TLR2 variants and Helicobacter pylori: revisiting a controversial link
Keywords:
TLR2, Helicobacter pylori, del -196 to -174, meta analysis, random-effects model
Abstract
Objective: Although polymorphisms in the Toll-like receptor 2 (TLR2) gene have been proposed as host genetic factors influencing susceptibility to Helicobacter pylori infection, existing data remain inconclusive. This meta-analysis aimed to clarify whether two common variants – rs3804099 and del –196 to –174 – contribute to infection risk across diverse populations.
Materials and methods: A systematic search of PubMed, Scopus, and Web of Science (up to January 2025) identified eligible case–control studies examining the association between TLR2 polymorphisms and H. pylori infection. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using random-effects models. Heterogeneity, publication bias, and sensitivity were assessed according to PRISMA 2020 guidelines.
Results: Ten studies comprising 4,521 subjects were included. Pooled analyses under allelic, dominant, recessive, homozygous, and heterozygous models revealed no significant association between either rs3804099 or del –196 to –174 polymorphisms and infection risk. Substantial inter-study heterogeneity was observed, particularly for rs3804099, but sensitivity analyses confirmed the stability of pooled results.
Conclusion: This meta-analysis refutes a consistent genetic association between TLR2 rs3804099 or del –196 to –174 polymorphisms and H. pylori infection. The findings suggest that host innate immunity variability alone does not explain differences in infection susceptibility among populations. Future studies integrating bacterial virulence genotypes and host immunogenetic profiles are warranted to delineate population-specific risk mechanisms.
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References
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29. Moura SB, Almeida LR, Guerra JB, Rocha GA, Rocha AM, Melo FF, et al. Toll-like receptor (TLR2, TLR4 and TLR5) gene polymorphisms and Helicobacter pylori infection in children with and without duodenal ulcer. Microbes Infect. 2008;10:1477–83. doi: https://doi.org/10.1016/j.micinf.2008.08.009
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2. Reyes VE. Helicobacter pylori and its role in gastric cancer. Microorganisms. 2023;11:1312. doi: https://doi.org/10.3390/microorganisms11051312
3. McConaghy JR, Decker A, Nair S. Peptic ulcer disease and H. pylori infection: common questions and answers. Am Fam Physician. 2023;107:165–72.
4. Kuo SH, Cheng AL. Helicobacter pylori and mucosa-associated lymphoid tissue: what’s new. Hematology Am Soc Hematol Educ Program. 2013;2013:109–17. doi: https://doi.org/10.1182/asheducation-2013.1.109
5. Li D, Jiang SF, Lei NY, Shah SC, Corley DA. Effect of Helicobacter pylori eradication therapy on the incidence of noncardia gastric adenocarcinoma in a large diverse population in the United States. Gastroenterology. 2023;165:391–401.e2. doi: https://doi.org/10.1053/j.gastro.2023.04.026
6. Kumar S, Patel GK, Ghoshal UC. Helicobacter pylori-induced inflammation: possible factors modulating the risk of gastric cancer. Pathogens. 2021;10:1099. doi: https://doi.org/10.3390/pathogens10091099
7. Kim SS, Ruiz VE, Carroll JD, Moss SF. Helicobacter pylori in the pathogenesis of gastric cancer and gastric lymphoma. Cancer Lett. 2011;305:228–38. doi: https://doi.org/10.1016/j.canlet.2010.07.014
8. Bridge DR, Merrell DS. Polymorphism in the Helicobacter pylori CagA and VacA toxins and disease. Gut Microbes. 2013;4:101–17. doi: https://doi.org/10.4161/gmic.23797
9. Šterbenc A, Jarc E, Poljak M, Homan M. Helicobacter pylori virulence genes. World J Gastroenterol. 2019;25:4870–84. doi: https://doi.org/10.3748/wjg.v25.i33.4870
10. Sharndama HC, Mba IE. Helicobacter pylori: an up-to-date overview on the virulence and pathogenesis mechanisms. Braz J Microbiol. 2022;53:33–50. doi: https://doi.org/10.1007/s42770-021-00675-0
11. Cheok YY, Tan GMY, Lee CYQ, Abdullah S, Looi CY, Wong WF. Innate immunity crosstalk with Helicobacter pylori: pattern recognition receptors and cellular responses. Int J Mol Sci. 2022;23:7561. doi: https://doi.org/10.3390/ijms23147561
12. Duan T, Du Y, Xing C, Wang HY, Wang RF. Toll-like receptor signaling and its role in cell-mediated immunity. Front Immunol. 2022;13:812774. doi: https://doi.org/10.3389/fimmu.2022.812774
13. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023. doi: https://doi.org/10.1038/sigtrans.2017.23
14. Meliț LE, Mărginean CO, Mărginean CD, Mărginean MO. The relationship between Toll-like receptors and Helicobacter pylori-related gastropathies: still a controversial topic. J Immunol Res. 2019;2019:8197048. doi: https://doi.org/10.1155/2019/8197048
15. Mirkamandar E, Nemati M, Hayatbakhsh MM, Bassagh A, Khosravimashizi A, Jafarzadeh A. Association of a single nucleotide polymorphism in the TLR2 gene (rs3804099), but not in the TLR4 gene (rs4986790), with Helicobacter pylori infection and peptic ulcer. Turk J Gastroenterol. 2018;29:283–91. doi: https://doi.org/10.5152/tjg.2018.17484
16. Chen L, Lin MJ, Zhan LL, Lv XP. Analysis of TLR4 and TLR2 polymorphisms in inflammatory bowel disease in a Guangxi Zhuang population. World J Gastroenterol. 2012;18:6856–60. doi: https://doi.org/10.3748/wjg.v18.i46.6856
17. Kaissarian NM, Meyer D, Kimchi-Sarfaty C. Synonymous variants: necessary nuance in our understanding of cancer drivers and treatment outcomes. J Natl Cancer Inst. 2022;114:1072–94. doi: https://doi.org/10.1093/jnci/djac090
18. Lourenço CM, Susi MD, do Nascimento MCA, Serafim Junior V, Vila APS, Rodrigues-Flemming GH, et al. Characterization and strong risk association of TLR2 del -196 to -174 polymorphism and Helicobacter pylori and their influence on mRNA expression in gastric cancer. World J Gastroenterol. 2020;12:535–48. doi: https://doi.org/10.4251/wjgo.v12.i5.535
19. BaniHani MN, Khabour OF, Alzoubi KH, Bashir NA, Shakhatreh MAK, Sabi SH, et al. The association between ABCB1 C1236T/C3435T SNPs and H. pylori infection among Jordanians. Genes (Basel). 2020;11:63. doi: https://doi.org/10.3390/genes11010063
20. 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:e0147410. doi: https://doi.org/10.1371/journal.pone.0147410
21. Ma X, Lu L, Tang Y, Luo W, Li J, Tang M. Association between Toll-like receptor gene polymorphisms and risk of Helicobacter pylori infection: a protocol for systematic review and meta-analysis. Medicine. 2021;100:e25729. doi: https://doi.org/10.1097/MD.0000000000025729
22. Hishida A, Matsuo K, Goto Y, Naito M, Wakai K, Tajima K, et al. No associations of Toll-like receptor 2 (TLR2)-196 to -174del polymorphism with the risk of Helicobacter pylori seropositivity, gastric atrophy, and gastric cancer in Japanese. Gastric Cancer. 2010;13:251–7. doi: https://doi.org/10.1007/s10120-010-0567-y
23. Naylor CD. Meta-analysis and the meta-epidemiology of clinical research. BMJ. 1997;315:617–9. doi: https://doi.org/10.1136/bmj.315.7109.617
24. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162:777–84. doi: https://doi.org/10.732/M14-2385
25. Panic N, Leoncini E, de Belvis G, Ricciardi W, Boccia S. Evaluation of the endorsement of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement on the quality of published systematic reviews and meta-analyses. PLoS One. 2013;8:e83138. doi: https://doi.org/10.1371/journal.pone.0083138
26. Schwarzer G. Meta: an R package for meta-analysis. R News. 2007;7:40–5.
27. Viechtbauer W. Conducting meta-analyses in R with the meta for package. J Stat Softw. 2010;36:1–48. doi: https://doi.org/10.18637/jss.v036.i03
28. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88. doi: https://doi.org/10.1016/0197-2456(86)90046-2
29. Moura SB, Almeida LR, Guerra JB, Rocha GA, Rocha AM, Melo FF, et al. Toll-like receptor (TLR2, TLR4 and TLR5) gene polymorphisms and Helicobacter pylori infection in children with and without duodenal ulcer. Microbes Infect. 2008;10:1477–83. doi: https://doi.org/10.1016/j.micinf.2008.08.009
30. Smith SM. Role of toll-like receptors in Helicobacter pylori infection and immunity. World J Gastrointest Pathophysiol. 2014;5:133–46. doi: https://doi.org/10.4291/wjgp.v5.i3.133
31. Flores-González J, Monroy-Rodríguez Z, Falfán-Valencia R, Buendía-Roldán I, Fricke-Galindo I, Hernández-Zenteno R, et al. Variants rs3804099 and rs3804100 in the TLR2 gene induce different profiles of TLR-2 expression and cytokines in response to spike of SARS-CoV-2. Int J Mol Sci. 2024;25:11063. doi: https://doi.org/10.3390/ijms252011063
32. Xia P, Wu Y, Lian S, Yan L, Meng X, Duan Q, et al. Research progress on toll-like receptor signal transduction and its roles in antimicrobial immune responses. Appl Microbiol Biotechnol. 2021;105:5341–55. doi: https://doi.org/10.1007/s00253-021-11406-8
Published
2025-12-22
How to Cite
Kirkik , D., Demircioğlu , S., & Kalkanlı Taş , S. (2025). TLR2 variants and Helicobacter pylori: revisiting a controversial link. Upsala Journal of Medical Sciences, 130, e13533. https://doi.org/10.48101/ujms.v130.13533
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