer Statistics, 2002), gastric cancer is the fourth common cancer (934 000 cases per year, 8.6% of total cancers) and the second most fatal malignancy worldwide (700 000 deaths/year, 10.4% of total cancers) (1). Although the incidence and mortality of gastric cancer have been decreasing in Western countries over the past few decades, high rates are still present in East Asia, Eastern Europe, parts of Central and South America (1,2). As indicated previously by us, the populations in developing countries adopt western diets and a high-stress lifestyle, the geographic distribution of many chronic diseases' incidence has changed (3–5). And an investigation in China including 169 871 men and women demonstrated that gastric cancer was in the third place among the five leading causes of death from cancer (6).

Gastric cancer has been considered to be a result of gene–environment interactions, which is a complex multifactorial and multistage process (7). Published studies have identified that gastric cancer is associated with polymorphisms in genes involved in inflammatory response, DNA repair, metabolic enzymes and oxidative damage (8). Previous studies in Chinese population also found that gastric cancer risk was associated with polymorphisms in DNA repair gene XRCC1 (9) and 5,10-methylenetetrahydrofolate reductase (MTHFR) (10). Oxidative stress has been confirmed to play important roles in various diseases. In our previous epidemiological studies, oxidative stress was found to be related to cataract (3) and coronary artery disease (4). The polymorphisms of oxidative stress-related enzymes have been detected in gastric cancer. NAD(P)H: quinone oxidoreductase 1 (NQO1) 609 CT/TT, glutathione S-transferases (GST) T1 null genotype and double null GST M1-GST T1 genotype were all found to be associated with an increased gastric cancer risk (11,12). However, the manganese superoxide dismutase (Mn SOD) polymorphisms at –102 C to T and the –9 T to C were not found to be associated with gastric cancer in a Polish case–control study (13).

As an oxidative stress-related enzyme, myeloperoxidase (MPO) is a lysosomal hemoprotein located in polymorphonuclear neutrophils and monocytes. It can catalyze a reaction that produces hypochlorous acid (HOCl), which may cause host DNA damage and lead to the mutation of oncogenes and tumor suppressor genes (14,15). Austin et al. (16) identified a G–463A polymorphism in the promoter region of the MPO gene among leukemia patients. It has been reported that the A allele was associated with a significantly decreased transcriptional activity compared with the G allele, because of the disruption of an SP1-binding site in an Alu hormone-responsive element (HRE) (17). Several epidemiological studies have examined the role of the MPO G–463A polymorphism in lung cancer (18–28), breast cancer (29,30), esophageal cancer (31), bladder cancer (32), ovarian cancer (33), malignant lymphoma (34), hepatoblastoma (35), larynx cancer and pharynx cancer (21). And a protective effect of the MPO A allele was observed in breast cancer (29,30), bladder cancer (32), esophageal cancer (31), hepatoblastoma (35) and laryngeal cancer (21), while the results were controversial in lung cancer (18–28).

Roe et al. (36) found that the MPO genotype was a critical host factor in the pathogenesis of Helicobacter pylori–induced atrophic gastritis, which is generally accepted as the precursor of gastric cancer. However, to our knowledge, there is no study concerning the MPO polymorphism and gastric cancer risk. In this hospital-based, case–control study, we examined the association between the risk of gastric cancer and the MPO G–463A polymorphism in Chinese population.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Statistics
 Results
 Discussion
 References
 
Subjects
Two hundred and eighty individuals (137 cases and 143 controls) in the Affiliated Hospital of Nanjing Medical University were recruited. The diagnoses of gastric cancer were all confirmed by endoscopic biopsy or surgical specimens. Six cases with secondary, recurrent tumors were excluded. Control subjects had no current or previous diagnosis of cancer and genetic disease. Eight individuals with coronary artery disease (four cases and four controls) were also excluded, considering the association between MPO genotype and the risk of coronary artery disease reported previously (37). Control patients were frequency-matched for sex and 5-year age groups. All subjects were interviewed to obtain information on residence (urban or rural), body weight, smoking status and medical treatment by questionnaires. Smoking was defined as ≥10 cigarettes per day. Approximately 5 ml venous blood sample was collected from each subject. Blood samples were anticoagulated with ethylenediamine tetraacetic acid and were separated by centrifugation immediately after collection. Leukocyte pellet obtained from each blood sample was stored at –80°C until required for analysis. The study was approved by the Nanjing Medical University Ethics Committee and informed consent was obtained from each participant.

MPO genotyping
Genomic DNA was isolated from frozen leukocyte pellet using standard phenol–chloroform extraction. The MPO G–463A polymorphism was detected by polymerase chain reaction (PCR)–restriction fragment length polymorphism (RFLP). A 350 bp DNA fragment containing the polymorphic site was amplified by PCR in the T1 Thermocycler (Biometra, Goettingen, Germany) using the forward primer 5'-CGG TAT AGG CAC ACA ATG GTG AG-3' and the reverse primer 5'-GCA ATG GTT CAA GCG ATT CTT C-3'. The PCR reaction was performed in a total volume of 20 µl containing 2 µl 10x PCR buffer, 1.5 mM MgCl2, 0.2 mM dNTPs, 0.375 µM each primer, 200 ng of genomic DNA and 1 U of Taq DNA polymerase (MBI Fermentas). The PCR conditions were 94°C for 5 min, followed by 35 cycles of 60 s at 94°C, 60 s at 56°C and 60 s at 72°C, with a final elongation at 72°C for 10 min. An aliquot of 10 µl of the PCR product was digested with 5 U of Aci (New England BioLabs) in 2 µl of 10x NEB buffer 3 (100 mM NaCl, 50 mM Tris–HCl, 10 mM MgCl2 and 1 mM dithiothreitol) and 7.5 µl dH2O at 37°C overnight. The DNA fragments were separated on a 2% agarose gel containing 0.5 µg/ml ethidium bromide. The G homozygous yields three bands at 169, 120 and 61 bp, and the A homozygous produces two bands at 289 and 61 bp, where the heterozygote (GA) has four bands at 289, 169, 120 and 61 bp. Approximately 10–15% of the samples were randomly selected for repeated assays, and the results were 100% concordant.


   Statistics
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 Introduction
 Materials and methods
 Statistics
Results
 Discussion
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The Student's t-test was used to identify differences in age and weight between the controls and gastric cancer cases. Discrete variables were represented as frequencies and were evaluated by the Pearson {chi}2-test. MPO genotype distribution and allele frequencies in the two groups were also investigated using the Pearson {chi}2-test. Hardy–Weinberg equilibrium was assessed for controls by a goodness-of-fit {chi}2-test. The association between the MPO G–463A polymorphism and the risk of gastric cancer was estimated by odds ratio (OR) and 95% confidence interval (CI). Carriers of the wild genotype GG comprised reference group. The crude OR was computed using the Woolf approximation method. Stratified analyses were conducted by the median age of controls, sex, smoking status, residence and differentiation of tumors. A multivariate analysis with unconditional logistic regression method was performed to assess the adjusted OR. Stata Version 7.0 (STATA Corporation, College Station, TX) was used for all the analyses. All statistical tests were based on two-tailed probability. A P-value of <0.05 was considered statistically significant.


   Results
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 Abstract
 Introduction
 Materials and methods
 Statistics
 Results
Discussion
 References
 
A total of 127 gastric cancer cases and 139 non-cancer controls were enrolled. The basic characteristics of the subjects including sex, age, weight, residence, smoking status and the tumor differentiation are displayed in Table I. No significant difference was found between the cases and controls in age (58.0 ± 13.1 versus 56.8 ± 14.0 years, P = 0.50) and sex (male: 75.6 versus 71.2%, P = 0.42), indicating that the matching for the subjects was successful. Among the cases, 54.3% were residing in the urban area compared with 47.5% of the controls (P = 0.26). More smokers were found among gastric cancer cases compared with controls (24.4% versus 13.7%, P = 0.025). Most of the cases were adenocarcinoma (96.1%).


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  		Table I Demographic information

 
Table II shows the distribution of genotypic characteristics in the cases and controls. The genotype distributions were in Hardy–Weinberg equilibrium in the control population ({chi}2 = 0.14, P = 0.71), indicating that there was no genetic drift or any selective advantage for particular MPO alleles. A significantly different distribution of the MPO –463G/A genotype was demonstrated among the cases and controls ({chi}2 = 7.42, P = 0.03). A lower frequency of A alleles was found in cases (12.6%) compared with the controls (21.2%). Only one AA genotype was identified in case group.


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  		Table II Distributions of the MPO –463G/A genotype in cases and controls

 
Table III shows the risk estimates for the variant MPO genotypes among gastric cancer patients compared with controls. Among total cases and controls, the crude OR for subjects with the variant genotypes (the sum of GA and AA) was 0.54 (95% CI = 0.32–0.92) relative to GG carriers. And we noted a more decreased risk for gastric cancer in subjects with the AA genotype (crude OR = 0.14, 95% CI = 0.02–1.05), although not statistically significant. When adjusted for age, sex, smoking status, hypertension, diabetes and residence, the OR for subjects with AA genotype and the OR for those with the variant genotypes (the sum of GA and AA) were 0.15 (95% CI = 0.02–1.24) and 0.56 (95% CI = 0.32–0.97), respectively.


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  		Table III Risk estimates for the variant MPO genotypes

 
Results of stratified analyses by the median age of controls (58 years), sex, smoking status and residence with the MPO variant genotypes are presented in Table IV. Crude and adjusted OR (for age, sex, smoking status, hypertension, diabetes and residence) with 95% CI for mutant genotypes are all described. In statistical analyses stratified by age, the decreased risk associated with the mutant genotypes tended to be more evident in younger subjects (age <58 years) (adjusted OR = 0.42, 95% CI = 0.18–0.94). But in older subjects (age ≥58 years), the association between the MPO polymorphism and gastric cancer risk was not statistically significant (P = 0.39). Compared with the GG genotype, the adjusted OR for the mutant genotypes was 0.68 (95% CI = 0.24–1.94) among female subjects and 0.51 (95% CI = 0.26–0.98) among male subjects. We did not note a statistically significant inverse association with gastric cancer risk in both non-smokers (adjusted OR = 0.59, 95% CI = 0.33–1.08) and smokers (adjusted OR = 0.50, 95% CI = 0.12–2.05). In rural subjects, possession of the variant genotypes was associated with an ~60% reduced risk of gastric cancer (adjusted OR = 0.41, 95% CI = 0.18–0.95), while the association was not statistically significant in urban subjects (P = 0.46).


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  		Table IV Stratified analyses for the variant MPO genotype in cases and controls

 
Further stratified analyses by tumors differentiation showed no significant association between the MPO genotype and tumor differentiation (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Statistics
 Results
 Discussion
References
 
To our knowledge, this is the first study linking the MPO G–463A polymorphism with gastric cancer risk. In this hospital-based, case–control study, we assessed the role of the MPO G–463A polymorphism in gastric cancer susceptibility in Chinese population. The results indicated that the MPO –463 G to A variant was associated with the reduced risk of gastric cancer.

As an important component of the neutrophil's antimicrobial armory, MPO catalyses the oxidation of chloride by hydrogen peroxide to produce bactericidal compound HOCl. HOCl and other reactive byproducts generated by MPO can also lead to damage to bystander cells and host DNA, which could drive the inflamed epithelia to malignancy at inflammatory sites (14,15,38,39). Since the MPO G–463A polymorphism was reported in 1993 by Austin et al. (16), it has been considered to be associated with a decreased risk of many human malignancies (18–35). It has also been confirmed that the G to A variant appears to decrease expression of MPO for the loss of a SP1 transcription factor binding site (17). A number of studies have shown the MPO AA/GA genotype to be associated with decreased susceptibility to lung cancer (18,19,21,23,27), while other studies have failed to replicate this inverse association (20,22,25). Findings by Hung et al. (32) suggested that individual susceptibility of bladder cancer may be modulated by MPO G–463A polymorphisms (OR = 0.31, 95% CI = 0.12–0.80). Having at least one A allele was found to be associated with an overall 13% reduction in breast cancer risk (30). Compared with wild-type GG, a protective factor of mutant genotype (AA + GA) was also found in laryngeal cancer patients (OR = 0.63, 95% CI = 0.43–0.92, P = 0.017) (21).

In this study, a significant difference of the MPO –463G/A genotype distribution was found between gastric cancer cases and controls. We observed a 44% reduced risk of gastric cancer in individuals with MPO –463GA/AA compared with the GG carriers (adjusted OR = 0.56, 95% CI = 0.32–0.97). A lower risk of borderline significance was emerged in individuals with AA genotype (adjusted OR = 0.15, 95% CI = 0.02–1.24, P = 0.078).

Recent data in the literature support an important role of oxidative damage in the stomach carcinogenesis. Hwang et al. (40) suggested that ROS-NF-{kappa}B signaling pathway was involved in the IL-1ß-induced IL-8 expression which directly correlates with the vascularity of human gastric carcinomas. Lin et al. (41) showed that serum levels of Cu/Zn SOD were significantly elevated in gastric cancer patients compared with healthy controls. Accordingly, the associations between the risk of gastric cancer and the polymorphisms of oxidative stress-related genes were also investigated. Subjects with 1 or 2 609T NQO1 alleles were noted to have higher risk of cardiac adenocarcinoma relative to wild-type CC (OR = 2.18, 95% CI = 1.38–3.44, P = 0.0007) (11). Palli et al. demonstrated that the GSTT1 null genotype was associated with an increased gastric cancer risk (OR = 1.68, 95% CI = 1.01–2.80, P = 0.04). A more significantly increased risk was found for the individuals with double null GSTM1-GSTT1 genotype (OR = 2.27, 95% CI = 1.14–4.53) (12). Nevertheless, the Mn SOD polymorphisms at –102 C to T and the –9 T to C were not found to be associated with gastric cancer in a Polish case–control study (13). Our results support that polymorphisms of oxidative stress-related enzymes may play important roles in the stomach carcinogenesis.

The precise mechanisms underlying the relationship of MPO polymorphism and stomach carcinogenesis remain unclear. MPO protein is mainly expressed at high levels in neutrophils, monocytes and some reactive microglial (16,42). The G allele is the wild type with normal MPO expression, while the A allele is a low-expression allele (17,43). The atrophic gastritis subsequent to Helicobacter pylori infection, which is the precursor of gastric cancer, is characterized by extensive infiltration of neutrophils. MPO protein released by neutrophils into the extracellular milieu amplifies the oxidative potential of hydrogen peroxides that induce gastric mucosal injury (36,44–46). In fact, a strong positive correlation between the levels of neutrophil infiltration and Helicobacter pylori-induced atrophic gastritis was found in the MPO (G/G) genotype but not in the MPO (G/A) genotype (36), and Helicobacter pylori water extract could activate neutrophils and increase the secretion of MPO (47–49). In addition, MPO levels of neutrophils in gastric cancer patients were found to be significantly higher than in healthy controls (50). However, more studies are needed to confirm this hypothesis.

Our data also showed that the association between reduced gastric cancer risk and the mutant genotypes (AA + GA) was more evident in younger subjects (age <58 years) than in older subjects. And Schabath et al. (19) observed a 72% reduced risk of lung cancer in younger subjects (age <61 years) (GA + AA versus GG) compared with a non-significant 22% reduced risk in older subjects. Relative high-level exposure to carcinogens and weak immune system in older individuals may account for these. Conversely, Cascorbi et al. (21) reported that a significant decreased risk of lung cancer and laryngeal cancer was found in older subjects (age ≥63 years) with GA or AA genotype. The reason for the different observations remains unclear.

We also found an interaction between MPO genotype and sex. The adjusted OR was 0.51 for GA/AA genotype compared with GG genotype among male individuals. But the OR was not statistically significant among female individuals. Our findings were consistent with previous observations of studies concerning lung cancer, laryngeal cancer, Alzheimer's disease or Helicobacter pylori infection (19,21,24,42,49). Reynolds et al. (42) reported that the Alu-HRE from the MPO A allele, with the –463A, was bound by estrogen receptor {alpha}, whereas the –463G element was not bound. And estrogen could increase MPO –463A promoter activity by several times, while has no significant effect on MPO –463G promoter activity. Thus it is a reasonable hypothesis that the absence of protective effect of the MPO –463A variant in female subjects may be due to the elevation of MPO –463A promoter activity by estrogen.

The stratified analyses by residence revealed that the protective effect of A allele was significant in rural subjects but not in urban subjects. Factors associated with residential environment (such as air, soil, diet, occupation, lifestyle) may be responsible for the different results between rural and urban subjects. The genetic differences have their strongest effects under conditions of low environmental pollution (7,32). Our results were plausibly consistent with that, considering the better environments in rural areas.

We found no evidence of interaction between MPO genotype and smoking status. Several studies have focused on this interaction and no consistent results have been concluded. Schabath et al. (19) observed that the MPO mutant genotype had a significant protective effect on lung cancer risk for current smokers. Similar interactions were documented by Lu et al. (23) and Hung et al. (32). However, other data could not find the interaction between MPO genotype and smoking status (18,20,21).

There are some limitations to the study that should be considered. Firstly, we used hospital-based controls recruited among patients with a variety of nonmalignant diseases. These may cause the possibility of selection bias and confound the results. Nevertheless, the genotype distribution of controls in our study met Hardy–Weinberg equilibrium conditions. In normal controls, the distribution of the MPO genotype has been shown to vary among populations. The frequencies of the A allele were found to be 20.9% in Caucasians (n = 1128) (20), 26.7% in French-Canadians (n = 217) (37) and 25% in Italians (n = 214) (32). In the present study, the frequency observed to be 21.2% in controls was in the range of those in previous reports in Chinese population (23,24). The second potential limitation of the present study is the relatively small sample size, which may limit statistical power. However, this internally consistent pilot study certainly provides valuable insights and interesting information and may serve to guide future studies in this area. Larger study should be conducted to confirm our results. Another limitation of the study is that the study was conducted in Chinese population. Caution should be exercised of extrapolating the data to other ethnic groups.

In conclusion, our results showed that the MPO –463 G to A variant may be associated with the decreased risk of gastric cancer in Chinese population, suggesting that the polymorphism of MPO G–463A is involved in the gastric tract carcinogenesis. The interactions between the MPO –463GA genotype and sex or age also have been demonstrated in this study. To provide a more definitive conclusion, further large case–control studies are needed to investigate interactions between MPO genotype, smoking and other risk factors with respect to gastric cancer risk.


   Footnotes
 
{dagger}The first two authors contributed equally to this work. Back


   Acknowledgments
 
This study was supported by grants from the National Natural Science Foundation of China (No. 30000207), the Natural Science Foundation of Jiangsu Province (No. BK2006525), Commercialization of Science and Technology Foundation of Education Department, Jiangsu Province (JH01-050) and Nanjing Medical University grant (CX2001003) to B.W.

Conflict of Interest Statement: None declared.


   References
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 Abstract
 Introduction
 Materials and methods
 Statistics
 Results
 Discussion
 References
 

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Received May 8, 2006; revised June 29, 2006; accepted July 5, 2006.


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