Identificação dos polimorfismos dos genes IL1B, IL1RN e TNFA na gastrite crónica associada à infecção por Helicobacter pylori e no carcinoma gástrico

 

M. R. Silva ^1,2, A. Sampaio ^2,3, A. Almeida ³, S. Balseiro ³, P. Santos ^2,3, L. Carvalho ¹

 

 

Resumo

Durante o curso da gastrite crónica, os alelos IL1B -511T, IL1RN +2018C e o haplótipoTNFA-308A/-238A estão associados ao aumento dos níveis de produção das respectivas citocinas. Os indivíduos portadores destes polimorfismos podem apresentar um aumento da produção de citocinas próinflamatórias, condicionando uma inflamação severa e constante, atrofia da mucosa gástrica, hipocloridria e, por fim, desenvolvimento de carcinoma gástrico devido a alterações genéticas das células epiteliais que, na tentativa de adaptação, sofrem fenómenos de metaplasia e displasia.

Pretendeu-se verificar a presença dos polimorfismos das citocinas pro-inflamatórias IL-1ß, IL-1RN e TNF-α no carcinoma gástrico e na gastrite crónica.

Os polimorfismos IL1B -511C>T, IL1RN +2018T>C e TNFA -308G>A e -208G>A foram analisados por ARMSPCR em 47 biopsias: 36 biopsias de carcinoma gástrico, 11 biopsias de Gastrite crónica com infecção moderada por Helicobacter pylori e 39 amostras de sangue de indivíduos saudáveis, usando o Cytokine Box Typing Kit (Genebox R&D, Coimbra, Portugal).

Foi encontrada associação entre o genótipo IL1RN +2018 CC (p=0.0002) e o carcinoma gástrico, sendo o genótipo IL1RN +2018 TT (p=0.01) associado com a ausência de doença. Os genótipos IL1RN +2018 CC (p=0.01), TNFA - 308 AA, alto produtor, (p=0.006) e o TNFA -238 AA, alto produtor, (p=0.0001) foram associados com a susceptibilidade à gastrite crónica, enquanto os genótipos TNFA -308 GG e TNFA-238 GG, baixos produtores, demonstraram um efeito protector.

Concluímos que os genótipos, altos produtores, do TNFA e IL1RN, têm um papel importante na manutenção da gastrite crónica e estão presentes no carcinoma gástrico, podendo o estudo dos polimorfismos destes genes ser um importante marcador para a susceptibilidade individual para o desenvolvimento do carcinoma na gastrite crónica.

 

 

Summary

In chronic gastritis the alleles IL1B -511T, IL1RN +2018C and the haplotype TNFA -308A/-238A are associated with high levels of the respective cytokine production. The referred polymorphisms may also induce a high production of pro-inflammatory cytokines leading to a constant and severe inflammatory response and subsequently, gastric mucosa atrophy, hypochloridria and finally gastric carcinoma as a consequence of genetic alterations in epithelial cells after metaplastic and dysplastic phenomena.

The presence of those polymorphisms representing the proinflammatory cytokines IL-1ß, IL-1RN and TNF-α were analysed in cases of chronic gastritis and gastric carcinoma.

The polymorphisms IL1B -511C>T, IL1RN +2018T>C and TNFA -308G>A and -208G>A were analysed by ARMSPCR in 47 biopsies: 36 cases of gastric carcinoma, 11 cases of chronic gastritis associated with Helicobacter pylori were  studied; 39 blood samples of healthy individuals were also analysed with the Cytokine Box Typing Kit (Genebox R&D, Coimbra, Portugal).

An association between the IL-1RN +2018 CC genotype and gastric carcinoma was observed (p=0.0002), while the genotype IL-1RN +2018 TT (p=0.01) was associated with disease absence. The genotypes IL-1RN +2018 CC (p=0.01), TNFA -308 AA (p=0.05) and TNFA -238 AA (p=0.0001) were demonstrated in cases of chronic gastritis and the TNFA - 308 GG and TNFA -238 GG genotypes, low producers, were associated with gastritis resistance.

In this study TNFA and IL1RN polymorphisms were associated with chronic gastritis due to Helicobacter pylori infection and were also present in patients with gastric carcinoma. Therefore, if these results are confirmed those polymorphisms may be used as a biological marker of individual susceptibility in the development of gastric carcinoma in chronic gastritis.

 

 

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(1) Instituto de Anatomia Patológica, Faculdade de Medicina da Universidade de Coimbra, Portugal.

(2) Escola Superior de Tecnologia da Saúde de Coimbra, Portugal.

(3) GeneBox R&D, Coimbra, Portugal.

 

 

Correspondência:

Prof. Doutora Lina Carvalho

Instituto de Anatomia Patológica

Faculdade de Medicina da Universidade de Coimbra

3004-504 Coimbra

Tel.: (+351) 239 857 700

Fax: (+351) 239 857 749

e-mail: lcarvalho@huc.min-saude-pt

 

Recebido para publicação: 10/10/2007

Aceite para publicação: 22/01/2008