POLYMORPHISMS OF THE GENES OF THE PRO-INFLAMMATORY CYTOKINES IN COELIAC DISEASE: ASSOCIATION OF THE IL1A2 AND TNF2 ALLELES

Abstract

111 The genes of the cytokines regulating the inflammatory reactions (e.g. IL-1a and IL-1b, TNF-a and TNF-b and IL-1 receptor antagonist (IL-1RA)) are polymorphic and it is known that certain alleles of these loci have a role in the genetic susceptibility in several autoimmune or inflammatory diseases. In the promoter of the TNF-a gene, at the position-308 relative to the transcriptional start site, there is a biallelic base exchange polymorphism defining the alleles TNF1 and TNF2. The frequency of the more rare allele, TNF2, is known to be increased in coeliac disease (CD), but as the TNF gene locates within the HLA complex, its role as an HLA-independent factor has been difficult to assess. Now we have analyzed the polymorphisms of the IL-1 gene complex in CD. In the IL-1a gene there is one base exchange polymorphism at the position-889(alleles IL1A1 and IL-1A2) and in the IL-1b two, at the positions-511 and+3953. The intron 2 of the IL-1RA gene contains variable numbers of 86-bp tandem repeats. In the 50 CD patients analyzed, the frequencies of all the alleles of these loci were similar to those found in 50 healthy blood donors. In accordance with the previous studies, the frequency of TNF2 was increased(0.49 in CD patients vs. 0.19 in the controls). However, when the associations between the different alleles were analyzed, it was observed that in CD patients, but not in controls, the IL1A2 and TNF2 alleles were strongly associated. These data suggest that polymorphisms of the cytokine genes have an influence on the genetic susceptibility to CD, but this effect may require co-operation between different alleles.