TNF2, A POLYMORPHISM OF THE TUMOR NECROSIS-ALPHA GENE PROMOTER, IS A COMPONENT OF THE CELIAC-DISEASE MAJOR HISTOCOMPATIBILITY COMPLEX HAPLOTYPE

Celiac disease (CD) is an immune disease triggered by the cereal antig en gliadin, resulting in villous atrophy in the small intestine. Susce ptibility to the development of CD is strongly influenced by genes in the major histocompatibility complex, in particular alleles of the DQ genes in the class II region. However recent evidence has suggested th at the major histocompatibility complex (MHC) class III region may be linked to celiac disease independently of the class II region. Among t he genes located in this area is TNF-alpha, which encodes the cytokine tumor necrosis factor-alpha which has a broad range of pro-inflammato ry, immunomodulatory and catabolic activities. Therefore, aberrant exp ression of TNF-alpha could be important in the pathogenesis of MHC-ass ociated immune disorders. A TNF-alpha variant with a polymorphism in i ts promoter region has been described and designated TNF2. TNF2 has be en associated with a variety of MHC-linked diseases, including systemi c lupus erythematosus, dermatitis herpetiformis and insulin-dependent diabetes mellitus (IDDM), as well as parasitic infections. TNF2 has pr eviously been shown to be associated with the MHC haplotype HLA A1-B8- DR3-DQ2, which confers susceptibility to CD. We have analyzed the dist ribution of TNF2 alleles in a group of celiac patients (n = 52) compar ed to controls (n = 52) in an effort to evaluate its role, if any, in susceptibility to the condition. TNF2 has a frequency of 0.5000 (SE +/ - 0.0490) in CD, compared to 0.1635 (+/- 0.0362) in a control sample ( p < 10(-6)). Of 52 patients, 44 carried one or more TNF2 alleles. Anal ysis indicates that the distribution of TNF2 is best explained by assu ming 100% allelic association between it and HLA-DQB10201 (frequency = 0.7791 +/- 0.0447). However, the number of TNF2 heterozygotes signif icantly exceeds expectations and measurements of linkage disequilibriu m confirm that allelic associations spanning the DQ and TNF regions ar e strongly maintained in CD. Taken together, these results indicate th at TNF2 may have a role in the pathogenesis of CD; however, since it i s not an independent association, the possibility that TNF2 constitute s a passive component of the CD haplotype cannot be excluded.