Investigation of the Association of TLR2 and TLR4 Polymorphisms with Susceptibility to Helicobacter pylori-Related Gastrointestinal Diseases

Takayoshi Suzuki^1*, Akira Meguro², Masashi Matsushima¹, Aya Masui¹, Shingo Tsuda¹, Jun Nakamura¹, Ryoko Nishina¹, Tetsufumi Uchida¹, Hiroki Yuhara¹, Muneki Igarashi¹, Jun Koike¹, Tetsuya Mine¹, Hidetoshi Inoko², Atsushi Takagi³

¹Division of Gastroenterology & Hepatology, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.
²Division of Molecular Life Science, Department of Genetic Information, Tokai University School of Medicine, Isehara, Japan.
³Division of General Internal Medicine, Department of Internal Medicine, Tokai University School of Medicine, Isehara, Japan.

DOI: 10.4236/ojim.2014.44020                

Abstract

Background and Aim: Toll-like receptor (TLR) 2 and TLR4 are cell surface signaling receptors that are involved in the recognition of and host response to Helicobacter pylori. Our aim was to investigate the association between TLR gene polymorphisms and susceptibility of Japanese subjects to 4 H. pylori-related gastrointestinal diseases. Methodology: A total of 100 patients with histologically diagnosed gastric cancer, 105 patients with gastric ulcer, 102 with atrophic gastritis, 72 with duodenal ulcer and 428 healthy controls were recruited. A TaqMan assay was used to genotype 7 single nucleotide polymorphisms (SNPs) in TLR2 and 6 SNPs in TLR4. Results: There was a tendency for TLR4 rs10759932 TC/CC genotypes to be associated with a decreased risk of gastric cancer (p = 0.059); however, this did not reach statistical significance. No significant associations were found between polymorphisms in TLR2 or TLR4 and the risks for gastric cancer, gastric ulcer, duodenal ulcer, or atrophic gastritis. Conclusion: The 13 SNPs inTLR2 and TLR4 examined in this study may not be linked with the development of H. pylori-related gastrointestinal diseases. Further studies with larger numbers of subjects are necessary to verify the present findings.

Keywords

TLR2, TLR4, Polymorphisms, Helicobacter pylori

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Blaser, M.J. and Atherton, J.C. (2004) Helicobacter pylori Persistence: Biology and Disease. Journal of Clinical Investigation, 113, 321-333. http://dx.doi.org/10.1172/JCI20925
[2]	El-Omar, E.M., Rabkin, C.S., Gammon, M.D., et al. (2003) Increased Risk of Noncardia Gastric Cancer Associated with Proinflammatory Cytokine Gene Polymorphisms. Gastroenterology, 125, 364-371.
[3]	Parkin, D.M., Pisani, P. and Ferlay, J. (1999) Estimates of the Worldwide Incidence of 25 Major Cancers in 1990. International Journal of Cancer, 80, 827-841. http://dx.doi.org/10.1002/(SICI)1097-0215(19990315)80:6<827::AID-IJC6>3.0.CO;2-P
[4]	Peek Jr., R.M. and Blaser, M.J. (2002) Helicobacter pylori and Gastrointestinal Tract Adenocarcinomas. Nature Reviews Cancer, 2, 28-37. http://dx.doi.org/10.1038/nrc703
[5]	Uemura, N., Okamoto, S., Yamamoto, S., et al. (2001) Helicobacter pylori Infection and the Development of Gastric Cancer. The New England Journal of Medicine, 345, 784-789. http://dx.doi.org/10.1056/NEJMoa001999
[6]	Barton, G.M. and Kagan, J.C. (2009) A Cell Biological View of Toll-Like Receptor Function: Regulation through Compartmentalization. Nature Reviews Immunology, 9, 535-542. http://dx.doi.org/10.1038/nri2587
[7]	Schmausser, B., Andrulis, M., Endrich, S., et al. (2004) Expression and Subcellular Distribution of Toll-Like Receptors TLR4, TLR5 and TLR9 on the Gastric Epithelium in Helicobacter pylori Infection. Clinical and Experimental Immunology, 136, 521-526. http://dx.doi.org/10.1111/j.1365-2249.2004.02464.x
[8]	Torok, A.M., Bouton, A.H. and Goldberg, J.B. (2005) Helicobacter pylori Induces Interleukin-8 Secretion by Toll- Like Receptor 2 and Toll-Like Receptor 5-Dependent and -Independent Pathways. Infection and Immunity, 73, 1523- 1531. http://dx.doi.org/10.1128/IAI.73.3.1523-1531.2005
[9]	Chang, Y.J., Wu, M.S., Lin, J.T., et al. (2005) Helicobacter pylori-Induced Invasion and Angiogenesis of Gastric Cells Is Mediated by Cyclooxygenase-2 Induction through TLR2/TLR9 and Promoter Regulation. Journal of Immunology, 175, 8242-5252. http://dx.doi.org/10.4049/jimmunol.175.12.8242
[10]	Schmausse, B., Andrulis, M., Endrich, S., et al. (2004) Expression and Subcellular Distribution of Toll-Like Receptors TLR4, TLR5 and TLR9 on the Gastric Epithelium in Helicobacter pylori Infection. Clinical and Experimental Immunology, 136, 521-526. http://dx.doi.org/10.1111/j.1365-2249.2004.02464.x
[11]	Pimentel-Nunes, P., Afonso, L., Lopes, P., Roncon-Albuquerque Jr., R., Gonçalves, N., Henrique, R., et al. (2011) Increased Expression of Toll-Like Receptors (TLR) 2, 4 and 5 in Gastric Dysplasia. Pathology & Oncology Research, 17, 677-683.
[12]	Smith Jr., M.F., Mitchell, A., Li, G., Ding, S., Marie Fitzmaurice, A., Ryan, K., Crowe, S. and Goldberg, J.B. (2003) Toll-Like Receptor (TLR) 2 and TLR5, but Not TLR4, Are Required for Helicobacter pylori-Induced NF-κB Activation and Chemokine Expression by Epithelial Cells. Journal of Biological Chemistry, 278, 32552-32560. http://dx.doi.org/10.1074/jbc.M305536200
[13]	Srivastava, K., Srivastava, A., Kumar, A. and Mittal, B. (2010) Significant Association between Toll-Like Receptor Gene Polymorphisms and Gallbladder Cancer. Liver International, 30, 1067-1072.
[14]	Slattery, M.L., Herrick, J.S., Bondurant, K.L. and Wolff, R.K. (2012) Toll-Like Receptor Genes and Their Association with Colon and Rectal Cancer Development and Prognosis. International Journal of Cancer, 130, 2974-2980. http://dx.doi.org/10.1002/ijc.26314
[15]	Pandey, S., Mittal, R.D., Srivastava, M., Srivastava, K., Singh, S., Srivastava, S. and Mittal, B. (2009) Impact of Toll-Like Receptors TLR2 (-196 to -174 Del) and TLR4 (Asp299Gly, Thr399Ile) in Cervical Cancer Susceptibility in North Indian Women. Gynecologic Oncology, 114, 501-505. http://dx.doi.org/10.1016/j.ygyno.2009.05.032
[16]	Tahara, T., Arisawa, T., Wang, F., Shibata, T., Nakamura, M., Sakata, M., et al. (2007) Toll-Like Receptor 2 -196 to 174 Del Polymorphism Influences the Susceptibility of Japanese People to Gastric Cancer. Cancer Science, 98, 1790- 1794. http://dx.doi.org/10.1111/j.1349-7006.2007.00590.x
[17]	Wu, M.S., Cheng, T.Y., Shun, C.T., Lin, M.T., Chen, L.C. and Lin, J.T. (2006) Functional Polymorphisms of CD14 and Toll-Like Receptor 4 in Taiwanese Chinese with Helicobacter pylori Related Gastric Malignancies. Hepato-Gas- troenterology, 53, 807-810.
[18]	Achyut, B.R., Ghoshal, U.C., Moorchung, N. and Mittal, B. (2007) Association of Toll-Like Receptor-4 (Asp299Gly and Thr399Ileu) Gene Polymorphisms with Gastritis and Precancerous Lesions. Human Immunology, 68, 901-907. http://dx.doi.org/10.1016/j.humimm.2007.10.006
[19]	de Oliveira, J.G. and Silva, A.E. (2012) Polymorphisms of the TLR2 and TLR4 Genes Are Associated with Risk of Gastric Cancer in a Brazilian Population. World Journal of Gastroenterology, 18, 1235-1242. http://dx.doi.org/10.3748/wjg.v18.i11.1235
[20]	Hold, G.L., Rabkin, C.S., Chow, W.H., Smith, M.G., Gammon, M.D., Risch, H.A., et al. (2007) A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors. Gastroenterology, 132, 905-912. http://dx.doi.org/10.1053/j.gastro.2006.12.026
[21]	Tahara, T., Arisawa, T., Shibata, T., Hirata, I. and Nakano, H. (2007) Absence of Common Polymorphisms of Toll Like Receptor 4 (TLR4): Asp299Gly, Thr399Ile in Patients with Gastroduodenal Diseases in Japan. Journal of Clinical Biochemistry and Nutrition, 40, 62-65. http://dx.doi.org/10.3164/jcbn.40.62
[22]	Fan, Y.F., Wu, Y.M., Liu, H., Yu, Y., Jiang, Y.Y., Xue, Y.Z., et al. (2014) TLR4 Polymorphisms Associated with Developing Gastric Pre-Cancer Lesions in a Chinese Han Population. Human Immunology, 75, 176-181. http://dx.doi.org/10.1016/j.humimm.2013.11.002
[23]	Huang, H., Wu, J., Jin, G., Zhang, H.Z., Ding, Y.B., Hua, Z.L., et al. (2010) A 5’-Flanking Region Polymorphism in Toll-Like Receptor 4 Is Associated with Gastric Cancer in a Chinese Population. Journal of Biomedical Research, 24, 100-106. http://dx.doi.org/10.1016/S1674-8301(10)60017-6
[24]	Hishida, A., Matsuo, K., Goto, Y., Mitsuda, Y., Hiraki, A., Naito, M., et al. (2009) Toll-Like Receptor 4 +3725 G/C Polymorphism, Helicobacter pylori Seropositivity, and the Risk of Gastric Atrophy and Gastric Cancer in Japanese. Helicobacter, 14, 47-53. http://dx.doi.org/10.1111/j.1523-5378.2009.00659.x
[25]	Zeng, H.M., Zhang, Y., Zhang, L., Ma, J.L., Zhou, T., Su, H.J., et al. (2011) Genetic Variants of Toll-Like Receptor 2 and 5, Helicobacter pylori Infection, and Risk of Gastric Cancer and Its Precursors in a Chinese Population. Cancer Epidemiology, Biomarkers & Prevention, 20, 2594-2602. http://dx.doi.org/10.1158/1055-9965.EPI-11-0702
[26]	Mandal, R.K., George, G.P. and Mittal, R.D. (2012) Association of Toll-Like Receptor (TLR) 2, 3 and 9 Genes Polymorphism with Prostate Cancer Risk in North Indian Population. Molecular Biology Reports, 39, 7263-7269. http://dx.doi.org/10.1007/s11033-012-1556-5