Comparative genetic association of human leukocyte antigen class II and tumor necrosis factor-alpha with dermatitis...

Dermatitis herpetiformis is a chronic subepidermal vesicular autoimmune skin disease characterized by a strong association with the human leukocyte antigen A1-B8-DR3-DQ2 haplotype. Although the strongest major histocompatibility complex association has been shown to be with the DQw2 (DQB1*0201/DQA1*0501) heterodimer, recent evidence has suggested that there may be up to three susceptibility loci within the major histocompatibility complex. Tumor necrosis factor-alpha (TNF-alpha) is a cytokine with a broad range of proinflammatory, immunomodulating, and catabolic activities. We have recently described the first known polymorphism in the human TNF-alpha gene, which is biallelic and lies in the promoter region. The rare allele, TNF2, is in strong linkage disequilibrium with the human leukocyte antigen A1-B8-DR3-DQ2 haplotype. We therefore examined TNF-alpha genotypes in patients with dermatitis herpetiformis and controls and compared the association with that of the class II alleles. Although TNF2 is strongly associated with dermatitis herpetiformis, this was weaker than the association with the class II loci, with DQw2 (DQB1*0201/DQA1*0501) showing the strongest disease association. Of the four patients negative for this marker, only one carried the TNF2 allele. These results indicate that TNF2 is not a major disease susceptibility marker, although our results do not exclude a minor role.