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Profiles of Gene Polymorphisms in Cytokines and Toll-Like Receptors with Higher Risk for Gastric Cancer

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Abstract

Background

Chronic inflammation and gastric carcinogenesis show a close association, so gene polymorphisms that modify the intensity of the inflammatory response may contribute to variations in gastric cancer risk.

Aims

The purpose of this study was to investigate the combined effect of the pro- and anti-inflammatory cytokines and toll-like receptors polymorphisms on the chronic gastritis and gastric cancer risk in a Brazilian population sample.

Methods

We evaluated 669 DNA samples (200 of gastric cancer [GC], 229 of chronic gastritis [CG], and 240 of healthy individuals [C]). Ten polymorphisms were genotyped: IL-1RN and TLR2 -196 to -174 del using the allele-specific PCR method and TNF-A (rs1800629; rs1799724), TNF-B (rs909253), IL-8 (rs4073; rs2227532), IL-10 (rs1800872) and TLR4 (rs4986790; rs4986791) using PCR–RFLP.

Results

Polymorphisms TNF-A-308G/A, IL-8-251A/T, TNF-B + 252A/G and TLR4 + 1196C/T were not associated with risk of any gastric lesion. However, an association with increased risk for GC was observed for polymorphisms IL-1RNL/2 (p < 0.001), TNF-A-857C/T (p = 0.022), IL-8-845T/C (p < 0.001), IL-10-592C/A (p < 0.001), TLR2ins/del (p < 0.001), and TLR4 + 896A/G (p = 0.033). In CG, an association was observed only with polymorphisms IL-1RNL/2 and IL-10-592A/C (p < 0.001 for both). A combined analysis of these six polymorphisms associated with GC revealed a profile with two to four combined genotypes which confer a higher risk of gastric carcinogenesis, with an OR increased 2.95-fold to 50.4-fold, highlighting the combinations IL-1RN2/TNF-A-857T/IL-8-845C, IL-1RN2/IL-8-845C/TLR2del, IL-1RN2/IL-10-592A/TLR4 + 896G, IL-10-592A/TLR2del/TLR4 + 896G, and IL-1RN2/TNFA-857T/IL8-845C/TLR2del.

Conclusions

Our findings evidenced that the combined effect of polymorphisms in genes involved in the inflammatory process may potentiate the risk of gastric cancer, thus emphasizing the importance of evaluating multiple polymorphisms together.

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Abbreviations

C:

Control

CG:

Chronic gastritis

CI:

Confidence interval

dNTPs:

Deoxyribonucleotide triphosphates

EDTA:

Ethylenediamine tetraacetic acid

GC:

Gastric cancer

IL-1β:

Interleukin 1-beta gene

IL-1RN:

Interleukin 1 receptor antagonist

IL-8:

Interleukin 8 gene

IL-10:

Interleukin 10 gene

MgCl2:

Magnesium chloride

N:

Number of individuals

OR:

Odds ratio

P:

Probability

PCR-RFLP:

Polymerase chain reaction-restriction fragment length polymorphism

SNP:

Single nucleotide polymorphism

T°:

Temperature

TLR2:

Toll-like receptor 2

TLR4:

Toll-like receptor 4

TNF-A:

Tumor necrosis factor alpha

TNF-B:

Tumor necrosis factor beta

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Acknowledgments

This study was supported by the Brazilian agencies FAPESP (São Paulo State Research Foundation)—No 2010/00507-0, CNPq (National Council for Scientific and Technological Development)—No. 471908/2010-0, and CAPES (Coordination of Improvement of Upper Level Personnel).

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Authors and Affiliations

  1. Department of Biology, São Paulo State University (UNESP), Rua Cristovão Colombo, 2265, São José do Rio Preto, 15054-000, SP, Brazil

    Juliana Garcia de Oliveira, Ana Flávia Teixeira Rossi, Daniela Manchini Nizato & Ana Elizabete Silva

  2. Health Center, Sacred Heart University (USC), Rua Irmã Arminda, 1050, Bauru, 17011-160, SP, Brazil

    Juliana Garcia de Oliveira

  3. Base Hospital, Service of Endoscopy, Av. Brigadeiro Faria Lima, 5444, São José do Rio Preto, 15090-000, SP, Brazil

    Kenji Miyasaki

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  1. Juliana Garcia de Oliveira
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  2. Ana Flávia Teixeira Rossi
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Correspondence to Ana Elizabete Silva.

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de Oliveira, J.G., Rossi, A.F.T., Nizato, D.M. et al. Profiles of Gene Polymorphisms in Cytokines and Toll-Like Receptors with Higher Risk for Gastric Cancer. Dig Dis Sci 58, 978–988 (2013). https://doi.org/10.1007/s10620-012-2460-5

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  • DOI: https://doi.org/10.1007/s10620-012-2460-5

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