Tumour necrosis factor (TNF) gene polymorphism in Crohn’s disease (CD): influence on disease behaviour?

Abstract

SUMMARYCrohn's disease (CD) is a multifactorial disease with genetic heterogeneity. TNF-a plays a key role in the development of the mucosal lesions. The aim of our work was to study a single base pair polymorphism located in the promoter region of TNF gene, in a large population of CD patients with well defined phenotypes. One hundred and ninety-three patients with CD and 98 ethnically matched controls were studied. The ¹308 single base pair polymorphism of TNF gene was studied using an allele-specific polymerase chain reaction. Genotype and allelic frequencies were compared between patients and controls and between subgroups of patients defined by sex, age at diagnosis, familial history, location of disease, type of disease, extra-intestinal manifestations, and response to steroid treatment. In 29 patients a measure of TNF-a production by colonic biopsies was performed. The frequency of the allele TNF2 as well as the proportion of carriers of the allele TNF2 were slightly but not significantly lower in CD than in controls (11·9% versus 14·8% and 21·5% versus 27·6%, respectively). A more prominent difference in frequencies of allele TNF2 and in proportions of TNF2 carriers was found when comparing subgroups of patients. The frequency of allele TNF2 was significantly higher in steroid-dependent than in non-steroid-dependent disease (28·1% versus 10·3%; D ¼ 17·8%, 95% confidence interval (CI) ¼ 6·3-29·5%, P ¼ 0·0027) and tended to be higher in colonic than in small bowel disease and in fistulizing than in stricturing disease. Furthermore, TNF2 carriers tended to be more frequent in patients with steroid-dependent than non-steroid-dependent disease (43·8% versus 19·3%; D ¼ 24·5%, 95% CI ¼ 3·6-45·4%, P ¼ 0·022), in patients with fistulizing than stricturing disease (26·5% versus 9·6%; D ¼ 16·9%, 95% CI ¼ 1·1-32·6%, P ¼ 0·036), and in patients with colonic than small bowel disease (26·5% versus 11·1%; D ¼ 15·4%, 95% CI ¼ ¹0·8-31·6%, P ¼ 0·063). Finally, patients carrying at least one copy of allele 2 were found to produce slightly more TNF-a at the colonic level. The ¹308 TNF gene polymorphism may have a slight influence on the behaviour of CD. The carriage of allele 2 may favour steroid-dependent disease and to a lesser extent fistulizing and colonic disease, possibly secondary to a more intense TNF-a-driven inflammatory reaction at the mucosal level.

Lack of association between adult asthma and the tumour necrosis factor α-308 polymorphism gene

“…The possibility of a particular association between TNF2 and severe asthma was examined for at least two reasons. The first is that such an association has been recently described for a subgroup of severe inflammatory bowel disease, the pathogenesis of which may somehow resemble that of asthma [16]. Secondly the inflammatory picture within the airways of severe asthmatics, involving both eosinophil and neutrophil (as opposed to the eosinophils alone in the mild to moderate forms of the disease) [17± 19] fits with a role for TNFa that favours the tissular recruitment of both type of granulocytes [20] partly through endothelial expression of ICAM-1 [21].…”

A systematic approach to the assessment of known TNF-α polymorphisms in Graves' disease

“…Studies looking for association with disease have been performed only in small ethnically diverse data sets of different autoimmune diseases, including rheumatoid arthritis, 16 Crohn's disease 17 and systemic lupus erythematosus. 18 Results are conflicting and accurate allele frequencies remain unknown, making meaningful interpretation of the data difficult.…”

Polymorphisms in the TNF-α Promoter and Variability in the Granulomatous Response in Patients with Crohn's Disease

“…Polymorphisms that have been reported to increase (308G/A) or decrease circulating TNF-␣ (238G/A, 857 C/T, 863 C/A) (27)(28)(29)(30)(31)(32)(33), as well as playing a possible role in disease phenotype and susceptibility (27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39). The 857C/T and 863C/A polymorphisms appear to be located at transcription factor binding sites (32,34,35).…”