Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

TNF and LTA gene polymorphisms reveal different risk in gastric and duodenal ulcer patients

Genes & Immunity volume 2, pages 415–421 (2001)Cite this article

Abstract

A small proportion of patients infected with Helicobacter pylori or using non-steroidal anti-inflammatory drugs (NSAIDs) develops peptic ulcer disease. Since family studies have shown the importance of the genetic background of the host in the development of gastric and duodenal ulcers, immunogenetic factors involved in the regulation of inflammation deserve further study. Polymorphisms in the genes encoding tumour necrosis factor (TNF) and lymphotoxin-α (LTA) have been shown to contribute to the severity of infectious disease. Our aim was to study four bi-allelic polymorphisms in the TNF and LTA genes, which occur as five haplotypes, in patients with peptic ulcer disease. A total of 130 patients with duodenal ulcer, 50 with gastric ulcer and 102 ethnically-matched Spanish Caucasian healthy controls were studied. H. pylori infection was determined by invasive and non-invasive tests. Odds ratios were obtained by logistic regression analysis. H. pylori was detected in 91.8% of peptic ulcer patients and in 73.3% of controls (P < 0.001). Patients with gastric ulcer had a lower frequency of the TNF−308 allele 2 and a higher frequency of the LTANcoI 2.2 genotype when compared with duodenal ulcer patients (P < 0.01 and P = 0.03, respectively). Carriers of haplotype TNF-I were more frequent in gastric ulcer patients (49%) than in controls (28%) (P < 0.05) and the haplotype TNF-E was significantly more frequent in duodenal ulcers than in gastric ulcers (27% vs 8.2%; P < 0.01). Logistic regression analysis identified haplotype TNF-I carrier status as an independent risk factor for peptic ulceration in H. pylori-infected patients (OR: 4.2; 95%CI: 1.7–10.2). These results suggest that TNF and LTA gene polymorphisms are related to the development of gastric and duodenal ulcer and may determine disease outcome in H. pylori infection.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Marshall BJ The 1995 Albert Lasker Medical Research Award. Helicobacter pylori. The etiologic agent for peptic ulcer JAMA 1995 274 1064–1066

    Article  CAS  PubMed  Google Scholar 

  2. Räihä I, Kemppainen H, Kaprio J, Koskenvuo M, Sourander L Lifestyle, stress, and genes in peptic ulcer disease. A nationwide twin cohort study Arch Intern Med 1998 158 698–704

    Article  PubMed  Google Scholar 

  3. Cover TL Commentary: Helicobacter pylori transmission, host factors, and bacterial factors Gastroenterology 1997 113 S29–S30

    Article  CAS  PubMed  Google Scholar 

  4. Crabtree JE, Shallcross TM, Heatley RV, Wyatt JI Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis Gut 1991 32 1473–1477

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fan XG, Chua A, Fan XJ, Keeling PW Increased gastric production of interleukin-8 and tumour necrosis factor in patients with Helicobacter pylori infection J Clin Pathol 1995 48 133–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Huseyinov A, Kutukculer N, Aydogdu S et al Increased gastric production of platelet-activating factor, leukotriene-B4, and tumor necrosis factor-alpha in children with Helicobacter pylori infection Dig Dis Sci 1999 44 675–679

    Article  CAS  PubMed  Google Scholar 

  7. Noach LA, Bosma NB, Jansen J et al Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection Scand J Gastroenterol 1994 29 425–429

    Article  CAS  PubMed  Google Scholar 

  8. Fiorucci S, Santucci L, Migliorati G et al Isolated guinea pig gastric chief cells express tumour necrosis factor receptors coupled with the sphingomyelin pathway Gut 1996 38 182–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Weigert N, Schaffer K, Schusdziarra V, Classen M, Schepp W Gastrin secretion from primary cultures of rabbit antral G cells: stimulation by inflammatory cytokines Gastroenterology 1996 110 147–154

    Article  CAS  PubMed  Google Scholar 

  10. Shibata J, Goto H, Arisawa T et al Regulation of tumour necrosis factor (TNF) induced apoptosis by soluble TNF receptors inHelicobacter pylori infection Gut 1999 45 24–31

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Appleyard CB, McCafferty DM, Tigley AW, Swain MG, Wallace JL Tumor necrosis factor mediation of NSAID-induced gastric damage: role of leukocyte adherence Am J Physiol 1996 270 G42–G48

    CAS  PubMed  Google Scholar 

  12. Santucci L, Fiorucci S, Di Matteo FM, Morelli A Role of tumor necrosis factor alpha release and leukocyte margination in indomethacin-induced gastric injury in rats Gastroenterology 1995 108 393–401

    Article  CAS  PubMed  Google Scholar 

  13. Mølvig J, Baek L, Christensen P et al Endotoxin-stimulated human monocyte secretion of interleukin-1, tumor necrosis factor-alpha, and prostaglandin-E2 shows stable interindividual differences Scand J Immunol 1988 27 705–716

    Article  PubMed  Google Scholar 

  14. Santamaria P, Gehrz RC, Bryan MK, Barbosa JJ Involvement of class II MHC molecules in the LPS-induction of IL-1/TNF secretions by human monocytes. Quantitative differences at the polymorphic level J Immunol 1989 143 913–922

    CAS  PubMed  Google Scholar 

  15. Jacob CO, Fronek Z, Lewis GD et al Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor alpha: relevance to genetic predisposition to systemic lupus erythematosus Proc Natl Acad Sci USA 1990 87 1233–1237

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Messer G, Spengler U, Jung MC et al Polymorphic structure of the tumor necrosis factor (TNF) locus: a NcoI polymorphism in the first intron of the human TNF-beta gene correlates with a variant amino acid in position 26 and a reduced level of TNF-beta production J Exp Med 1991 173 209–219

    Article  CAS  PubMed  Google Scholar 

  17. Ferencik S, Lindemann M, Horsthemke B, Grosse-Wilde H A new restriction fragment length polymorphism of the human TNF-B gene detected by AspHI digest Eur J Immunogenet 1992 19 425–430

    Article  CAS  PubMed  Google Scholar 

  18. D’Alfonso S, Momigliano Richiardi P A polymorphic variation in a putative regulation box of the TNFA promoter region Immunogenetics 1994 39 150–154

    PubMed  Google Scholar 

  19. Wilson AG, di Giovine FS, Blakemore AIF, Duff GW Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product Hum Mol Genet 1992 1 353

    Article  CAS  PubMed  Google Scholar 

  20. Crusius JBA, Bing X, Mulder CJJ, Mearin ML, Peña AS Relevance of haplotypes in the TNF region in celiac disease. (Abstract) Eur Cytok Network 1994 2 168

    Google Scholar 

  21. Bouma G, Xia B, Crusius JBA et al Distribution of four polymorphisms in the tumour necrosis factor (TNF) genes in patients with inflammatory bowel disease (IBD) Clin Exp Immunol 1996 103 391–396

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bouma G, Crusius JBA, Oudkerk Pool M et al Secretion of tumour necrosis factor alpha and lymphotoxin alpha in relation to polymorphisms in the TNF genes and HLA-DR alleles: relevance for inflammatory bowel disease Scand J Immunol 1996 43 456–463

    Article  CAS  PubMed  Google Scholar 

  23. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW Effects of a polymorphism in the human tumor necrosis factor a promoter on transcription activation Proc Natl Acad Sci USA 1997 94 3195–3199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Moffatt MF, Cookson WO Tumour necrosis factor haplotypes and asthma Hum Mol Genet 1997 6 551–554

    Article  CAS  PubMed  Google Scholar 

  25. Warzocha K, Ribeiro P, Bienvenu J et al Genetic polymorphisms in the tumor necrosis factor locus influence non-Hodgkin’s lymphoma outcome Blood 1998 91 3574–3581

    CAS  PubMed  Google Scholar 

  26. Davies FE, Rollison SJ, Rawstron AC High-producer haplotypes of tumor necrosis factor alpha and lymphotoxin alpha are associated with an increased risk of myeloma and have an improved progression-free survival after treatment J Clin Oncol 2000 18 2843–2851

    Article  CAS  PubMed  Google Scholar 

  27. Go MF What are the host factors that place an individual at risk for Helicobacter pylori infection-associated disease? Gastroenterology 1997 113 S15–S20

    Article  CAS  PubMed  Google Scholar 

  28. Clarke CA, Wyn Edwards J, Haddock RW, Howel-Evans AW, McConenell RB ABO blood groups and secretor character in duodenal ulcer. Population and sibship studies Br Med J 1956 3 725–731

    Article  Google Scholar 

  29. Borén T, Falk P, Roth KA, Larson G, Normark S Attachment of Helicobacter pylori to human gastric epithelium mediated by blood group antigens Science 1993 262 1892–1895

    Article  PubMed  Google Scholar 

  30. Dickey W, Collins JSA, Watson RGP, Sloan JM, Porter KG Secretor status and Helicobacter pylori infection are independent risk factors for gastroduodenal disease Gut 1993 34 351–353

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Niv Y, Fraser G, Delpre G et al Helicobacter pylori infection and blood groups Am J Gastroenterol 1996 91 101–104

    CAS  PubMed  Google Scholar 

  32. Azuma T, Ito Y, Miyaji H et al Immunogenetic analysis of the human leukocyte antigen DQA1 locus in patients with duodenal ulcer or chronic atrophic gastritis harbouring Helicobacter pylori Eur J Gastroenterol Hepatol 1995 7 S71–S73

    PubMed  Google Scholar 

  33. Azuma T, Ito S, Sato F et al The role of the HLA-DQA1 gene in resistance to atrophic gastritis and gastric adenocarcinoma induced by Helicobacter pylori infection Cancer 1998 82 1013–1018

    Article  CAS  PubMed  Google Scholar 

  34. Beales ILP, Davey NJ, Pusey CD, Lechler RI, Calam J Long-term sequelae of Helicobacter pylori gastritis Lancet 1995 346 381–382

    Article  CAS  PubMed  Google Scholar 

  35. Santolaria S, Barrios Y, Quintero E, Benito R, Lanas A El gen HLADQA1 en la susceptibilidad a la infección por Helicobacter pylori en la úlcera péptica Gastroenterol Hepatol 2001 24 117–121

    Article  CAS  PubMed  Google Scholar 

  36. Weissensteiner T, Lanchbury JS TNFB polymorphisms characterize three lineages of TNF region microsatellite haplotypes Immunogenetics 1997 47 6–16

    Article  CAS  PubMed  Google Scholar 

  37. Degli-Esposti MA, Leaver AL, Christiansen FT et al Ancestral haplotypes; conserved population MHC haplotypes Hum Immunol 1992 34 242–252

    Article  CAS  PubMed  Google Scholar 

  38. Abraham LJ, Marley JV, Nedospasov SA et al Microsatellite, restriction fragment-length polymorphism, and sequence-specific oligonucleotide typing of the tumor necrosis factor region. Comparisons of the 4AOHW cell panel Hum Immunol 1993 38 17–23

    Article  CAS  PubMed  Google Scholar 

  39. Tarnawski A, Ohta M, Wahlstrom K, Itani R, Sarfeh IJ Expression of cytokines: IL-1alpha, IL-6 and TNFalpha in normal and ulcerated duodenal mucosa. Effect of sucralfate treatment Gastroenterology 1997 112 309 (Abstract)

    Article  Google Scholar 

  40. Beales ILP, Calam J Interleukin 1-beta and tumour necrosis factor alpha inhibit acid secretion in cultured rabbit parietal cells by multiple pathways Gut 1998 42 227–234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Pasparakis M, Alexopoulou L, Douni E, Kollias G Tumour necrosis factors in immune regulation: everything that’s interesting is…new Cytokine Growth Factor Rev 1996 7 223–229

    Article  CAS  PubMed  Google Scholar 

  42. Rotter JI, Petersen GM, Samloff IM Pepsinogens and other physiologic markers in genetic studies of peptic ulcer and related disorders Prog Clin Biol Res 1985 173 227–244

    CAS  PubMed  Google Scholar 

  43. Hein HO, Suadicani P, Gyntelberg F Genetic markers for peptic ulcer. A study of 3387 men aged 54 to 74 years: the Copenhagen Male Study Scand J Gastroenterol 1997 32 16–21

    Article  CAS  PubMed  Google Scholar 

  44. Patiño-García A, Sotillo-Piñeiro E, Modesto C, Sierrasesúmaga L Screening of the human tumor necrosis factor-alpha (TNF-α) gene promoter polymorphisms by PCR-DGGE analysis Mutat Res 1999 406 121–125

    PubMed  Google Scholar 

  45. De la Concha EG, Fernández-Arquero M, Vigil P et al Celiac disease and TNF promoter polymorphisms Hum Immunol 2000 61 513–517

    Article  CAS  PubMed  Google Scholar 

  46. Castro J, Telleria JJ, Linares P, Blanco-Quiros A Increased TNFA*2, but not TNFB*1, allele frequencies in Spanish atopic patients J Investig Allergol Clin Immunol 2000 10 149–154

    CAS  PubMed  Google Scholar 

  47. Lanas A, Sekar MC, Hirschowitz BI Objective evidence of aspirin use in both ulcer and nonulcer upper and lower gastrointestinal bleeding Gastroenterology 1992 103 862–869

    Article  CAS  PubMed  Google Scholar 

  48. Peña AS, Crusius JBA, Koutroubakis I et al Preliminary results on cytokine genes and mucin genes polymorphisms. In: Inflammatory Bowel Diseases. Netherlands Falk Symposium No. 85, Kluwer Academic Publishers: Den Haag 1995 pp 232–238

  49. Fanning GC, Bunce M, Black CM, Welsh KI Polymerase chain reaction haplotyping using 3′ mismatches in the forward and reverse primers: application to the biallelic polymorphisms of tumor necrosis factor and lymphotoxin alpha Tissue Antigens 1997 50 23–31

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank the support of AstraZeneca BV, the Netherlands, and the ‘DGA-CAI (CM2/97)’ for financial support to MA García-González. This study was also supported in part by grants from the ‘Asociación de Investigaciones Gastroenterológicas de la Provincia de Zaragoza’ and the University of Zaragoza. The authors would like to thank Prof. Guillermo Marcos of the Service of Epidemiology (UMI) for his invaluable assistance with the statistical analysis.

Author information

Author notes

  1. MA García-González

    Present address: Unidad Mixta de Investigación, Hospital Clínico Universitario, Zaragoza, Spain

Authors and Affiliations

  1. Department of Gastroenterology, Hospital Clínico Universitario, Zaragoza, Spain

    A Lanas, S Santolaria & MT Serrano

  2. Unidad Mixta de Investigación, Hospital Clínico Universitario, Zaragoza, Spain

    MA García-González

  3. Department of Gastroenterology and Laboratory of Gastrointestinal Immunogenetics, VU Medical Centre, Amsterdam, The Netherlands

    MA García-González, JBA Crusius & AS Peña

  4. Department of Microbiology, Hospital Clínico Universitario, Zaragoza, Spain

    R Benito

Authors
  1. A Lanas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. MA García-González
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Santolaria
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. JBA Crusius
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. MT Serrano
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R Benito
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. AS Peña
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to AS Peña.

Additional information

This work was supported by grants from the ‘Asociación de Investigaciones Gastroenterológicas de la Provincia de Zaragoza’, ‘Caja de Ahorros de la Inmaculada de Aragón’ (DGA-CAI, CM2/97), the University of Zaragoza, and AstraZeneca BV, the Netherlands.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lanas, A., García-González, M., Santolaria, S. et al. TNF and LTA gene polymorphisms reveal different risk in gastric and duodenal ulcer patients. Genes Immun 2, 415–421 (2001). https://doi.org/10.1038/sj.gene.6363798

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6363798

Keywords

This article is cited by

Search

Advanced search

Quick links