HLA-DRB1ASTERISK03, BUT NOT THE TNFA-308 PROMOTER GENE POLYMORPHISM, CONFERS PROTECTION AGAINST FISTULISING CROHNS-DISEASE

Crohn's disease (CD) appears in forms so diverse that it has been hypo thesized CD might be a syndrome, with different pathogenic mechanisms leading to the various clinical phenotypes. This may plausibly explain the conflicting and inconclusive results with regard to HLA associati ons in unselected groups of patients. The power of these association s tudies may increase when disease heterogeneity is taken into account. As fistulising CD has been proposed as a separate subgroup of patients with CD, we studied the carrier frequencies (CF) of the DRB1 alleles in 35 unrelated Caucasian Dutch CD patients with proven peri-anal fist ulas. A striking decrease in the frequency of the DRB103 allele was f ound in those patients with perianal fistulas when compared with a pan el of 2400 healthy controls (HC) (3% vs 25%; P = 0.005; Odds Ratio [OR ] = 0.09). The DRBI03 allele is in strong linkage disequilibrium with a polymorphism at position -308 in the promoter region of the gene en coding TNF alpha (TNFA-3082). We investigated whether this allele fre quency was decreased as well. Surprisingly, the CF of TNFA-3082 was 2 9%, not different from the CF of 98 HC (34%; P = 0.7; OR = 0.8). This study is the first showing a significant negative association between DRBI03 and a particular subgroup of CD patients. Thus, patient select ion may largely determine the outcome of genetic association studies i n CD, as we previously observed no association with this allele in an unselected population of CD patients. As DRB103 frequency, but not th e closely linked TNFA-3082, was decreased, this suggests recombinatio n between the DRB1 and TNFA loci in this group of patients, and may he lp to define the biological basis of fistula formation.