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Association of the IL-1RN variable number of tandem repeat polymorphism and Helicobacter pylori infection: A meta-analysis

  • Jinhua Zhang ,

    hanj@lzu.edu.cn (JH); zjh51272@163.com (JHZ)

    Affiliations Department of Gastroenterology, Second Hospital of Gansu Province, Lanzhou, China, Department of Medicine, School of Second Clinical Medicine, Northwest University for Nationalities, Lanzhou, China

  • Xudong Sun,

    Affiliation Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China

  • Jiemin Wang,

    Affiliation Department of Gastroenterology, Liangzhou Hospital, Wuwei, China

  • Fuhua Zhang,

    Affiliations Department of Gastroenterology, Second Hospital of Gansu Province, Lanzhou, China, Department of Medicine, School of Second Clinical Medicine, Northwest University for Nationalities, Lanzhou, China

  • Xiaohua Li,

    Affiliation Department of Gastroenterology, Liangzhou Hospital, Wuwei, China

  • Jian Han

    hanj@lzu.edu.cn (JH); zjh51272@163.com (JHZ)

    Affiliation Department of Pathogenic Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou, China

Association of the IL-1RN variable number of tandem repeat polymorphism and Helicobacter pylori infection: A meta-analysis

  • Jinhua Zhang, 
  • Xudong Sun, 
  • Jiemin Wang, 
  • Fuhua Zhang, 
  • Xiaohua Li, 
  • Jian Han
PLOS
x

Abstract

The aim of this study was to clarify the association of IL-1RN variable number of tandem repeat (VNTR) polymorphism and H. pylori infection. We performed a meta-analysis of studies retrieved by systematic searches of Pubmed, Embase and the Cochrane Library. Data were analyzed with STATA 13.1 using pooled odds ratios (ORs) with 95% confidence intervals (CIs). A total of 18 studies were included in our meta-analysis, and IL-1RN VNTR was found to be significantly associated with H. pylori infection in the comparisons of 22+2L vs. LL (OR = 1.17, 95% CI = 1.02–1.33) and 2 allele vs. L allele (OR = 1.18, 95% CI = 1.00–1.40). Stratified analyses on study designs and ethnicities were also conducted. IL-1RN VNTR was positively correlated with H. pylori infection in Asian subgroup and Hospital-Based subgroup (i.e., study samples obtained from hospital inpatients). In conclusion, our study demonstrated that IL-1RN VNTR polymorphism might increase the risk of H. pylori infection, especially in Asians.

Introduction

Helicobacter pylori is a pathogen that was discovered by Warren and Marshall in 1983 [1], and is thought to be involved in gastritis, peptic ulcers, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma [24]. More than half of the world’s population is infected with H. pylori. Multiple factors influence the outcomes of H. pylori infection. Host genetic factors, interacting with H. pylori virulence (VacA, CagA etc.), and environmental factors (high salt intake and nitrate consumption, etc.), are involved in the pathogenesis of gastric cancer [57]. H. pylori infection elicits adaptive and innate immune responses in the gastric mucosa that produce significant inflammation [6]. H. pylori can stimulates host secretion of cytokines including interleukin (IL)-1, -2, -4, -8, -10, -1 receptor antagonist (rα), tumor necrosis factor (TNF)-α and others that may contribute to persistent infection [6, 810]. Host genetic polymorphisms of several cytokine genes (e.g., IL-1B-511*T, IL-1-RN*2, IL-10-1082/-819/-592, TNF-A-308*A, and IL-8-251*A), innate immune response gene (TLR4+896*G), HLA (DQA1*03:01, DQA1*04:01, and DQB1*05:01:01) are involved in all stages of the neoplastic process in gastric carcinoma [6, 1116]. Previous reports of the relationship of host genetic polymorphisms and H. pylori susceptibility are inconsistent. To begin to address these inconsistencies, we previously conducted two meta-analysis of the relationship between host IL1B -31C > T and TNFA gene polymorphisms and H. pylori infection [9, 10]. This meta-analysis focuses on the association of host IL-1RN variable number of tandem repeat (VNTR) polymorphism and H. pylori infection.

The IL-1 genes cluster is located on the long arm of human chromosome 2, comprising IL-1A, IL-1B and IL-1RN [17]. IL-1RN encodes IL-1rα, which is the endogenous receptor antagonist of IL-1α and IL-1β. A penta-allelic 86-bp VNTR polymorphism is located in intron 2 of the IL-1RN gene. Alleles 1–5 contain 4 repeats, 2 repeats, 5 repeats, 3 repeats, and 6 repeats, respectively. The repeats can be divided into a long allele (IL-1RN *L, including alleles 1, 3, 4 and 5) and a short allele (IL-1RN *2, including allele 2) [18]. LL and 22 are homozygous genotypes, while 2L is heterozygous genotype. Some studies reported that IL-1RN VNTR polymorphism is associated with the secretion of IL-1rα, which could influence H. pylori infection by antagonizing IL-1α and IL-1β [19, 20].

The association between IL-1RN VNTR polymorphism and H. pylori related-diseases has been extensively investigated [2123]. One meta-analysis reported that the short genotype of IL-1RN VNTR significantly increases the risk of gastric cancer [24]; another paper found that IL-1RN VNTR has no association with duodenal ulcer [25]. A number of studies performed on H. pylori related-diseases have explored the association between IL-1RN VNTR polymorphism and H. pylori infection simultaneously, but their results have been inconsistent. Therefore, we performed this meta-analysis to explore and analyze these inconsistent results. This is the first meta-analysis that focused on clarifying the relationship between IL-1RN VNTR polymorphism and H. pylori infection.

Materials and methods

Search strategy

A systematic literature search of the Pubmed, Embase and Cochrane Library databases entries to August 2016 was conducted. The following search terms were used: (IL-1RN OR IL1RN OR interleukin-1RN) AND (polymorphism OR polymorphisms OR SNP) AND (Helicobacter pylori OR H. pylori OR HP). The search was limited to the English language publications with available full-text. The reference lists of retrieved papers were also examined to search for potentially relevant studies. We contacted authors requesting the full-text of their work if necessary. When more than one report of the same case series had been published, only the study with the largest sample size was included in the meta-analysis.

Selection criteria

The inclusion criteria of our meta-analysis were (1) investigation of the association of IL-1RN VNTR polymorphism and H. pylori infection was evaluated; (2) case-control designed on unrelated individuals; (3) use of objective and clearly described methods for detecting H. pylori infection; and (4) reporting of genotype data sufficient to calculate odds ratios (ORs) with 95% confidence intervals (CIs).

Data extraction and quality appraisal

The authors; year of publication; country; ethnicity of participants; study design; number of cases and controls; methods of detecting H. pylori infection and distribution of polymorphism were extracted from each article. We evaluated study quality with the Newcastle-Ottawa scale (NOS) [26], which adopts three main criteria: selection of cases and controls; comparability of cases and controls; and exposure to risk factors. NOS scores were ranged from 0 to 9 stars. Articles with a final score 7 or more were considered to be of high quality, whereas those with a final score 5 or less were considered of low quality. Two authors (JZ and XS) independently extracted the data and performed the quality appraisal. Any disagreements between these two authors were resolved by discussion with the other authors.

Statistical analysis

All statistical analyses were carried out using STATA 13.1 (STATA Corp, College Station, TX, USA). The combined ORs and their corresponding 95% CIs were used to assess the strength of the association between IL-1RN VNTR polymorphism and H. pylori infection. The Q-test and I2 index were used to determine heterogeneity across studies, with P < 0.10 or I2 > 50% considered significant [27]. The ORs were pooled using a random effect model in the presence of significant heterogeneity; otherwise, a fixed effect model was used. Sensitivity analyses were conducted to identify the effect of each study on the combined results by omitting each one in turn. Subgroup analyses were conducted based on ethnicities (Asian or Non-Asian) and study designs (population-based (PB) or hospital-based (HB)). Publication bias was evaluated by Begg’s funnel plots and Egger’s plots, with a significance of 0.05. Hardy-Weinberg equilibrium (HWE) was calculated by the χ2-square test.

Results

Study characteristics

The study selection process is shown in Fig 1. A total of 139 articles were retrieved in the initial search. 59 articles were excluded after screening the titles and abstracts, and 64 articles were excluded after reading the full text. Two articles were added after scanning references lists. In total, 18 articles were included in our meta-analysis [18, 19, 2843]. Table 1 lists the major characteristics of the included studies. Of the included studies, 11 were performed in Asians, 1 was in Europeans, 1 was in Africans and 5 were in mixed-ethnicity populations.

Meta-analysis results

IL-1RN VNTR polymorphism was significantly associated with H. pylori infection in the comparisons of 22+2L vs. LL and 2 allele vs. L allele (22+2L vs. LL, OR = 1.17, 95% CI = 1.02–1.33; 22 vs. 2L+LL, OR = 1.24, 95% CI = 0.82–1.86; 22 vs. LL, OR = 1.19, 95% CI = 0.77–1.83; 2 allele vs. L allele, OR = 1.18, 95% CI = 1.00–1.40; Fig 2).

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Fig 2. Forest plots of IL-1RN VNTR polymorphism and H. pylori infection for all genetic models.

https://doi.org/10.1371/journal.pone.0175052.g002

Our subgroup analysis on ethnicity showed that in Asian populations, IL-1RN VNTR significantly increased the risk of H. pylori infection in the comparisons of 22 vs. 2L+LL and 22 vs. LL. When the analysis was stratified by study design, IL-1RN VNTR was significantly correlated with H. pylori infection in the comparisons of 22+2L vs. LL, 22 vs. 2L+LL and 2 allele vs. L allele for HB subgroup, but not for PB subgroup. The meta-analysis results are summarized in Table 2.

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Table 2. Meta-analysis of the association between IL-1RN VNTR polymorphism and H. pylori infection.

https://doi.org/10.1371/journal.pone.0175052.t002

Heterogeneity and sensitivity analysis

Significant heterogeneity among studies existed in the comparison of 22 vs. 2L+LL, 22 vs. LL and 2 allele vs. L allele. A study by Queiroz et al. [39] was found to be the source of heterogeneity by omitting each study in turn. When sensitivity analyses were conducted, the pooled ORs were not significantly altered.

Publication bias

Funnel plots are commonly used to evaluate publication bias, with asymmetry indicating possible publication bias. Begg’s funnel plot was performed in our meta-analysis, and the plot showed a nearly symmetrical distribution for the comparison of 22+2L vs. LL (Fig 3), Publication bias was not indicated by either Begg’s or Egger’s tests (22+2L vs. LL, Begg’s test P = 0.76, Egger’s test P = 0.93; 22 vs. 2L+LL, Begg’s test P = 0.75, Egger’s test P = 0.30; 22 vs. LL, Begg’s test P = 1.00, Egger’s test P = 0.30; and 2 allele vs. L allele, Begg’s test P = 0.60, Egger’s test P = 0.94).

thumbnail
Fig 3. Begg’s funnel plot of studies included in the meta-analysis.

s.e.: standard error.

https://doi.org/10.1371/journal.pone.0175052.g003

Discussion

Previous studies demonstrated that polymorphisms of some host cytokine genes such as IL-1β, IL-8 et al. are correlated with H. pylori infection related-diseases [17, 44, 45]. IL-1rα can influence IL-1β levels, and some studies have focused on the relationship between IL-1RN VNTR polymorphism and H. pylori infection related-diseases [46, 47]. Others have investigated the association between IL-1RN VNTR polymorphism and H. pylori infection. Because the conclusions of the available studies were not consistent [9, 48], we performed this meta-analysis to investigate the role of IL-1RN VNTR polymorphism on the risk for H. pylori infection.

We found that IL-1RN VNTR polymorphism has significant association with H. pylori infection, especially in Asians. These results differ from the findings of a genome wide association study in Europeans [49]. Based on including studies of our meta-analysis, we found that the frequency of IL-1RN *2 in Asians is lower than that in other ethnicities. Different ethnicities with different genetic background and living habits might be the source of discrepancy. Genetic differences of H. pylori (cagA positive or negative) might also influence the association of host IL-1RN VNTR polymorphism and H. pylori infection. Nearly all H. pylori in East Asian, but not Western, are cagA positive strains [50]. Stratified analysis revealed that IL-1RN VNTR polymorphism increased the risk of H. pylori infection for HB subgroups. This indicates that IL-1RN VNTR polymorphism may be associated with outcomes of H. pylori infection and warrants further investigation. Studies included in meta-analyses frequently differ to an extent that leads to significant heterogeneity. In this analysis, the heterogeneity decreased after excluding the study of Queiroz et al, which included 125 Brazilian children and adolescents undergoing gastrointestinal endoscopy. Specific ethnicity and age composition might be the source of heterogeneity. We used a random effects model when heterogeneity was detected among the evaluated studies.

IL-1RN gene encodes the cytokine IL-1rα, which is an endogenous receptor antagonist of IL-1β. Previous studies indicated that carriers of the IL-1RN*2 allele had significantly higher expression of the IL-1β than carriers of other genotypes had [51, 52]. A high level of IL-1β in the gastric mucosa can inhibit the function of gastrin-stimulated enterochromaffin cells and parietal cells, which leads to low histamine concentration and decreased gastric acid secretion [53, 54]. In addition, IL-1β can also amplify immune responses by activating neutrophils, T cells and B cells [55]. The combined activity change from the decreased acid secretion and amplified immune responses may lead to tissue damage of the gastric mucosa, which can facilitate the colonization of H. pylori from the gastric antrum to the corpus [56]. This colonization can contribute to persistent H. pylori infection and increase the risk of developing atrophic gastritis and gastric cancer.

CagA is an important H. pylori virulence factor, and is associated with severe gastritis and gastric carcinoma [57, 58]. CagA-negative H. pylori is weakly pathogenic or nonpathogenic. Differences of the repeat sequences of the 3′ region of cagA have led to recognition of East Asian-type and Western-type CagA [5]. East Asian-type cagA strains have greater pathogenicity and posing an increased risk of peptic ulcer or gastric cancer than Western-type cagA strains. CagA can be inserted into gastric epithelial cells by the cag PAI-encoded type IV secretion system and perform virulence through phosphorylation-dependent and phosphorylation-independent manner. Src homology-2 domain-containing phosphatase 2 (SHP2) is an important intracellular target of CagA in phosphorylation-dependent pathway [5, 57, 59]. The difference of East Asian-type and Western-type CagA in pathogenicity may result from the higher binding affinity of East Asian-type CagA for SHP-2 by Glu-Pro-Ile-Tyr-Ala (EPIYA)-D segments than Western-type CagA, which binds to SHP-2 by EPIYA-C segments [50]. East Asian-type cagA strains primarily circulate in East Asia (e.g., China, Japan, and Korea). Although the H. pylori cagA genotype has a significantly wider geographical distribution, our analysis was not stratified by H. pylori cagA genotypes because only one of the 18 articles selected for analyses assayed host IL-1RN gene polymorphism and H. pylori cagA genotypes [42]. The investigators found that host IL-1 polymorphism and the H. pylori cagA genotype influenced gastric mucosal cytokine levels in patients in Thailand [42].

This is the first meta-analysis that investigated the association between IL-1RN VNTR polymorphism and H. pylori infection across multiple studies. However, there were some limitations to our study. Most of included studies were performed on Asian populations, so further research with other ethnic populations is needed. We only chose the English literatures retrieved from databases of PubMed, Embase and Cochrane library, which might lead to bias on collecting literatures.

Conclusion

Based on including studies of our meta-analysis, we concluded that IL-1RN VNTR*2 may increase the risk of H. pylori infection, especially in Asians. Our findings provide insights into the role of IL-1RN VNTR polymorphism in H. pylori infection and related diseases. Further studies with larger sample sizes and various ethnicities are required to validate these results.

Supporting information

S3 File. Meta-analysis on genetic association studies checklist.

https://doi.org/10.1371/journal.pone.0175052.s003

(DOCX)

S4 File. Articles excluded from the meta-analysis.

https://doi.org/10.1371/journal.pone.0175052.s004

(DOCX)

Author Contributions

  1. Conceptualization: JHZ XDS JH.
  2. Data curation: JHZ XDS FHZ.
  3. Formal analysis: JHZ XDS JMW.
  4. Funding acquisition: JHZ JH.
  5. Investigation: JHZ XDS JMW FHZ XHL.
  6. Methodology: JHZ XDS JH.
  7. Project administration: JHZ JH.
  8. Resources: JHZ XDS JH.
  9. Supervision: JHZ JH.
  10. Validation: JHZ XDS JMW FHZ XHL JH.
  11. Writing – original draft: JHZ XDS JH.
  12. Writing – review & editing: JHZ XDS JH.

References

  1. 1. W J Robin, Barry M. Unidentified curved bacilli on gastric epithelium in active chronic gastritis. Lancet (London, England). 1983;1(8336):1273–5. Epub 1983/06/04.
  2. 2. Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. The New England journal of medicine. 2001;345(11):784–9. Epub 2001/09/15. pmid:11556297
  3. 3. Covacci A, Telford JL, Del Giudice G, Parsonnet J, Rappuoli R. Helicobacter pylori virulence and genetic geography. Science (New York, NY). 1999;284(5418):1328–33. Epub 1999/05/21.
  4. 4. Stolte M. Helicobacter pylori gastritis and gastric MALT-lymphoma. Lancet (London, England). 1992;339(8795):745–6. Epub 1992/03/21.
  5. 5. Yamaoka Y. Mechanisms of disease: Helicobacter pylori virulence factors. Nature reviews Gastroenterology & hepatology. 2010;7(11):629–41. Epub 2010/10/13.
  6. 6. El-Omar EM. Role of host genes in sporadic gastric cancer. Best practice & research Clinical gastroenterology. 2006;20(4):675–86. Epub 2006/09/26.
  7. 7. Sgouras DN, Trang TT, Yamaoka Y. Pathogenesis of Helicobacter pylori Infection. Helicobacter. 2015;20 Suppl 1:8–16. Epub 2015/09/16.
  8. 8. Sugimoto M, Furuta T, Yamaoka Y. Influence of inflammatory cytokine polymorphisms on eradication rates of Helicobacter pylori. Journal of gastroenterology and hepatology. 2009;24(11):1725–32. pmid:20136959
  9. 9. Sun X, Xu Y, Zhang F, Jing T, Han J, Zhang J. Association between the IL1B -31C > T polymorphism and Helicobacter pylori infection in Asian and Latin American population: A meta-analysis. Microbial pathogenesis. 2015;86:45–52. Epub 2015/07/19. pmid:26188264
  10. 10. Sun X, Xu Y, Wang L, Zhang F, Zhang J, Fu X, et al. Association between TNFA Gene Polymorphisms and Helicobacter pylori Infection: A Meta-Analysis. PloS one. 2016;11(1):e0147410. Epub 2016/01/28. pmid:26815578
  11. 11. Rad R, Prinz C, Neu B, Neuhofer M, Zeitner M, Voland P, et al. Synergistic effect of Helicobacter pylori virulence factors and interleukin-1 polymorphisms for the development of severe histological changes in the gastric mucosa. The Journal of infectious diseases. 2003;188(2):272–81. Epub 2003/07/11. pmid:12854083
  12. 12. Hold GL, Rabkin CS, Chow WH, Smith MG, Gammon MD, Risch HA, et al. A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors. Gastroenterology. 2007;132(3):905–12. Epub 2007/02/28. pmid:17324405
  13. 13. Perez-Rodriguez M, Partida-Rodriguez O, Camorlinga-Ponce M, Flores-Luna L, Lazcano E, Gomez A, et al. Polymorphisms in HLA-DQ genes, together with age, sex, and Helicobacter pylori infection, as potential biomarkers for the early diagnosis of gastric cancer. Helicobacter. 2017;22(1). Epub 2016/06/24.
  14. 14. Sugimoto M, Furuta T, Shirai N, Nakamura A, Kajimura M, Sugimura H, et al. Effects of interleukin-10 gene polymorphism on the development of gastric cancer and peptic ulcer in Japanese subjects. Journal of gastroenterology and hepatology. 2007;22(9):1443–9. Epub 2007/08/25. pmid:17716348
  15. 15. Xue H, Liu J, Lin B, Wang Z, Sun J, Huang G. A meta-analysis of interleukin-8–251 promoter polymorphism associated with gastric cancer risk. PloS one. 2012;7(1):e28083. Epub 2012/01/27. pmid:22279522
  16. 16. Gorouhi F, Islami F, Bahrami H, Kamangar F. Tumour-necrosis factor-A polymorphisms and gastric cancer risk: a meta-analysis. British journal of cancer. 2008;98(8):1443–51. Epub 2008/03/06. pmid:18319718
  17. 17. El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404(6776):398–402. pmid:10746728
  18. 18. Kim N, Cho SI, Yim JY, Kim JM, Lee DH, Park JH, et al. The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea. Helicobacter. 2006;11(2):105–12. Epub 2006/04/04. pmid:16579840
  19. 19. Kimang'a AN. IL-1B-511 Allele T and IL-1RN-L/L Play a Pathological Role in Helicobacter Pylori (H. Pylori) Disease Outcome in the African Population. Ethiopian journal of health sciences. 2012;22(3):163–9. Epub 2012/12/05. pmid:23209350
  20. 20. Gobert AP, Wilson KT. The Immune Battle against Helicobacter pylori Infection: NO Offense. Trends Microbiol. 2016.
  21. 21. Yang J, Hu ZB, Xu YC, Shen J, Niu JY, Hu X, et al. Association between polymorphisms of interleukin-1B and interleukin-1 receptor antagonist genes and host susceptibility to gastric cancer. World Chinese Journal of Digestology. 2004;12(8):1769–73.
  22. 22. Martínez T, Hernández-Suárez G, Bravo MM, Trujillo E, Quiroga A, Albis R, et al. Association of interleukin-1 genetic polymorphism and CagA positive Helicobacter pylori with gastric cancer in Colombia. Revista Medica de Chile. 2011;139(10):1313–21. pmid:22286731
  23. 23. Alpízar-Alpízar W, Pérez-Pérez GI, Une C, Cuenca P, Sierra R. Association of interleukin-1B and interleukin-1RN polymorphisms with gastric cancer in a high-risk population of Costa Rica. Clinical and Experimental Medicine. 2005;5(4):169–76. pmid:16362796
  24. 24. Zhang Y, Liu C, Peng H, Zhang J, Feng Q. IL1 receptor antagonist gene IL1-RN variable number of tandem repeats polymorphism and cancer risk: a literature review and meta-analysis. PloS one. 2012;7(9):e46017. pmid:23049925
  25. 25. Zhang BB, Li Y, Feng JQ, Bian DL, Gao XM, Ran MY. No association between IL-1RN VNTR and the risk of duodenal ulcer: a meta-analysis. Hum Immunol. 2013;74(9):1170–8. Epub 2013/06/27. pmid:23800434
  26. 26. GA Wells BS, D O'Connell, J Peterson, V Welch, M Losos, P Tugwell. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses Ottawa Health Research Institute2011. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp.
  27. 27. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Statistics in medicine. 2002;21(11):1539–58. pmid:12111919
  28. 28. Hamajima N, Matsuo K, Saito T, Tajima K, Okuma K, Yamao K, et al. Interleukin 1 polymorphisms, lifestyle factors, and Helicobacter pylori infection. Jpn J Cancer Res. 2001;92(4):383–9. pmid:11346459
  29. 29. Chakravorty M, Ghosh A, Choudhury A, Santra A, Hembrum J, Roychoudhury S. Interaction between IL1B gene promoter polymorphisms in determining susceptibility to Helicobacter pylori associated duodenal ulcer. Human mutation. 2006;27(5):411–9. pmid:16550552
  30. 30. Furuta T, El–Omar EM, Xiao F, Shirai N, Takashima M, Sugimurra H. Interleukin 1β polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. Gastroenterology. 2002;123(1):92–105. pmid:12105837
  31. 31. Lobo Gatti L, Rodríguez Burbano R, Pimentel de Assumpção P, de Arruda Cardoso Smith M, Marques Payão SL. Interleukin-1β polymorphisms, Helicobacter pyloriinfection in individuals from Northern Brazil with gastric adenocarcinoma. Clinical and Experimental Medicine. 2004;4(2):93–8. pmid:15672946
  32. 32. García-González MA, Aísa MAP, Strunk M, Benito R, Piazuelo E, Jiménez P, et al. Relevance of IL-1 and TNF gene polymorphisms on interleukin-1β and tumor necrosis factor-α gastric mucosal production. Human Immunology. 2009;70(11):935–45. pmid:19664671
  33. 33. He BS, Pan YQ, Xu YF, Zhu C, Qu LL, Wang SK. Polymorphisms in interleukin-1B (IL-1B) and interleukin 1 receptor antagonist (IL-1RN) genes associate with gastric cancer risk in the Chinese population. Digestive diseases and sciences. 2011;56(7):2017–23. pmid:21243433
  34. 34. Kang JM, Kim N, Shin CM, Lee HS, Lee DH, Jung HC, et al. Predictive factors for improvement of atrophic gastritis and intestinal metaplasia after Helicobacter pylori eradication: a three-year follow-up study in Korea. Helicobacter. 2012;17(2):86–95. Epub 2012/03/13. pmid:22404438
  35. 35. Kulmambetova GN, Imanbekova MK, Logvinenko AA, Sukashev AT, Filipenko ML, Ramanculov EM. Association of cytokine gene polymorphisms with gastritis in a Kazakh population. Asian Pacific journal of cancer prevention: APJCP. 2014;15(18):7763–8. pmid:25292060
  36. 36. Kumar S, Kumar A, Dixit VK. Evidences showing association of interleukin-1B polymorphisms with increased risk of gastric cancer in an Indian population. Biochemical and biophysical research communications. 2009;387(3):456–60. pmid:19607807
  37. 37. Li C, Xia HH, Xie W, Hu Z, Ye M, Li J, et al. Association between interleukin-1 gene polymorphisms and Helicobacter pylori infection in gastric carcinogenesis in a Chinese population. J Gastroenterol Hepatol. 2007;22(2):234–9. Epub 2007/02/14. pmid:17295877
  38. 38. Queiroz DM, Saraiva IE, Rocha GA, Rocha AM, Gomes LI, Melo FF, et al. IL2-330G polymorphic allele is associated with decreased risk of Helicobacter pylori infection in adulthood. Microbes and infection / Institut Pasteur. 2009;11(12):980–7.
  39. 39. Queiroz DM, Rocha AM, Melo FF, Rocha GA, Teixeira KN, Carvalho SD, et al. Increased gastric IL-1beta concentration and iron deficiency parameters in H. pylori infected children. PloS one. 2013;8(2):e57420. pmid:23451225
  40. 40. Santos JC, Ladeira MS, Pedrazzoli J Jr, Ribeiro ML. Relationship of IL-1 and TNF-alpha polymorphisms with Helicobacter pylori in gastric diseases in a Brazilian population. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas. 2012;45(9):811–7. Epub 2012/06/21. pmid:22714811
  41. 41. Uno M, Hamajima N, Ito LS, Oba SM, Marie SKN, Shinjo SK, et al. Helicobacter pylori seropositivity and IL-1B C-31T polymorphism among Japanese Brazilians. Int J Mol Med. 2002;10(3):321–6. pmid:12165808
  42. 42. Vilaichone RK, Mahachai V, Tumwasorn S, Wu JY, Graham DY, Yamaoka Y. Gastric mucosal cytokine levels in relation to host interleukin-1 polymorphisms and Helicobacter pyloricagA genotype. Scandinavian journal of gastroenterology. 2005;40(5):530–9. pmid:16036505
  43. 43. Drici Ael M, Moulessehoul S, Tifrit A, Diaf M, Turki DK, Bachir M, et al. Effect of IL-1beta and IL-1RN polymorphisms in carcinogenesis of the gastric mucosa in patients infected with Helicobacter pylori in Algeria. The Libyan journal of medicine. 2016;11:31576. Epub 2016/06/25. pmid:27340011
  44. 44. Kang JM, Kim N, Lee DH, Park JH, Lee MK, Kim JS, et al. The effects of genetic polymorphisms of IL-6, IL-8, and IL-10 on Helicobacter pylori-induced gastroduodenal diseases in Korea. Journal of clinical gastroenterology. 2009;43(5):420–8. Epub 2008/12/17. pmid:19077731
  45. 45. Zhang L, Du C, Guo X, Yuan L, Niu W, Yu W, et al. Interleukin-8-251A/T polymorphism and Helicobacter pylori infection influence risk for the development of gastric cardiac adenocarcinoma in a high-incidence area of China. Molecular biology reports. 2010;37(8):3983–9. Epub 2010/03/20. pmid:20300863
  46. 46. Mattar R, Marques SB, dos Santos AF, Monteiro MS, Iriya K, Carrilho FJ. A possible role of IL-1RN gene polymorphism in the outcome of gastrointestinal diseases associated with H. pylori infection. Clinical and Experimental Gastroenterology. 2013;6(1):35–41.
  47. 47. Oliveira JG, Duarte MC, Silva AE. IL-1ra anti-inflammatory cytokine polymorphism is associated with risk of gastric cancer and chronic gastritis in a Brazilian population, but the TNF-β pro-inflammatory cytokine is not. Molecular Biology Reports. 2012;39(7):7617–25. pmid:22327782
  48. 48. Lu W, Pan K, Zhang L, Lin D, Miao X, You W. Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population. Carcinogenesis. 2005;26(3):631–6. Epub 2004/12/08. pmid:15579481
  49. 49. Mayerle J, den Hoed CM, Schurmann C, Stolk L, Homuth G, Peters MJ, et al. Identification of genetic loci associated with Helicobacter pylori serologic status. Jama. 2013;309(18):1912–20. Epub 2013/05/09. pmid:23652523
  50. 50. Shiota S, Suzuki R, Yamaoka Y. The significance of virulence factors in Helicobacter pylori. Journal of digestive diseases. 2013;14(7):341–9. Epub 2013/03/05. pmid:23452293
  51. 51. Kumar S, Kumari N, Mohindra S, Mittal RD, Ghoshal UC. IL-8-251 T/A gene polymorphism with their serum level influencing host's susceptibility to gastric cancer in H. Pylori endemic area. Journal of gastroenterology and hepatology. 2012;27:431.
  52. 52. Hwang IR, Kodama T, Kikuchi S, Sakai K, Peterson LE, Graham DY, et al. Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. Gastroenterology. 2002;123(6):1793–803. Epub 2002/11/28. pmid:12454835
  53. 53. Goto H. Helicobacter pylori and gastric diseases. Nagoya J Med Sci. 2003;66(3–4):77–85. Epub 2004/01/20. pmid:14727684
  54. 54. Figueiredo CA, Marques CR, Costa RS, da Silva HBF, Alcantara-Neves NM. Cytokines, cytokine gene polymorphisms and Helicobacter pylori infection: Friend or foe? World Journal of Gastroenterology. 2014;20(18):5235–43. pmid:24833853
  55. 55. Datta De D, Roychoudhury S. To be or not to be: The host genetic factor and beyond in Helicobacter pylori mediated gastro-duodenal diseases. World Journal of Gastroenterology. 2015;21(10):2883–95. pmid:25780285
  56. 56. Robinson K, Argent RH, Atherton JC. The inflammatory and immune response to Helicobacter pylori infection. Best practice & research Clinical gastroenterology. 2007;21(2):237–59.
  57. 57. Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science (New York, NY). 2002;295(5555):683–6. Epub 2001/12/18.
  58. 58. Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nature reviews Cancer. 2004;4(9):688–94. Epub 2004/09/03. pmid:15343275
  59. 59. Tegtmeyer N, Wessler S, Backert S. Role of the cag-pathogenicity island encoded type IV secretion system in Helicobacter pylori pathogenesis. The FEBS journal. 2011;278(8):1190–202. Epub 2011/03/01. pmid:21352489