Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype

A. Ruzzo1, F. Graziano2,*, F. Pizzagalli1, D. Santini3, V. Battistelli1, S. Panunzi4, E. Canestrari1, V. Catalano5, B. Humar6, R. Ficarelli7, I. Bearzi8, S. Cascinu9, N. Naldi10, E. Testa2 and M. Magnani1

1 Institute of Biochemistry ‘G Fornaini’, University of Urbino, Italy; 2 Medical Oncology, Hospital of Urbino, Italy; 3 Medical Oncology, University Campus Biomedico, Rome, Italy; 4 Laboratory of Biomatematics CNR IASI, Rome, Italy; 5 Medical Oncology, Hospital of Pesaro, Italy; 6 Cancer Genetics Laboratory, University of Otago, Dunedin, New Zealand; 7 Medical Oncology, Hospital of Senigallia, Italy; 8 Institute of Histopathology, 9 Medical Oncology, University of Ancona, Italy; 10 Medical Oncology Unit, Hospital of Parma, Italy

* Correspondence to: Dr F. Graziano, Unità Operativa di Oncologia Medica, Ospedale di Urbino, 61029 Urbino, Italy. Email: frada{at}tin.it


    Abstract
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Background:: Polymorphisms in the interleukin 1ß gene (IL-1B-31T/C and IL-1B-511C/T single nucleotide changes) and in the interleukin 1 receptor anatagonist gene (IL-1RN2 variable number of tandem repeats) have been studied with respect to gastric cancer susceptibility. Available data support an aetiologic role of these genetic variants in the presence of concomitant Helicobacter pylori infection. Their contribution without H. pylori infection is still an open field of investigation.

Materials and methods:: IL-1B and IL-1RN polymorphisms were investigated in 138 H. pylori-negative Italian patients with sporadic gastric cancer and 100 H. pylori-negative controls. Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with disease.

Results:: In all gastric cancer cases, carriers of the homozygous IL-1B-511T/T genotype showed a significant risk for the development of the disease (OR 3.2 with 95% CI 1.27–8.05). In cases with intestinal-type gastric cancer, however, both IL-1B-511T and IL-1RN2 alleles were associated with disease. In this subgroup, the odds ratio for carriers of both IL-1B-511T and IL-1RN2 was 6.49 (95% CI 2.07–20.4). Haplotype analysis supported the aetiologic contribution of these alleles in gastric cancer of the intestinal histotype.

Conclusions:: In conclusion, IL-1B-511T and IL-1RN2 may contribute to intestinal gastric cancer risk in the absence of concomitant H. pylori infection. In this setting, future epidemiologic studies should consider dietary habits and exposure to carcinogens interacting with pro-inflammatory host genotypes.

Key words: gastric neoplasms, interleukin, polymorphisms, susceptibility, Helicobacter pylori


    Introduction
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Polymorphic variants of genes are common and usually do not affect gene fuction. In some instances, allelic variants such as single nucleotide changes (SNP) or variable number of tandem repeats (VNTR) polymorphisms, can occur within gene regulatory sequences leading to alterations at the transcriptional or translational level. Such functional gene variants have been shown to influence the proper function of tumour suppressor and oncogenes, the efficiency of carcinogen activation or detoxification, the balanced production of inflammatory cytokines and of factors for mucosal protection. Accordingly, common gene variants may modify cancer susceptibility associated with environmental factors [1Go–3Go].

In 2000, El-Omar et al. [4Go, 5Go] reported the first positive association between gastric cancer risk and polymorphisms in the genes coding for the cytokines interleukin 1B(IL-1B) and interleukin 1 receptor antagonist (IL-1RN). Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) are located on chromosome 2q14, within a 360-kb region [6Go]. IL-1RN counterbalances the potentially injurious proinflammatory effects of IL-1B [7Go]. Functional polymorphisms in IL-1B and IL-1RN have been found to impair this fine interplay, causing an unfavourable high IL-1B/IL-1RN ratio [8Go, 9Go]. IL-1B is not only a determinant of a proinflammatory phenotype but it also seems to be a major co-factor promoting and maintaining Helicobacter pylori infection [10Go, 11Go], which is a recognised aetiologic factor for gastric cancer [12Go].

The role of IL-1B and IL-1RN polymorphisms in gastric cancer susceptibility is still under investigation [13Go–21Go]. Variable frequencies of these polymorphisms across populations, absence of concomitant H. pylori infection and different genetic pathways for the development of intestinal and diffuse gastric carcinomas, may all represent factors confounding the real contribution of these variants to disease [22Go–24Go].

We have, therefore, investigated in a case–control study the potential aetiologic role of IL-1B and IL-1RN polymorphisms in H. pylori-negative, Italian gastric cancer patients.


    Materials and methods
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Study subjects
Consecutive patients with H. pylori-negative, sporadic gastric cancer were enrolled from five medical oncology units in central Italy. Eligibility criteria (Caucasian ethnicity, residency in central Italy, and lack of history for H. pylori infection) were verified during an interview with the designed investigator at each participating Institution. Also, pedigrees were traced back for at least three generations and laterally to second- and third-degree relatives to exclude the fulfilment of the hereditary diffuse gastric cancer syndrome and of the hereditary non-polyposis colorectal cancer syndrome criteria. Before study entry, H. pylori infection was excluded by histology search in biopsy specimen taken during diagnostic endoscopy and by serum testing for anti-H. pylori IgG antibodies. At least four biopsies from the body-antrum gastric mucosa had to be available for each case. Corresponding tissue sections were stained with the modified Silver Stainer technique [25Go]. Blood samples were assayed for the presence of the high molecular weight Campylobacter-associated protein (HM-CAP, Enteric Products, Inc., Stony Brook, NY). Negativity was defined according to ELISA values below the cut-off assessed by global standards and following the suppliers' manual. Gastric cancer cases with negative histology, but positive serology, were excluded. The specifity of the HM-CAP assay has been reported as high as 100% in populations from Western countries [26Go].

The same criteria as the cancer cases plus lack of personal history of cancer were adopted for selecting controls. They were identified through the pools of current and former blood donors available at each participating Institution. Controls were randomly selected and frequency matched to cases by age (±2 years) and sex. In healthy controls, the absence of H. pylori infection was determined by the same serum testing for anti-H. pylori IgG antibodies.

Eligible patients and healthy controls were also interviewed about education, tobacco smoking and alcohol intake (threshold of 20 g/day of alcohol intake was estimated as approximately two cans of beer, two glasses of wine or two shots of spirit). The study met the ethical requirements of the internal review boards and all participants gave their written informed consent.

Analysis of the IL-1B-31, IL-1B-511 and IL1-RN polymorphisms
The IL-1B-31C and the IL-1B-511T polymorphisms are single nucleotide changes in the promoter region, while the IL-1RN polymorphism is a 86-base pair VNTR within the second intron. DNA was extracted from 200 µl of peripheral blood samples by the use of GeneElute Mammalian Genomic DNA (Sigma-Aldrich) and genotyped for the three polymorphisms. Corresponding primers and PCR/restriction fragment length polymorphism (RFLP) conditions have been described previously [4Go] and are shown in Table 1. In brief, 25–50 ng of DNA was used in a volume of 25 µl with 150 µM of dNTPs, 6.25 pmol of each primer, 1 U of Hot-Rescue DNA Polymerase (Diatheva-Italy), 5% DMSO, 4 mM MgCl2 and 2.5 µl of 10x PCR buffer. Amplified/digested fragments were visualized by ethidium bromide on 2.5% agarose gels.


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Table 1. Primers and conditions for analysis of the IL-1B and IL-1RN polymorphisms

 
The IL-1RN alleles were coded conventionally [4Go, 13Go] as follows: allele 1, four repeats; allele 2, two repeats; allele 3, five repeats; allele 4, three repeats; and allele 5, six repeats. According to previous studies [4Go, 13Go], the IL-1RN alleles were dichotomized into two categories: long genotype (L; ≥ three repeats; alleles 1, 3, 4, 5) and short genotype (2; two repeats; allele 2).

Statistical methods
The significance of the difference in the distribution of the polymorphisms among different groups was calculated using the {chi}2 test. All allelic distributions were examined for deviations from their corresponding Hardy–Weinberg equilibrium. Unconditional logistic regression models were used to obtain odds ratios (ORs) and 95% confidence intervals (CI), adjusting for age (age at diagnosis for case patients and age at selection for control subjects), sex, alcohol intake (current drinker of ≥20 g of ethanol per day and non-drinker or drinker <20 g ethanol per day) and smoking status (current smoker and non-smoker). All values were two-sided and statistical significance was defined as P <0.05. Additional aetiologic information on the studied polymorphisms was obtained by analysing patterns of allelic combinations of the three closely linked variants in IL-1B and IL-1RN. For this purpose, haplotypes and linkage disequilibrium between loci were studied via the GLUE (Genetic Linkage User Environment) interface (available at: www.hgmp.mrc.ac.uk) using the Unphased software package. Linkage disequilibrium was estimated by r2, which can range from 0 (random co-inheritance of alleles) to 1 (complete linkage disequilibrium). Values <0.33 suggest the absence of strong linkage disequilibrium [27Go].


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study population consisted of 138 patients and 100 healthy controls. According to Lauren's classification, gastric carcinomas were of intestinal histotype in 76 patients (55%) and of diffuse histotype in 62 patients (45%). The median age among patients was 59 years (range 33–83 years) and among controls it was 59 years (range 35–80 years). The male/female ratio was 64/36 among cases and 60/40 among controls. Educational level ≤8 years and >8 years, indicating high school and beyond, was comparable between patients and controls. IL-1RN and IL-1B allelic distributions (Table 2) did not deviate significantly from those expected under Hardy–Weinberg equilibrium.


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Table 2. Distribution of the genotypes with results of regression analysis in the study populations

 
IL-1RN and IL-1B polymorphisms and gastric cancer risk
As shown in Table 2, only the homozygous IL-1B-511T/T genotype showed a significant association with gastric cancer risk if all patients were included. In the subgroup of patients with intestinal-type gastric cancer, a significant risk was associated with the IL-1B-511T/T and the heterozygous IL-1RN2/L genotype. No correlation with gastric cancer risk was observed for IL-1B-31 genotypes in the group of all patiens or in the histological subgroups.

Based on these data, an additional analysis of ORs for the combined IL-1B-511 and IL-1RN genotypes was performed (Table 3). In the group of all patients, the risk of IL-1B-511T and IL-1RN2 carriers for tumour development did not achieve the threshold of statistical significance. However, a significant risk (OR = 6.49) for intestinal-type gastric cancer was observed in carriers of both the IL-1B-511T and the IL-1RN2 alleles.


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Table 3. Regression analysis of combined IL-1RN and IL-1B-511 genotypes in 100 controls and 138 gastric cancer cases

 
Haplotype analysis
As shown in Table 4, haplotype and single allele analyses support the aetiologic role of IL-1RN2 and IL-1B-511T alleles in gastric cancer of the intestinal histoype. In this group, the 2-T-C haplotype, including the two risk alleles IL-1RN2 and IL-1B-511T, was more frequent in intestinal gastric cancer cases than controls (P=0.03), while the L-C-T haplotype, including the wild-type alleles IL-1RNL and IL-1B-511C, was more frequent among controls than intestinal gastric cancer cases (P=0.01). No strong linkage disequilibrium was observed between the IL-1RN and IL-1B-511 alleles (r2 for cases = 0.032, r2 for controls = 0.148). Again, although included in the risk haplotype, the IL-1B-31C allele does not appear to be associated with the disease. Indeed, the IL-1B-31C single allele distribution between intestinal gastric cancer cases and controls was not significantly different (Table 4). IL-1B-31 was in rather strong linkage disequilibrium with IL-1B-511 (r2 cases = 0.89, r2 controls = 0.78), but not with IL-1RN (r2 cases = 0.073, r2 controls = 0.091). Other observed significant P values for the L-C-C haplotype (<0.0001) and for the L-T-T haplotype (<0.001) do not supply reliable disease marker estimates given their rare frequencies in this subgroup analysis.


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Table 4. Haplotype and single allele analyses in 138 patients and 100 controls

 
In diffuse gastric cancer cases (Table 4), haplotype and single allele frequencies did not show any significant difference with respect to controls, except for one rare haplotype (L-C-C).


    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The first investigation on IL-1RN and IL-1B polymorphisms and gastric cancer susceptibility was reported in 2000 by El-Omar et al. [4Go, 5Go]. They studied 429 gastric cancer cases and 366 controls who were enrolled in Scotland and Poland. Carriers of the homozygous IL-1B-31C genotype (65% in patients and 49% in controls) and carriers of the homozygous IL-1RN2 genotype (25% in cases and 9% in controls) showed an increased gastric cancer risk, which was similar in subgroups defined by age, sex and histological type. In the same study [4Go], these genotypes were found to increase the likelihood of a chronic hypochlorhydric response to H. pylori infection, which was therefore considered as a necessary gene-environment interaction for a contribution of IL-1B-31C and IL-1RN2 to the development of early stage gastric carcinomas. In 2001, Machado et al. [13Go] reported the results of a case–control study on the aetiologic role of IL-1B-511T and IL-1RN2 alleles in a Portuguese population of 152 gastric cancer cases and 220 controls with unknown H. pylori infection status. In this study, 67% of patients compared with 53% of controls were carriers of the IL-1B-511T allele and 15% of patients compared with 9% of controls were homozygous carriers of the IL-1RN2 allele. The IL-1B-511T allele and the homozygous IL-1RN2 genotype correlated with a significant risk of developing intestinal-type gastric carcinoma. In 2002, Figueiredo et al. [14Go] confirmed the influence of the bacterial/host genotype interaction on gastric cancer risk by analysing IL-1B-511T and IL-1RN2 alleles in 221 subjects with chronic gastritis and 222 patients with gastric carcinomas and concomitant H. pylori infection. In Western countries, recent studies have also investigated the role of IL-1B and IL-1RN polymorphisms in the devolopment of gastric cancer in different anatomic sites [15Go] and in combination with other gene variants, which enhance the proinflammatory status [16Go]. The increased risk of non-cardia gastric adenocarcinoma was deemed a possible effect of the host genetic susceptibility with hypochlorhydria and atrophic response to gastric H. pylori infection.

Early information on the frequency of IL-1B genotypes in Asian populations dates back to 2001 [17Go]. In three subsequent case–control studies in the Chinese population, the IL-1B-511T allele showed a significant association with gastric cancer risk [18Go–20Go]. Only one of these studies revealed a potential aetiologic role for the IL-1RN2 allele [19Go]. In 192 Korean gastric cancer patients and 172 healthy subjects, Lee et al. [21Go] did not find any association between the IL-1B-31C and the IL-1RN2 alleles with gastric cancer risk. None of the studies in Asian populations addressed a subgroup analysis to patients without H. pylori infection and these results may reflect a different and more complex genetic aetiology in Asian compared with Caucasian populations.

To the best of our knowledge, this is the first report on the association between IL-1B and IL-1RN polymorphisms and gastric cancer risk in H. pylori-negative patients. In addition, data on IL-1B and IL-1RN allele frequencies in Italian gastric cancer patients were lacking so far. We observed an increased risk for intestinal gastric cancer in carriers of the IL-1B-511T and IL-1RN2 alleles, notably in the absence of H. pylori infection. The absence of strong linkage disequilibrium and the additive increase of the OR in carriers of the two risk alleles suggest that both contribute to disease risk independently. The highest risk for the IL-1RN2 allele was associated with its heterozygous state, contrary to other studies [4Go, 13Go, 14Go]. This difference may be due to different biology underlying H. pylori-negative gastric cancer or, more likely, could reflect inaccurate risk estimates based on the low number of IL-1RN2 homozygotes in this study. Indeed, a potential limitation of the present investigation is the relatively small study sample. However, it must be considered that asymptomatic, H. pylori infection in Western populations is frequent and H. pylori-negative gastric carcinoma is estimated to occur in about one-third of all gastric cancer cases [12Go]. Accordingly, our study population is of interest in comparison with larger published studies that include patients and controls with unknown/positive H. pylori status.

Alternative molecular mechanisms for explaining the aetiologic role of the polymorphisms in the absence of H. pylori infection could be the direct effect of the induced proinflammatory cytokines on the gastric mucosa and their interactions with environmental carcinogens. In experimental models, IL-1B and IL-1RN have been found to independently promote cell proliferation and tumorigenesis [28Go, 29Go]. N-nitroso compounds and polycyclic aromatic hydrocarbons have been shown to increase IL-1B levels [30Go–32Go]. Environment and diet are among the potential sources for these agents, which are both mutagens and carcinogens, and they have been associated with increased risks for both stomach and oesophageal cancer [33Go]. Notably, this investigation has been conducted in central Italy, which is traditionally considered a high-risk area for gastric cancer, with peculiar dietary habits of resident populations [34Go].

In conclusion, polymorphisms in IL-1B and IL-1RN may contribute to gastric cancer risk even in the absence of H. pylori infection. As emerged in previous investigations, this aetiologic effect is mainly in the intestinal histotype of gastric carcinomas. The lack of a significant association between IL-1B and IL-1RN polymorphisms and the diffuse gastric cancer suggest potential additional differences in the molecular mechanisms, which lead to the two histologic types of gastric cancer. It may also be a type 2 statistical error, which reflects the lack of statistical power to detect a low risk. So far, interactions between IL-1B/IL-1RN polymorphisms and host susceptibility have been addressed to the presence of H. pylori infection. Future epidemiologic studies should also consider interactions between proinflammatory genotypes, dietary habits and exposure to environmental carcinogens.


    Acknowledgements
 
This study was sponsored by the Italian Ministry of Scientific and Technology Research (MURST), no. FIRB 2001 RBNE01T8C8-008.

Received for publication October 15, 2004. Accepted for publication January 7, 2005.


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