Independent contribution of HLA-DRB1 and TNF alpha promoter polymorphisms to the susceptibility to Crohn's disease.

Although a number of studies reported the association of HLA-DRB1 and Crohn's disease (CD), the actual alleles associated with CD are considerably variable among populations. On the other hand, the relevance of tumor necrosis factor alpha (TNF alpha) in the pathogenesis of CD is established through experimental as well as clinical studies, raising the possibility that TNFA polymorphism is primarily or independently contribute to the association of HLA region genes with CD. New polymorphisms which may affect the transcriptional activity were recently reported within the upstream promoter region of TNFA gene. In the present study, we compared HLA-DRB1, TNFA promoter and TNF receptor 2 (TNFR2) genotypes in 154 Japanese patients with CD and 265 unrelated healthy controls to evaluate the individual contribution of these genes to the genetic predisposition to CD. Significant positive association was observed in HLA-DRB1*0405 (P = 0.001, odds ratio (OR) = 2.02) and 0410 (P = 0.002, OR = 4.79). Among the TNFA promoter haplotypes, TNFA-U03 (-1031C, -863A, -857C) was significantly increased (P = 0.008, OR = 1.64), while TNFA-U04 (-1031C, -863C, -857C) was significantly decreased (P = 0.014, OR = 0.12), in CD. The association with TNFA-U03 was independent of that with DRB1*0405 and 0410, and apparent additive or multiplicative effect was not observed between these susceptibility alleles. No association was observed between TNFR2-196M/R polymorphism and CD. These results indicated that both of HLA-DRB1 and TNFA promoter polymorphisms contribute to the susceptibility to CD in an independent manner.