Ulcerative colitis: a genetically heterogeneous disorder defined by genetic (HLA class II) and subclinical (antineutrophil cytoplasmic antibodies) markers.

Newly described distinct associations of HLA class II genes with ulcerative colitis (UC) (DR2) and Crohn's disease (CD) (DR1/DQ5) provide strong evidence for genetic heterogeneity of susceptibility between these two forms of inflammatory bowel disease. A familial distribution of antineutrophil cytoplasmic antibodies (ANCAs, a subclinical marker of UC) in UC families has further implied the existence of heterogeneity within UC. To test the hypothesis that the heterogeneity within UC indicated by ANCAs has a genetic basis that resides within the HLA region, we studied 89 UC cases and an ethnically matched control group (n = 50). Serological and molecular typing techniques were applied to define HLA class II genes (DR, DQ). ANCAs were detected using an enzyme-linked immunosorbent assay, and positive values were confirmed by indirect immunofluorescence. We observed that ANCA-positive UC patients (n = 70) had a significantly increased frequency of DR2 compared with ANCA-negative controls (n = 46) (44% vs 22%, P = 0.01). In contrast, the frequency of DR2 in ANCA-negative UC cases (21%) was virtually identical to that in controls (22%, P = 0.9). Furthermore, the ANCA-negative UC patients had an increase in the DR4 allele compared with ANCA-positive UC (P = 0.004). Thus, with the combination of a subclinical marker (ANCAs) and molecular genetic markers, genetic heterogeneity has been demonstrated within UC: ANCA-positive UC associated with DR2, and ANCA-negative UC likely associated with DR4.

Distinct associations of HLA class II genes with inflammatory bowel disease.

BACKGROUND: There are relatively few studies of HLA class II association either with Crohn's disease (CD) or ulcerative colitis (UC). The few available association studies have been carried out by serological techniques, and the results from these studies are inconclusive. METHODS: The association between HLA class II genes was studied using molecular genotyping in combination with allele-specific oligonucleotide hybridization by polymerase chain reactions. RESULTS: In UC (n = 74), we observed a positive association with the HLA DR2 allele (P = 0.008) and negative associations with the DR4 (P = 0.018) and DRw6 (P = 0.028) when compared with ethnically matched controls (n = 77). No associations were observed with any DQ alleles. In contrast, in CD (n = 95) we observed a positive association with the combination of DR1 and DQw5 alleles (P = 0.021). Furthermore, stratifying DR1 and DQw5 alleles indicated that neither allele was independently associated with CD, suggesting that the association was with the haplotype rather than either of the alleles individually. A suballele of DQw5, DQB1*0501, contributed this haplotypic association (P = 0.012). CONCLUSIONS: DR and DQ molecules firmly separate UC and CD on genetic grounds, suggesting that the contribution of the HLA class II genes to the disease susceptibility is quite different for the two disorders.

Lack of an association between polymorphisms of the T-cell receptor alpha-chain and ulcerative colitis.

It was recently reported that, using a T-cell receptor alpha-chain complementary deoxyribonucleic acid probe (pGA5) and the restriction enzyme Eco RV, a 10-kilobase restriction fragment length polymorphism was detected significantly more frequently in patients with ulcerative colitis than in patients with Crohn's disease and controls. This finding had great potential importance, as no gene marker had previously been found to be strongly associated with inflammatory bowel disease. Therefore, an attempt to confirm it in an independent laboratory and patient population has been made in this study. Thirty patients with ulcerative colitis, 30 with Crohn's disease, and 30 healthy control subjects were studied using the Eco RV restriction enzyme and the same T-cell receptor alpha-chain complementary deoxyribonucleic acid probe as was used in the prior report. No 10-kilobase fragment or any other polymorphism using this probe-enzyme combination was found in any of the individuals studied. Polymorphisms were observed with the restriction enzyme Bgl II, but their frequencies did not distinguish between cases and controls. Therefore, there is as yet no evidence for an association between polymorphisms of Eco RV-digested genomic DNA probed with the pGA5 T-cell receptor alpha-chain complementary deoxyribonucleic acid and the predisposition to inflammatory bowel disease.