Japanese Journal of Clinical Oncology 33:192-197 (2003)
© 2003 Foundation for Promotion of Cancer Research
Helicobacter Pylori Seropositivity and the Myeloperoxidase G-463A Polymorphism in Combination with Interleukin-1B C-31T in Japanese Health Checkup Examinees
1 Nagoya Kita Health Center, Nagoya, 2 Department of Preventive Medicine/Biostatistics and Medical Decision Making, Nagoya University Graduate School of Medicine, 3 Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi and 4 Aichi Cancer Center, Aichi, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Objective: Genetic susceptibility appears to play an important role in Helicobacter pylori (HP) infection. The present study was conducted to re-examine the reported association between the myeloperoxidase (MPO) G-463A polymorphism and HP seropositivity in different subjects and to investigate interactions with smoking behavior and the interleukin-1B (IL-1B) C-31T polymorphism.
Methods: The subjects were 468 health checkup examinees in Nagoya, who consented to anonymous genotyping of residual blood samples. Genotyping was conducted by PCR-RFLP for MPO G-463A and PCR–CTPP for IL-1B C-31T.
Results: Among the successfully genotyped 437 participants without a cancer history, the HP seropositive rate was 56.2% for –463GG (n = 354), 49.4% for –463GA (n = 77) and 83.3% for –463AA (n = 6). The gender–age-adjusted odds ratio (aOR) for GA/AA relative to GG was 0.86 (95% confidence interval, 0.32–1.34) among males, 0.84 (0.47–1.49) among females, 0.83 (0.22–3.05) among current smokers and 0.87 (0.50–1.51) among never smokers. Analysis by IL-1B C-31T genotype revealed a significantly reduced OR of 0.41 (0.18–0.93) among the participants with IL-1B –31CT. The OR for IL-1B –31TT relative to –31CC/CT was 1.59 (1.00–2.55) among those with MPO –463GG and 3.36 (1.16–9.77) with MPO –463GA/AA. None of the gene–environment or gene–gene interactions proved to be statistically significant.
Conclusions: The association between MPO G-463A and HP seropositivity was not reproduced in this study. The effect of IL-1B –31TT was more prominent among individuals with the low expression MPO –463A allele, but it remains to be confirmed for other datasets.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Helicobacter pylori (HP) infection, a well-known risk factor for digestive ulcers, atrophic gastritis, stomach cancer and gastric mucosa-associated lymphoid tissue lymphomas (1), depends largely on sanitary conditions, especially during childhood (2). There are still substantial differences in childhood prevalence between developed and developing countries, reportedly ranging from 4 to 82% (3). In many developed countries, the infection rate has been shown to increase with age, this being considered to be due to a cohort effect (4).
HP infection is prevalent in many developing countries, but the prevalence is not 100% even in those areas where presumably all individuals are exposed to the bacterium (5). The changing virulence/strain of the bacterium (6,7) may impact on the infection rate, along with lifestyle factors such as salty food intake, fruit consumption and smoking (2). Although these environmental factors are influential, susceptibility of the host could also play a pivotal role in determining persistent HP infection. A twin study showed that the concordance of anti-HP antibody status was higher in monozygotic twin pairs than in dizygotic twin pairs (8), strongly indicating a genetic role in susceptibility and, to date, associations with HLA types (9) and polymorphisms of secretor (10), Lewis (10), interleukin-1B (IL-1B) (11–13), myeloperoxidase (MPO) (14) and tumor necrosis factor A (TNF-A) (15) have been reported.
MPO, located on chromosome 17q23.1, encodes a lysosomal enzyme which produces hypochlorous acid (HOCl) from hydrogen peroxide in polymorphonuclear neutrophils and monocytes (16). HOCl is a highly oxidative reactant with microbicidal activity against a wide range of organisms. Although HP is non-invasive in the gastric mucosa, the infection is characterized by extensive infiltration of neutrophils and HP water extract can activate neutrophils (17) and enhance the secretion of MPO (18). HP itself can survive the extracellular release of oxygen radicals from neutrophils due to its catalase activity (19) and for such microorganisms resistant to oxygen radicals, gastric mucosal damage induced by MPO may be a favored condition for colonization.
One polymorphism, MPO G-463A, located in a hormone response element region, has been reported to influence mRNA expression through loss of an SP1 transcription factor binding site. The G allele is associated with a 25-fold higher transcription than the A allele (20). Recently, involvement of MPO G-463A polymorphism has been described in numerous ailments such as atherosclerosis (21), cancer (22–25), periodontal disease (26), Alzheimer’s disease (27) and multiple sclerosis (28). Concerning atrophic gastritis, a strong positive correlation between the levels of neutrophil infiltration and atrophy in the stomach was found in 104 Koreans with the MPO –463GG genotype, but not in 23 with the MPO –463GA genotype (29). These findings indicate that MPO G-463A truly has functional significance, sufficient to impact on pathogenic processes.
Interleukin-1ß (IL-1ß), a pro-inflammatory cytokine with multiple biological effects (30) induced by HP infection (31), is a potent inhibitor of gastric acid secretion (32), providing a favorable condition for HP to survive in the stomach. IL-1B in chromosome 2q14 encoding IL-1ß has a T-to-C single nucleotide polymorphism making a TATA box at –31, whose T allele is presumably combined with transcription factors (33). An association between the T allele and HP seropositivity has been consistently observed (11–13).
The present study was conducted with the aim of re-examining the association earlier found between MPO G-463A polymorphism and HP seropositivity in a different dataset, in addition to possible gene–environment interactions with smoking, reported in our previous study of non-cancer outpatients (14). An additional goal was to examine gene–gene interactions with the IL-1B C-31T polymorphism. To our knowledge, this is only the second study focusing on MPO G-463A polymorphism and HP seropositivity and the first of interactions between MPO G-463A and IL-1B C-31T. An association between the IL-1B C-31T polymorphism and HP seropositivity for the present dataset was reported previously (12).
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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The subjects were described in our previous paper (12). Briefly, they were 468 examinees who attended a health checkup program supported by the Nagoya municipal government in 2000. The examinees were inhabitants of West ward of Nagoya City, who had no chance to attend health checkups at their workplaces. Written informed consent to anonymous use of the residual blood and information on demographic characteristics and smoking habit were obtained after the blood was drawn for health checkups. Usually, about 2 ml of blood remained after scheduled tests. No extra blood was sampled. Out of 489 examinees invited to participate in the study, 468 (96%) agreed to provide their residual blood for genetic tests along with the requested information. Three residual blood samples did not allow DNA extraction. Eleven participants with a cancer history, including two individuals with stomach cancer, were excluded. The remaining 454 persons (126 males and 328 females), aged 35–85, years were the subjects of this study. The Ethical Committee of Aichi Cancer Center approved this study in 2000 (Approval No. 12–23).
An anti-HP IgG antibody test, High-Molecular weight Campylobacter-Associated-Protein (HM-CAP) ELISA (Enteric Product, USA) was conducted for detecting HP-infected participants by SRL, Tokyo. AN ELISA value of 2.3 or over was regarded as HP infection positive. The sensitivity of HM-CAP is reported to be 98.7% with a specificity 100% in the USA (34), although a lower sensitivity was found in one study of Japanese (35).
Genotyping was conducted for MPO G-463A by a PCR–RFLP (polymerase chain reaction–restriction fragment length polymorphism) method (14) and for IL-1B C-31T by PCR–CTPP (polymerase chain reaction with confronting two-pair primers) (11,36).
An unconditional logistic model was applied for estimating gender–age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs). The Hardy–Weinberg equilibrium was examined for discrepancy between genotype and allele distributions using a 
2 test. The calculations were performed with the computer program STATA Version 7 (STATA, College Station, TX).
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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Table 1 shows the characteristics of the participants and anti-HP antibody positive rates according to gender, age group, smoking habit and genotypes of MPO G-463A. About three-quarters of the study subjects were females and about four-fifths of the males were over 60 years old. Most subjects (82.8%) were never smokers, reflecting the female predominance. The seropositive rate tended to increase with age, but the values were rather similar among those aged 50 years or over. The age-specific HP seropositive rate among males was similar to or higher than that among females. Current smokers had a lower positive rate than never smokers, when males and females were observed separately. These results were partly reported in a previous paper (12).
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Out of 454 subjects, 437 could be successfully genotyped for MPO G-463A. The MPO genotype was distributed 81.0% GG, 17.6% GA and 1.4% AA. The distribution was in Hardy–Weinberg equilibrium (
2 = 0.590, P = 0.442). The HP seropositive rate of males was 67.7% for GG and 59.1% for GA. No AA genotype was found among male examinees. The rates among female examinees were 51.8, 45.5 and 83.3, respectively. The AA genotype was found in only six females and the expression of AA genotype was biologically considered to be lower than that of GA genotype, so that AA and GA genotypes were combined for the subsequent analysis. Table 2 shows gender–age-adjusted ORs for HP seropositivity with the GA/AA relative to the GG genotype: 0.86 (95% CI, 0.32–2.34) for males, 0.84 (95% CI, 0.47–1.49) for females and 0.84 (95% CI, 0.51–1.37) for all subjects. There were no differences in ORs between current smokers and never smokers; former smokers numbered only 10 and were excluded from the analysis. Subgroup analysis according to IL-1B C-31T revealed a significantly reduced OR among examinees with the CT genotype (OR = 0.41; 95% CI, 0.18–0.93).
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Table 3 shows the gender–age-adjusted ORs for HP seropositivity with the IL-1B –31TT (higher risk genotype) relative to the IL-1B –31CC/CT (lower risk genotypes) by MPO G-463A genotype. The TT genotype was significantly associated with HP seropositivity (OR = 1.74; 95% CI, 1.15–2.63), as reported previously (12). The OR was higher among those with MPO –463GA/AA (OR = 3.36; 95% CI, 1.16–9.77) than with MPO –463GG (OR = 1.59; 95% CI, 1.00–2.55). Table 4 shows the gender–age-adjusted ORs for the combinations of MPO and IL-1B genotypes relative to MPO –463GA/AA and IL-1B –31CC/CT, the lowest risk combination, as a reference. A multiplicative effect of MPO –463GG and IL-1B –31TT was not observed. The gene–gene interaction was 0.47 (95% CI, 0.15–1.43).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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We previously reported the low expression genotypes, MPO –463GA/AA, to be negatively associated with HP seropositivity with a series of outpatients who participated in an HP eradication program (HPE) at Aichi Cancer Center Hospital, especially for male subjects; the gender–age-adjusted OR was 0.69 (95% CI, 0.35–1.35) for all subjects and 0.31 (0.11–0.84) for males. In that dataset, current smokers with MPO –463GG had a significantly higher odds ratio relative to current smokers with –463GA/AA or non-current smokers with –463GG (14). Although not significant for all subjects or for males, the present study of health checkup examinees (HCE) also showed OR below unity. We can preclude selection/information bias, because (1) cases (seropositive participants) and controls (seronegative participants) were enrolled in the same framework, (2) the participation rate was 96%, (3) the anti-HP antibody test and genotyping were conducted independently and (4) neither participants nor enrollment staff knew the results of both tests.
There were no substantial differences in findings between our HCE and HPE studies and the MPO genotype distribution here found for GG, GA and AA was similar to that established previously, 79.7, 19.5 and 0.8% among HPE (14) and 81.0, 17.6 and 1.4% among HCE, respectively. The values are in line with those reported for 127 Koreans (81.9, 18.1 and 0.0%, respectively) (29), but different from the distribution among 459 Caucasians (61.0, 31.2 and 7.8%, respectively) (22) and 244 African-Americans (49.6, 41.0 and 9.4%, respectively) (22). The HP seropositivity rate was slightly lower with HPE (62.7%) than HCE (55.1%) although the laboratory methods applied were the same (14).
Although slightly different results could be due to a random effect, they might also be partly attributable to variations in the source of study subjects. The HPE participants were recruited from outpatients who sought an endoscopic examination of the upper gastrointestinal tract at Aichi Cancer Center Hospital, whereas the HCE subjects were mainly housewives and self-employed residents who participated in a health checkup provided by a local government. Most subjects in the HCE group were never smokers, because of the female predominance. Percentages of current and former smokers were 15.0 and 2.2% among HCE and 22.8 and 19.1% among HPE, respectively (14). In addition, the HPE subjects might be more likely to have had upper gastrointestinal symptoms or related health concerns (11).
MPO is an oxidative enzyme expressed mainly in polymorphonuclear leukocytes. Despite the primary role of the oxygen-dependent MPO system in the destruction of certain phagocytosed microbes, subjects with total or partial MPO deficiency generally do not have an increased frequency of infections, probably because other MPO-independent mechanisms for microbicidal activity compensate for the lack of MPO. Since knockout mice became available, MPO deficiency can be explored more thoroughly. The mice have shown increased susceptibility to severe infection by Candida albicans, but had no problems handling Staphylococcus aureus (37). These results suggest that the MPO-dependent oxidative system is important for host defense against fungi and bacteria, although the effect varies with the pathogen species (38).
Although HP is known to be non-invasive and colonizes mainly the surface mucosal layer of the gastric epithelium, infection is characterized by extensive infiltration of neutrophils and monocytes. HP-induced neutrophil recruitment may be mediated by CXC chemokines such as IL-8 and, in comparison with non-infected persons, those infected have higher levels of this factor in their gastric mucosa, with decreased protein and mRNA levels in antral biopsy specimens after eradication (39). HP is not engulfed efficiently by professional phagocytes such as neutrophils and induces extracellular release of oxygen radicals, itself surviving using catalase (19). This mechanism benefits HP by facilitating persistent infection.
It might seem to be contradictory that the high expression allele of MPO is associated with a high HP seropositive rate, because a high microbicidal enzyme level should work against HP survival in the stomach. However, HP can survive MPO-promoted inflammation, which decreases acid secretion through the inducement of IL-1ß and TNF-
. A certain level of inflammation may make a favorable condition for persistent HP infection. This hypothesis is supported by the consistent association observed with the IL-1B –31TT high expression genotype (11–13). The present study showed no multiplicative effect between MPO –463GG and IL-1B –31TT genotype, but individuals with MPO –463GA/AA and IL-1B –31CC/CT demonstrated the lowest risk suggesting that lower levels of both MPO and IL-1ß may disturb the persistent HP infection.
No interaction between MPO G-463A and smoking was observed in this dataset whereas in the HPE study, a marginally significant link was apparent (P = 0.08; OR = 4.57) (14). This inconsistency might be due to random effects, but since smoking could interact with IL-1B C-31T (11–13), an indirect weak interaction with MPO G-463A cannot be denied solely on the basis of our two studies.
In conclusion, individuals with MPO –463GA/AA here demonstrated only a non-significant association with low HP seropositivity, in contrast to the situation with IL-1B C–31T. Furthermore, no interaction between MPO G-463A and smoking was observed. However, the relation between IL-1B –31TT genotype and HP seropositivity tended to be stronger among those with MPO –463GA/AA, suggesting that genetic polymorphisms pertaining to inflammation do play a role in HP susceptibility. Further studies with a larger sample size are now required with other Japanese populations and ethnic groups.
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ACKNOWLEDGMENTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONACKNOWLEDGMENTSREFERENCES |
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This work was supported in part by a Grant-in-Aid for the 2nd Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan. The authors are grateful to Ms Michiyo Yagyu and Ms Mayumi Kato for genotyping.
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FOOTNOTES |
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+ For reprints and all correspondence: Nobuyuki Katsuda, Nagoya Kita Health Center, 4–17–1 Shimizu, Kita Ward, Nagoya 462-8522, Japan. E-mail: katsuda{at}nifty.com
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Received January 5, 2003; accepted February 27, 2003
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