TUMOR-NECROSIS-FACTOR MICROSATELLITES DEFINE A CROHNS DISEASE-ASSOCIATED HAPLOTYPE ON CHROMOSOME-6

Background & Aims: HLA class II associations have been described in Cr ohn'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 TN F-alpha and TNF-beta, is located on chromosome 6 within the major hist ocompatibility complex loci. To investigate potential genetic associat ions in inflammatory bowel disease at the TNF locus, we studied 75 pat ients with CD, 73 patients with UC, and 60 ethnically matched controls using microsatellite markers. Methods: Five TNF microsatellite loci ( TNFa; TNFb, TNFc, TNM, and TNFe) were typed using polymerase chain rea ction. Results: A CD-associated allelic combination, TNFa2b1c2d4e1, wa s found in 24% of patients with CD, 4.1% of patients with UC (P = 0.00 1; 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 de scribed HLA-DR1/DQ5 combination in CD. Conclus ions: The TNFa2b1c2d4e1 allelic combination is the strongest genetic r isk factor described in CD and, with HLA class Il;alleles, defines a g roup of markers on chromosome 6 that extends from HLA class II to upst ream of the TNF-beta gene.