Tumor necrosis factor microsatellites define a Crohn's disease-associated haplotype on chromosome 6

Abstract

Background and Aims: HLA class II associations have been described in Crohn's disease (CD) and ulcerative colitis (UC) and may be markers for other closely linked genes that are involved in disease pathogenesis. The tumor necrosis factor (TNF) locus, which contains the genes for TNF-α and TNF-β, is located on chromosome 6 within the major histocompatibility complex loci. To investigate potential genetic associations in inflammatory bowel disease at the TNF locus, we studied 75 patients with CD, 73 patients with UC, and 60 ethnically matched controls using microsatellite markers. Methods: Five TNF microsatellite loci (TNFa, TNFb, TNFc, TNFd, and TNFe) were typed using polymerase chain reaction. Results: A CD-associated allelic combination, TNFa2b1c2d4e1, was found in 24% of patients with CD, 4.1% of patients with UC (P = 0.001; odds ratio, 7.4; CD vs. UC), and 6.7% of control subjects (P = 0.01; odds ratio, 4.4; CD vs. controls). This TNF haplotype was associated with the previously described HLA-DR1/DQ5 combination in CD. Conclusions: The TNFa2b1c2d4e1 allelic combination is the strongest genetic risk factor described in CD and, with HLA class II alleles, defines a group of markers on chromosome 6 that extends from HLA class II to upstream of the TNF-β gene.